When a pharmaceutical company changes an SPC or PIL, a new version is published on medicines.ie. For each version, we show the dates it was published on medicines.ie and the reasons for change.
Section 4.2: addition of subheadings - Posology, Paediatric populations, Special populations and Pregnancy and Postpartum. Updates to Table 1 and subsections - paediatric patients (less than 6 years of age) and addition of text for pregnancy and postpartum subsection. Section 4.5: deletion of text "<->", twice daily as "BID" and once daily as "QD")."<->". Replacement of Table 2. Section 4.6: Update to section title "Fertility, pregnancy and lactation", addition of subheadings - "Pregnancy", "Breast-feeding" and "Fertility". Text updated under each subsection. Section 4.7: deletion of "No studies on the effects on the ability to drive and use machines have been performed." Section 4.8: addtion of subheadings - "a. Summary of the safety profile"; "b. Tabulated list of adverse reactions"; "c. Dscription of selected adverse reactions", "d. Paediatric population" and "e. Other sepcial populations". entire section has been reformatted to add relevant text under each subsection. Section 5.1: addition of final paragraph "The European Medicines Agency has waived the obligation to submit the results of studies with Reyataz hard capsules in all subsets of the paediatric population in treatment of immunodeficiency virus (HIV-1) infection (see section 4.2 for information on paediatric use). Section 5.2: addtion of subheadings "Pregnancy" and "Paediatric population". Paediatric text under "Specific populations moved to new Paediatric subsection. Addition of pregnancy subsection. Section 6.5: updated to reflect details for product marketed in the UK. Section 8: updated to reflect details for product marketed in the UK. Section 10: Updated to reflect approval date of change Addition of Legal category: POM
The followign text has been deleted from section 5.2: The pharmacokinetics of atazanavir were evaluated in healthy adult volunteers and in HIV infected patients; significant differences were observed between the two groups. The pharmacokinetics of atazanavir exhibit a non linear disposition. In healthy subjects, the AUC of atazanavir from the capsules and oral powder were similar
SPC:
Section 4.3
The following text has been added:
The PDE5 inhibitor sildenafil is contraindicated when used for the treatment of pulmonary
arterial hypertension (PAH) only (see section 4.5). For co-administration of sildenafil for the
treatment of erectile dysfunction see section 4.4 and section 4.5.
Section 4.4
The following text has been added
Atazanavir is metabolised principally by CYP3A4. Co-administration of REYATAZ with
ritonavir and medicinal products that induce CYP3A4 is not recommended (see sections 4.3
and 4.5).
PDE5 inhibitors used for the treatment of erectile dysfunction: particular caution should be
used when prescribing PDE5-inhibitors (sildenafil, tadalafil, or vardenafil) for the treatment
of erectile dysfunction in patients receiving REYATAZ with concomitant low-dose ritonavir.
Co-administration of REYATAZ with these medicinal products is expected to substantially
increase their concentrations and may result in PDE5-associated adverse events such as
hypotension, visual changes and priapism (see section 4.5).
Co-administration of voriconazole and REYATAZ with ritonavir is not recommended unless
an assessment of the benefit/risk justifies the use of voriconazole (see section 4.5).
Concomitant use of REYATAZ/ritonavir and fluticasone or other glucocorticoids that are
metabolized by CYP3A4 is not recommended unless the potential benefit of treatment
outweighs the risk of systemic corticosteroid effects, including Cushing's syndrome and
adrenal suppression (see section 4.5).
Concomitant use of salmeterol and REYATAZ/ritonavir may result in increased
cardiovascular adverse events associated with salmeterol. Co-administration of salmeterol and
REYATAZ is not recommended (see section 4.5).
The absorption of atazanavir may be reduced in situations where gastric pH is increased
irrespective of cause.
Section 4.5
ALPHA 1-ADRENORECEPTOR ANTAGONIST
Alfuzosin
Potential for increased alfuzosin concentrations which can result
Co-administration of
in hypotension. The mechanism of interaction is CYP3A4
REYATAZ/ritonavir
inhibition by atazanavir/ritonavir.
with alfuzosin is contraindicated (see section 4.3)
PDE5 Inhibitors
Sildenafil, tadalafil,
Sildenafil, tadalafil, and vardenafil are metabolised by CYP3A4.
Patients should be
vardenafil
Co-administration with REYATAZ/ritonavir may result in
warned about these
increased concentrations of the PDE5 inhibitor and an increase in
possible side effects
PDE5-associated adverse events, including hypotension, visual
when using PDE5
changes, and priapism. The mechanism of this interaction is
inhibitors for erectile
CYP3A4 inhibition.
dysfunction with REYATAZ/ritonavir (see section 4.4). Also see
PULMONARY
ATERIAL
HYPERTENSION
in this table for
futher information
regarding co-administration of
REYATAZ/ritonavir with sildenafil.
INHALED BETA AGONISTS
Salmeterol
increased concentrations of salmeterol and an increase in
salmeterol with
salmeterol-associated adverse events.
REYATAZ/ritonavir is not recommended
The mechanism of interaction is CYP3A4 inhibition by atazanavir/ritonavir.
(see section 4.4).
PULMONARY ARTERIAL HYPERTENSION
Sildenafil
A safe and effective
dose in combination
PDE5-inhibitor-associated adverse events.
with
The mechanism of interaction is CYP3A4 inhibition by
has not been
atazanavir/ritonavir.
established for sildenafil when used
to treat pulmonary arterial hypertension. Sildenafil, when
used for the
treatment of
pulmonary arterial
hypertension, is
contraindicated (see
section 4.3).
Integrase Inhibitors
Raltegravir 400 mg BID
(atazanavir/ritonavir)
raltegravir
↑ 41%
↑ 24%
C12hr↑ 77%
No dose adjustment required for Isentress.
The mechanism is UGT1A1 inhibition.
new paediatric inidcation approved 4.1 Therapeutic indications
REYATAZ capsules, co-administered with low dose ritonavir, are indicated for the treatment of HIV‑1 infected adults and paediatric patients 6 years of age and older in combination with other antiretroviral medicinal products.
Based on available virological and clinical data from adult patients, no benefit is expected in patients with strains resistant to multiple protease inhibitors (³ 4 PI mutations). There are very limited data available from children aged 6 to less than 18 years (see sections 4.4 and 5.1). The choice of REYATAZ in treatment experienced adult and paediatric patients should be based on individual viral resistance testing and the patient’s treatment history (see sections 4.4 and 5.1). 4.2 Posology and method of administration Therapy should be initiated by a physician experienced in the management of HIV infection. Adults: the recommended dose of REYATAZ capsules is 300 mg once daily taken with ritonavir 100 mg once daily and with food. Ritonavir is used as a booster of atazanavir pharmacokinetics (see sections 4.5 and 5.1). Paediatric patients (6 years to less than 18 years of age): The dose of REYATAZ capsules for paediatric patients is based on body weight as shown in Table 1 and should not exceed the recommended adult dose. REYATAZ capsules must be taken with ritonavir and have to be taken with food. Table 1: Dose for Paediatric Patients (6 years to less than 18 years of age) for REYATAZ capsules with ritonavir Body Weight (kg) REYATAZ dose ritonavir dosea 15 to less than 20 150 mg 100 mgb 20 to less than 40 200 mg 100 mg at least 40 300 mg 100 mg a Ritonavir capsules, tablets or oral solution. b Ritonavir oral solution no lower than 80 mg and not more than 100 mg may be used for paediatric patients from 15 kg to less than 20 kg who cannot swallow ritonavir capsules/tablets. The available data do not support the use of REYATAZ in combination with low dose ritonavir in paediatric patients weighing less than 15 kg.
The choice of REYATAZ in treatment experienced adult and paediatric patients should be based on individual viral resistance testing and the patient’s treatment history (see sections 4.4 and 5.1).
4.2 Posology and method of administration
Therapy should be initiated by a physician experienced in the management of HIV infection.
Adults: the recommended dose of REYATAZ capsules is 300 mg once daily taken with ritonavir 100 mg once daily and with food. Ritonavir is used as a booster of atazanavir pharmacokinetics (see sections 4.5 and 5.1).
Paediatric patients (6 years to less than 18 years of age): The dose of REYATAZ capsules for paediatric patients is based on body weight as shown in Table 1 and should not exceed the recommended adult dose. REYATAZ capsules must be taken with ritonavir and have to be taken with food.
Table 1: Dose for Paediatric Patients (6 years to less than 18 years of age) for REYATAZ capsules with ritonavir
Body Weight (kg)
REYATAZ dose
ritonavir dosea
15 to less than 20
150 mg
100 mgb
20 to less than 40
200 mg
100 mg
at least 40
300 mg
a Ritonavir capsules, tablets or oral solution. b Ritonavir oral solution no lower than 80 mg and not more than 100 mg may be used for paediatric patients from 15 kg to less than 20 kg who cannot swallow ritonavir capsules/tablets. The available data do not support the use of REYATAZ in combination with low dose ritonavir in paediatric patients weighing less than 15 kg.
b Ritonavir oral solution no lower than 80 mg and not more than 100 mg may be used for paediatric patients from 15 kg to less than 20 kg who cannot swallow ritonavir capsules/tablets.
The available data do not support the use of REYATAZ in combination with low dose ritonavir in paediatric patients weighing less than 15 kg.
Paediatric patients (less than 6 years of age): REYAYAZ is not recommended in paediatric patients less than 6 years of age due to insufficient data on pharmacokinetics, safety, and efficacy. REYATAZ has not been studied in children less than 3 months of age and is not recommended especially taking into account the potential risk of kernicterus.
Patients with renal impairment: no dosage adjustment is needed. REYATAZ with ritonavir is not recommended in patients undergoing haemodialysis (see sections 4.4 and 5.2).
Patients with hepatic impairment: REYATAZ with ritonavir has not been studied in patients with hepatic impairment. REYATAZ with ritonavir should be used with caution in patients with mild hepatic impairment. REYATAZ must not be used in patients with moderate to severe hepatic impairment (see sections 4.3, 4.4, and 5.2).
Method of administration: for oral administration. The capsules should be swallowed whole. REYATAZ oral powder is available for adult patients who are unable to swallow capsules (see Summary of Product Characteristics for REYATAZ oral powder). REYATAZ oral powder must not be used in paediatric patients unable to swallow capsules due to insufficient data on pharmacokinetics, safety, and efficacy.
Paediatric population
Safety:
Asymptomatic PR interval prolongation was more frequent in paediatric patients than adults. Asymptomatic first- and second-degree AV block was reported in paediatric patients (see section 4.8). Caution should be used with medicinal products known to induce PR prolongations. In paediatric patients with pre‑existing conduction problems (second degree or higher atrioventricular or complex bundle‑branch block), REYATAZ should be used with caution and only if the benefits exceed the risk. Cardiac monitoring is recommended based on the presence of clinical findings (e.g., bradycardia).
Efficacy
Atazanavir/ritonavir is not effective in viral strains harbouring multiple mutations of resistance. While in adults no benefit can be expected in patients with ³4 PI mutations, in treatment experienced children even lower numbers of PI mutations may be predictive of a lack of benefit (see section 5.1).
Only when atazanavir with ritonavir is co-administered with efavirenz, a dose increase of ritonavir to 200 mg once daily could be considered. In this instance, close clinical monitoring is warranted (see Interaction with other Medicinal Products below). Section 4.5 spc add: Rifabutin 150 mg twice weekly (atazanavir 300 mg and ritonavir 100 mg QD) rifabutin ↑1.48 ** (1.19, 1.84) ↑2.49 ** (2.03, 3.06) ↑1.40 ** (1.05, 1.87) When given with REYATAZ/ritonavir, the recommended dose of rifabutin is 150 mg 3 times per week on set days (for example Monday-Wednesday-Friday). Increased monitoring for rifabutin-associated adverse reactions including neutropenia and uveitis is warranted due to an expected increase in exposure to rifabutin. Further dosage reduction of rifabutin to 150 mg twice weekly on set days is recommeded for patients in whom the 150 mg dose 3 times per week is not tolerated. It should be kept in mind that the twice weekly dosage of 150 mg may not provide an optimal exposure to rifabutin thus leading to a risk of rifamycin resistance and a treatment failure. No dose adjustment is needed for REYATAZ/ritonavir.
Rifabutin 150 mg twice weekly
(atazanavir 300 mg and ritonavir 100 mg QD)
rifabutin
↑1.48 **
(1.19, 1.84)
↑2.49 **
(2.03, 3.06)
↑1.40 **
(1.05, 1.87)
When given with REYATAZ/ritonavir, the recommended dose of rifabutin is 150 mg 3 times per week on set days (for example Monday-Wednesday-Friday). Increased monitoring for rifabutin-associated adverse reactions including neutropenia and uveitis is warranted due to an expected increase in exposure to rifabutin. Further dosage reduction of rifabutin to 150 mg twice weekly on set days is recommeded for patients in whom the 150 mg dose 3 times per week is not tolerated. It should be kept in mind that the twice weekly dosage of 150 mg may not provide an optimal exposure to rifabutin thus leading to a risk of rifamycin resistance and a treatment failure. No dose adjustment is needed for REYATAZ/ritonavir.
** When compared to rifabutin 150 mg QD alone. Total rifabutin and 25-O-desacetyl-rifabutin AUC: ↑2.19 (1.78, 2.69). In previous studies, the pharmacokinetics of atazanavir was not altered by rifabutin.
In previous studies, the pharmacokinetics of atazanavir was not altered by rifabutin.
4.4 Special warnings and precautions for use
The concomitant use of REYATAZ and oral contraceptives should be avoided (see section 4.5).
4.5 Interaction with other medicinal products and other forms of interaction
Table 1: Interactions between REYATAZ and other medicinal products
Co‑administered medicinal products (dose in mg)
Medicinal product assessed
AUC
(90% CI)
Cmax
Cmin
Recommendations concerning co‑administration
HORMONAL CONTRACEPTIVES
Ethinyloestradiol 35 μg + norethindrone (atazanavir 400 mg QD)
ethinyloestradiol
↑1.48
(1.31, 1.68)
↑1.15
(0.99, 1.32)
↑1.91
(1.57, 2.33)
The co If an oral contraceptive is administered with REYATAZ/ritonavir, it is recommended that the oral contraceptive contain at least 30 μg of ethinyloestradiol and that the patient be reminded of the need for strict compliance with the contraceptive dosing regimen. Co-administration of REYATAZ/ritonavir and oral with other hormonal contraceptives should be avoided (see section 4.4). Alternateor oral contraceptives containing progestogens other than norethindrone or norgestimate has not been studied; therefore, alternate reliable methods of contraception should be considered.are recommended.
norethindrone
↑2.10
(1.68, 2.62)
↑1.67
(1.42, 1.96)
↑3.62
(2.57, 5.09)
The concentration of oral contraceptives was increased due to UGT inhibition. In contrast, ritonavir may decrease ethinyloestradiol concentrations. The effects of co-administration of oral contraceptives and REYATAZ/ritonavir have not been studied.
Ethinyloestradiol 25 μg + norgestimate (atazanavir 300 QD with ritonavir 100 mg QD)
↓0.81
(0.75, 0.87)
↓0.84
(0.74, 0.95)
↓0.63
(0.55, 0.71)
norgestimate
↑1.85
(1.67, 2.05)
↑1.68
(1.51, 1.88)
↑2.02
(1.77, 2.31)
The concentration of oral contraceptives was increased due to UGT inhibition. In contrast, ritonavir may decrease ethinyloestradiol concentrations. Potential safety risks include substantial increases in progesterone exposure. The long-term effects of increases in concentration of the progestational agent are unknown and could increase the risk of insulin resistance, dyslipidemia, and acne.
Patients with renal impairment: no dosage adjustment is needed. REYATAZ with ritonavir is not recommended in patients undergoing haemodialysis (see sectionsections 4.4 and 5.2).
Addition of:
No dosage adjustment is needed in patients with renal impairment. However, REYATAZ with ritonavir is not recommended in patients undergoing haemodialysis (see sections 4.2 and 5.2). (.......) Co‑administration of REYATAZ/ritonavir in combination with tenofovir and an H2‑receptor antagonist should be avoided (see section 4.5). 4.5 Interaction with other medicinal products and other forms of interaction (....) Table 1: Interactions between REYATAZ and other medicinal products ACID REDUCING AGENTS H2‑Receptor antagonists Famotidine 40 mg BID (atazanavir 300 mg QD with ritonavir 100 mg QD) atazanavir ↓ 0.82 (0.75, 0.89) ↓0.86 (0.79, 0.94) ↓0.72 (0.64, 0.81) No dosage adjustment of REYATAZ/ ritonavir is required when co‑administered with an H2‑receptor antagonist, all as a single daily dose with food. Reductions in atazanavir concentrations may be avoided by temporal separation of REYATAZ and an H2‑receptor antagonist as follows: REYATAZ 300 mg with ritonavir 100 mg once daily with food, 2 hours before and at least 10 hours following the administration of an H2‑receptor antagonist. Although not studied, similar results are expected with other H2‑receptor antagonists. The relevance of these data for HIV infected patients is unknown since the intragastric pH may be higher in this population. Therefore, the magnitude of this effect may be more pronounced. The mechanism of interaction is decreased solubility of atazanavir as intra-gastric pH increases with H2 blockers. Without Tenofovir For patients not taking tenofovir, if REYATAZ 300 mg/ritonavir 100 mg and H2‑receptor antagonists are co‑administered, a dose equivalent to famotidine 20 mg BID should not be exceeded. If a higher dose of an H2‑receptor antagonist is required (eg, famotidine 40 mg BID or equivalent) an increase of the REYATAZ/ritonavir dose from 300/100 mg to 400/100 mg can be considered. In HIV‑infected patients with atazanavir/ritonavir at the recommended dose 300/100 mg QD ‑ famotidine 20 mg BID atazanavir ↓0.82 (0.75, 1.01) ↓0.80 (0.68, 0.93) ↔0.99 (0.84, 1.18) ‑ famotidine 40 mg BID atazanavir ↓0.77 (0.68, 0.86) ↓0.77 (0.67, 0.88) ↓0.80 (0.69, 0.92) In Healthy volunteers with atazanavir/ritonavir at an increased dose of 400/100 mg QD ‑ famotidine 40 mg BID atazanavir ↔1.03 (0.86, 1.22) ↔1.02 (0.87, 1.18) ↓0.86 (0.68, 1.08) With Tenofovir 300 mg QD In HIV‑infected patients with atazanavir/ritonavir at the recommended dose of 300/100 mg QD For patients who are taking tenofovir, Co‑administration of REYATAZ/ritonavir in combination with tenofovir and an H2‑receptor antagonist should be avoided (see section 4.4). If the combination of REYATAZ/ritonavir with both tenofovir and an H2‑receptor antagonist is judged unavoidable, close clinical monitoring is recommended. A dose increase of REYATAZ to 400 mg with 100 mg of ritonavir may be considered but is still under evaluation. ‑ famotidine 20 mg BID atazanavir ↓0.79* (0.66, 0.96) ↓0.79* (0.64, 0.96) ↓0.81* (0.63, 1.05) ‑ famotidine 40 mg BID atazanavir ↓0.76* (0.64, 0.89) ↓0.77* (0.64, 0.92) ↓0.75* (0.53, 1.07) * When compared to atazanavir 300 mg QD with ritonavir 100 mg QD and tenofovir disoproxil fumarate 300 mg all as a single dose with food. When compared to atazanavir 300 mg with ritonavir 100 mg without tenofovir, atazanavir concentrations are expected to be additionally decreased by about 20%. The mechanism of interaction is decreased solubility of atazanavir as intra‑gastric pH increases with H2 blockers. Proton pump inhibitors Omeprazole 40 mg QD (atazanavir 400 mg QD with ritonavir 100 mg QD) atazanavir (am): 2 hr after omeprazole ↓0.39 (0.35, 0.45) ↓0.44 (0.38, 0.51) ↓0.35 (0.29, 0.41) Co-administration of REYATAZ/ritonavir with proton pump inhibitors is not recommended. If the combination of REYATAZ/ritonavir with a proton pump inhibitor is judged unavoidable, close clinical monitoring is recommended in combination with an increase in the dose of REYATAZ to 400 mg with 100 mg of ritonavir; doses of proton pump inhibitors comparable to omeprazole 20 mg should not be exceeded (see section 4.4). Omeprazole 20 mg QD (atazanavir 400 mg QD with ritonavir 100 mg QD) Omeprazole 20 mg QD (atazanavir 400 mg QD with ritonavir 100 mg QD) atazanavir (am): 1 hr after omeprazaoleomeprazole ↓0.70* (0.57, 0.86) ↓0.69* (0.58, 0.83) ↓0.69* (0.54, 0.88) * When compared to atazanavir 300 mg QD with ritonavir 100 mg QD The decrease in AUC, Cmax, and Cmin was not mitigated when an increased dose of REYATAZ/ritonavir (400/100 mg once daily) was temporally separated from omeprazole by 12 hours. Although not studied, similar results are expected with other proton pump inhibitors. This decrease in atazanavir exposure might negatively impact the efficacy of atazanavir. The mechanism of interaction is decreased solubility of atazanavir as intra‑gastric pH increases with proton pump inhibitors. 4.8 Undesirable effects REYATAZ has been evaluated for safety in combination therapy with other antiretroviral medicinal products in controlled clinical trials in 1,806 adult patients receiving REYATAZ 400 mg once daily (1,151 patients, 52 weeks median duration and 152 weeks maximum duration) or REYATAZ 300 mg with ritonavir 100 mg once daily (655 patients, 48 96°weeks median duration and 101108 weeks maximum duration). (.....) Laboratory abnormalities The most frequently reported laboratory abnormality in patients receiving regimens containing REYATAZ and one or more NRTIs was elevated total bilirubin reported predominantly as elevated indirect [unconjugated] bilirubin (8487% Grade 1, 2, 3, or 4). Grade 3 or 4 elevation of total bilirubin was noted in 35% (537% (6% Grade 4). Among experienced patients treated with REYATAZ 300 mg once daily with 100 mg ritonavir once daily for a median duration of 95 weeks, 53% had Grade 3‑4 total bilirubin elevations. Among naive patients treated with REYATAZ 300 mg once daily with 100 mg ritonavir once daily for a median duration of 4896 weeks, 3948% had Grade 3‑4 total bilirubin elevations (see section 4.4). Other marked clinical laboratory abnormalities (Grade 3 or 4) reported in ≥ 2% of patients receiving regimens containing REYATAZ and one or more NRTIs included: elevated creatine kinase (7%), elevated alanine aminotransferase/serum glutamic‑pyruvic transaminase (ALT/SGPT) (45%), low neutrophils (45%), elevated aspartate aminotransferase/serum glutamic‑oxaloacetic transaminase (AST/SGOT) (3%), and elevated lipase (23%). OneTwo percent of patients treated with REYATAZ experienced concurrent Grade 3‑4 ALT/AST and Grade 3‑4 total bilirubin elevations. 5.1 Pharmacodynamic properties Antiviral activity in vitro: atazanavir exhibits anti‑HIV‑1 activity (EC50 of 2 to 5 nM) in the absence of human serum against a variety of laboratory(including all clades tested) and clinical anti‑HIV isolates. Atazanavir has‑2 activity against HIV‑1 Group M subtype viruses A, B, C, D, AE, AG, F, G, and J isolates in cell culture. Atazanavir has activity against HIV‑2 isolates (EC50 of 1.9 to 32 nM). Combinations of atazanavir with stavudine, didanosine, lamivudine, zidovudine, nelfinavir, indinavir, ritonavir, saquinavir, amprenavir, did not result in antagonistic anti‑HIV activity or enhanced cytotoxic effects at the highest concentrations used for antiviral evaluation. Resistance Antiretroviral treatment naive patients In clinical trials of antiretroviral treatment naive patients treated with unboosted atazanavir, the I50L substitution, sometimes in combination with an A71V change, is the signature resistance substitution for atazanavir. An atazanavir resistance phenotype is expressed in all recombinant viral clones containing the I50L substitution in a variety of genetic backgrounds. Resistance levels to atazanavir ranged from 3.5‑ to 29‑fold. There was no without evidence of phenotypic cross‑resistance between atazanavir and amprenavir, with the presence resistance to other PIs. In clinical trials of antiretroviral treatment naive patients treated with boosted atazanavir, the I50L and I50Vsubstitution did not emerge in any patient without baseline PI substitutions yielding selective resistance to atazanavir and amprenavir, respectively. The N88S substitution has been rarely observed in patients with virologic failure on atazanavir treatment(with or without ritonavir). While it may contribute to decreased susceptibility to atazanavir when it occurs with other protease substitutions, in clinical studies N88S by itself does not always lead to phenotypic resistance to atazanavir or have a consistent impact on clinical efficacy. Table 2. De novo substitutions in treatment naive patients failing therapy with atazanavir + ritonavir (Study 138, 96 weeks) Frequency de novo PI substitution (n=26)a >20% none 10-20% none a Number of patients with paired genotypes classified as virological failures (HIV RNA ≥ 400 copies/ml). The M184I/V substitution emerged in 5/26 REYATAZ/ritonavir and 7/26 lopinavir/ritonavir virologic failure patients, respectively. Antiretroviral treatment experienced patients In antiretroviral treatment experienced patients from Studies 009, 043, and 045, 100 isolates from patients designated as virological failures on therapy that included either atazanavir, atazanavir + ritonavir, or atazanavir + saquinavir were determined to have developed resistance to atazanavir. Of the 60 isolates from patients treated with either atazanavir or atazanavir + ritonavir, 18 (30%) displayed the I50L phenotype previously described in naive patients. Table 3. De novo substitutions in treatment experienced patients failing therapy with atazanavir + ritonavir (Study 045, 48 weeks) Frequency de novo PI substitution (n=35)a,b >20% M36, M46, I54, A71, V82 10-20% L10, I15, K20, V32, E35, S37, F53, I62, G73, I84, L90 a Number of patients with paired genotypes classified as virological failures (HIV RNA ≥ 400 copies/ml). b Ten patients had baseline phenotypic resistance to atazanavir + ritonavir (fold change [FC]>5.2). FC susceptibility in cell culture relative to the wild-type reference was assayed using PhenoSenseTM (Monogram Biosciences, South San Francisco, California, USA) None of the de novo substitutions (see Table 3) are specific to atazanavir and may reflect re-emergence of archived resistance on atazanavir + ritonavir in Study 045 treatment-experienced population. The resistance in antiretroviral treatment experienced patients mainly occurs by accumulation of the primary and secondarymajor and minor resistance substitutions described previously to be involved in protease inhibitor resistance. These isolates developed higher levels of resistance to the other protease inhibitors. Cross‑resistance in vitro in viruses resistant to other protease inhibitors Atazanavir susceptibility was evaluated in 943 clinical isolates from patients without prior atazanavir exposure and exhibited a wide array of genotypic and phenotypic patterns. In vitro, there was a clear trend toward decreased susceptibility to atazanavir as isolates exhibited high resistance levels to multiple protease inhibitors. In general, susceptibility to atazanavir was retained (83% of isolates displayed < 2.5 fold change in EC50) among isolates resistant to no more than 2 protease inhibitors. Eighteen percent of isolates had 4 or more of the following 6 substitutions considered critical substitutions for protease inhibitors: positions L10, M46, I54, V82, I84, and L90. These isolates expressed a median fold change in EC50 relative to wildtype of 12.0 for atazanavir. Therefore, viral isolates having at least 4 of these specific mutations would be considered resistant for atazanavir. Clinical results In antiretroviral naive patients Study 138 is an international randomised, open‑label, multicenter, prospective trial of 883 antiretroviral treatment naïve patients comparing REYATAZ/ritonavir (300 mg/100 mg once daily) to lopinavir/ritonavir (400 mg/100 mg twice daily), each in combination with fixed dose tenofovir/emtricitabine (300 mg/200 mg tablets once daily). The mean baseline CD4 cell count was 214 cells/mm3 (range: 2 to 810 cells/ mm3) and mean baseline plasma HIV‑1 RNA was 4.94 log10 copies/ml (range: 2.6 to 5.88 log10 copies/ml). The REYATAZ/ritonavir arm hasshowed similar (non-inferior) antiviral efficacy compared to the lopinavir/ritonavir arm, as assessed by the proportion of patients with HIV RNA < 50 copies/ml at week 48: 78% of patients on REYATAZ/ritonavir compared to 76% on lopinavir/ritonavir (difference estimate of ATV/RTV-LPV/RTV: 1.7% [95% CI, -3.8%, 7.1%] according to the Confirmed Virologic Response (CVR) Non-Completer = Failure (NC = F) definition of response. In a per protocol analysis which excluded non-completers (i.e. patients who discontinued before the week 48 HIV RNA assessment) and patients with major protocol deviations, the proportion of patients with HIV RNA < 50 copies/ml at week 48 was 86% (338/392) for REYATAZ/ritonavir and 89% (332/372) for lopinavir/ritonavir (difference estimate of ATV/RTV-LPV/RTV: -3% [95% CI, -7.6%, 1.5%]. (Table 2: 4). Analyses of data through 96 weeks of treatment demonstrated durability of antiviral activity (Table 4). Table 4: Efficacy Outcomes at Week 48 (in Study 138) for the CVR (NC=F) analysis a Parameter REYATAZ/ritonaviraritonavirb (300 mg/100 mg once daily) n=440 lopinavir/ritonavirbLopinavir/ritonavirc (400 mg/100 mg twice daily) n=443 HIV RNA <50 copies/ml, % c All patients 78 76 Baseline Characteristics HIV RNA <100,000 copies/ml 82 (n=217d) 81 (n=218) ≥100,000 copies/ml 74 (n=223) 72 (n=225) CD4 count <50 cells/mm3 78 (n=58) 63 (n=48) 50 to <100 cells/mm3 76 (n=45) 69 (n=29) 100 to <200 cells/mm3 75 (n=106) 78 (n=134) ≥200 cells/mm3 80 (n=222) 80 (n=228) Week 48 Week 96 Week 48 Week 96 HIV RNA <50 copies/ml, % All patientsd 78 74 76 68 Difference estimate [95% CI]d Week 48: 1.7% [-3.8%, 7.1%] Week 96: 6.1% [0.3%, 12.0%] Per protocol analysise 86 (n=392f) 91 (n=352) 89 (n=372) 89 (n=331) Difference estimatee [95% CI] Week 48: -3% [-7.6%, 1.5%] Week 96: 2.2% [-2.3%, 6.7%] HIV RNA <50 copies/ml, % by Baseline Characteristicd HIV RNA <100,000 copies/ml 82 (n=217) 75 (n=217) 81 (n=218) 70 (n=218) ≥100,000 copies/ml 74 (n=223) 74 (n=223) 72 (n=225) 66 (n=225) CD4 count <50 cells/mm3 78 (n=58) 78 (n=58) 63 (n=48) 58 (n=48) 50 to <100 cells/mm3 76 (n=45) 71 (n=45) 69 (n=29) 69 (n=29) 100 to <200 cells/mm3 75 (n=106) 71 (n=106) 78 (n=134) 70 (n=134) ≥ 200 cells/mm3 80 (n=222) 76 (n=222) 80 (n=228) 69 (n=228) HIV RNA Mean Change from Baseline, log10 copies/ml All patients -3.09 (n=397) -3.13 (n=379) All patients -3.09 (n=397) -3.21 (n=360) -3.13 (n=379) -3.19 (n=340) CD4 Mean Change from Baseline, cells/mm3 All patients 203 (n=370) 268 (n=336) 219 (n=363) 290 (n=317) CD4 Mean Change from Baseline, cells/mm3 by Baseline Characteristic HIV RNA <100,000 copies/ml 179 (n=183) 243 (n=163) 194 (n=183) 267 (n=152) ≥100,000 copies/ml 227 (n=187) 291 (n=173) 245 (n=180) 310 (n=165) a Mean baseline CD4 cell count was 214 cells/mm3 (range 2 to 810 cells/mm3) and mean baseline plasma HIV-1 RNA was 4.94 log10 copies/ml (range 2.6 to 5.88 log10 copies/ml) b REYATAZ/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily). c Lopinavir/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily). d Intent-to-treat analysis, with missing values considered as failures. e Per protocol analysis: Excluding non-completers and patients with major protocol deviations. f Number of patients evaluable. In antiretroviral experienced patients Study 045 is a randomised, multicenter trial comparing REYATAZ/ritonavir (300/100 mg once daily) and REYATAZ/saquinavir (400/1,200 mg once daily), to lopinavir + ritonavir (400/100 mg fixed dose combination twice daily), each in combination with tenofovir (see sections 4.5 and 4.8) and one NRTI, in patients with virologic failure on two or more prior regimens containing at least one PI, NRTI, and NNRTI. For randomised patients, the mean time of prior antiretroviral exposure was 138 weeks for PIs, 281 weeks for NRTIs, and 85 weeks for NNRTIs. At baseline, 34% of patients were receiving a PI and 60% were receiving an NNRTI. Fifteen of 120 (13%) patients in the REYATAZ + ritonavir treatment arm and 17 of 123 (14%) patients in the lopinavir + ritonavir arm had four or more of the PI substitutions L10, M46, I54, V82, I84, and L90. Thirty‑two percent of patients in the study had a viral strain with fewer than two NRTI substitutions. The primary endpoint was the time‑averaged difference in change from baseline in HIV RNA through 48 weeks (Table 5). Table 5: Efficacy Outcomes at Week 48a and at Week 96 (Study 045) Parameter ATV/RTVb (300 mg/ 100 mg once daily) n=120 LPV/RTVc (400 mg/ 100 mg twice daily) n=123 Time-averaged difference ATV/RTV-LPV/RTV [97.5% CId] Week 48 Week 96 Week 48 Week 96 Week 48 Week 96 HIV RNA Mean Change from Baseline, log10 copies/ml All patients -1.93 (n=90 e) -2.29 (n=64) -1.87 (n=99) -2.08 (n=65) 0.13 [‑0.12, 0.39] 0.14 [‑0.13, 0.41] HIV RNA <50 copies/ml, %f (responder/evaluable) All patients 36 (43/120) 32 (38/120) 42 (52/123 35 (41/118) NA NA HIV RNA <50 copies/ml by select baseline PI substitutions,f, g % (responder/evaluable) 0-2 44 (28/63) 41 (26/63) 56 (32/57) 48 (26/54) NA NA 3 18 (2/11) 9 (1/11) 38 (6/16) 33 (5/15) NA NA ≥4 27 (12/45) 24 (11/45) 28 (14/50) 20 (10/49) NA NA CD4 Mean Change from Baseline, cells/mm3 All patients 203 (n=370) 219 (n=363) Baseline Characteristics HIV RNA <100,000 copies/ml 179 (n=183) 194 (n=183) ≥100,000 copies/ml 227 (n=187) 245 (n=180) All patients 110 (n=83) 122 (n=60) 121 (n=94) 154 (n=60) NA NA a REYATAZ/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily). b Lopinavir/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily). c Intent-to-treat analysis, with missing values considered as failures. d Number of patients evaluable. In antiretroviral experienced patients Study 045 is a randomised, multicenter trial comparing REYATAZ (300 mg once daily) with ritonavir (100 mg once daily) to REYATAZ (400 mg once daily) with saquinavir soft gelatine capsules (1,200 mg once daily), and to lopinavir + ritonavir (400/100 mg fixed dose combination twice daily), each in combination with tenofovir (see sections 4.5 and 4.8) and one NRTI, in 347 (of 358 randomised) patients with virologic failure on two or more prior regimens containing at least one PI, NRTI, and NNRTI. For randomised patients, the mean time of prior antiretroviral exposure was 138 weeks for PIs, 281 weeks for NRTIs, and 85 weeks for NNRTIs. At baseline, 34% of patients were receiving a PI and 60% were receiving an NNRTI. Fifteen of 120 (13%) patients in the REYATAZ + ritonavir treatment arm and 17 of 123 (14%) patients in the lopinavir + ritonavir arm had four or more of the PI substitutions L10, M46, I54, V82, I84, and L90. Thirty‑two percent of patients in the study had a viral strain with fewer than two NRTI substitutions. The mean baseline CD4 cell count was 337 cells/mm3 (range: 14 to 1,543 cells/mm3) and the mean baseline plasma HIV‑1 RNA level was 4.4 log10 copies/ml (range: 2.6 to 5.88 log10 copies/ml). The population included in this study was moderately pretreated. The primary endpoint was the time‑averaged difference in change from baseline in HIV RNA through 48 weeks. Through 48 weeks of treatment, the decreases from baseline in HIV RNA levels (primary endpoint) were 1.93 log10 copies/ml for REYATAZ + ritonavir and 1.87 log10 copies/ml for lopinavir + ritonavir. REYATAZ + ritonavir was similar (non‑inferior) to lopinavir + ritonavir on this efficacy measure (time‑averaged difference of 0.13, 97.5% confidenceb ATV/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily). c LPV/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily). d Confidence interval [‑0.12, 0.39]).. e Number of patients evaluable. f Intent-to-treat analysis, with missing values considered as failures. Responders on LPV/RTV who completed treatment before Week 96 are excluded from Week 96 analysis. The proportion of patients with HIV RNA < 400 copies/ml were 53% and 43% for ATV/RTV and 54% and 46% for LPV/RTV at weeks 48 and 96 respectively. g Select substitutions include any change at positions L10, K20, L24, V32, L33, M36, M46, G48, I50, I54, L63, A71, G73, V82, I84, and L90 (0-2, 3, 4 or more) at baseline. NA = not applicable. Through 48 weeks of treatment, the mean changes from baseline in HIV RNA levels for REYATAZ + ritonavir and lopinavir + ritonavir were similar (non‑inferior). Consistent results were obtained with the last observation carried forward method of analysis (time‑averaged difference of 0.11, 97.5% confidence interval [‑0.15, 0.36]). The proportions of patients with HIV RNA < 400 copies/ml in the REYATAZ + ritonavir arm and the lopinavir + ritonavir arm were 53% and 54%, respectively, by intent‑to‑treat analysis, with missing values considered as failures. The proportions of patients with HIV RNA < 50 copies/ml in the REYATAZ + ritonavir arm and the lopinavir + ritonavir arm were 36% and 42%, respectively. By as‑treated analysis, excluding missing values, the proportions of patients with HIV RNA < 400 copies/ml (< 50 copies/ml) in the REYATAZ + ritonavir arm and the lopinavir + ritonavir arm were 55% (40%) and 56% (46%), respectively. The mean increases from baseline in CD4 cell count were 110 cells/mm3 and 121 cells/mm3 in the REYATAZ + ritonavir and lopinavir + ritonavir arms, respectively. Analyses of data through 96 Through 96 weeks of treatment demonstrated durability of antiviral activity. Mean, mean HIV RNA changes from baseline at Week 96 (‑2.29 log10 copies/ml for REYATAZ + ritonavir and ‑2.08 log10 copies/ml for lopinavir + ritonavir, time‑averaged difference of 0.14, 97.5% confidence interval [‑0.13, 0.41]) met criteria for non‑inferiority based on observed cases. Consistent results were obtained with the last observation carried forward method of analysis. The proportions of patients with HIV RNA <400 copies/ml (<50 copies/ml) for REYATAZ + ritonavir were 43% (32%) and for lopinavir + ritonavir were 46% (35%). Patients completing treatment while in response after 48 weeks were censored. By as‑treated analysis, excluding missing values, the proportions of patients with HIV RNA <400 copies/ml (<50 copies/ml) for REYATAZ + ritonavir were 84% (72%) and for lopinavir + ritonavir were 82% (72%). It is important to note that at time of the 96‑week analysis, 48 % of patients overall remained on study. Through 48 weeks of treatment, two types of analyses were performed based on baseline genotypic mutations. The first consisted in assessing the HIV RNA change from baseline in the subgroup of patients with < or ≥ of 4 of the following set of mutations: 10, 20, 24, 32, 33, 36, 46, 48, 50, 54, 63, 71, 73, 82, 84 and 90. The second consisted in assessing the HIV RNA change from baseline in the subgroup of patients with < or ≥ of 4 of the following more specific set of mutations: 10, 46, 54, 82, 84, 90. In the analysis performed for patients with ≥ 4 protease gene mutations among the following set of mutations 10, 20, 24, 32, 33, 36, 46, 48, 50, 54, 63, 71, 73, 82, 84 and 90, the results significantly favoured the lopinavir + ritonavir arm. There were too few patients with ≥ 4 of the second more specific set of mutations (i.e. 10, 46, 54, 82, 84, 90) to assess the comparability of the REYATAZ + ritonavir and lopinavir + ritonavir regimens, but reduced virologic activity may be anticipated among patients with this resistance profile. REYATAZ + saquinavir was shown to be inferior to lopinavir + ritonavir. 5.2 Pharmacokinetic properties Special populations Impaired renal function: in healthy subjects, the renal elimination of unchanged atazanavir was approximately 7% of the administered dose. There are no pharmacokinetic data available on for REYATAZ with ritonavir in patients with renal insufficiency (see section 4.2); however, the impact of renal impairment on atazanavir elimination is anticipated to be minimal.. REYATAZ (without ritonavir) has been studied in adult patients with severe renal impairment (n=20), including those on haemodialysis, at multiple doses of 400 mg once daily. Although this study presented some limitations (i.e., unbound drug concentrations not studied), results suggested that the atazanavir pharmacokinetic parameters were decreased by 30% to 50% in patients undergoing haemodialysis compared to patients with normal renal function. The mechanism of this decrease is unknown. (See sections 4.2 and 4.4.) 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 02 March 2004 Date of latest renewal : 09 February: 02 March 2009 10. DATE OF REVISION OF THE TEXT 9th FebruaryJuly 2009 Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/http://www.emea.europa.eu
(.......) Co‑administration of REYATAZ/ritonavir in combination with tenofovir and an H2‑receptor antagonist should be avoided (see section 4.5). 4.5 Interaction with other medicinal products and other forms of interaction (....) Table 1: Interactions between REYATAZ and other medicinal products ACID REDUCING AGENTS H2‑Receptor antagonists Famotidine 40 mg BID (atazanavir 300 mg QD with ritonavir 100 mg QD) atazanavir ↓ 0.82 (0.75, 0.89) ↓0.86 (0.79, 0.94) ↓0.72 (0.64, 0.81) No dosage adjustment of REYATAZ/ ritonavir is required when co‑administered with an H2‑receptor antagonist, all as a single daily dose with food. Reductions in atazanavir concentrations may be avoided by temporal separation of REYATAZ and an H2‑receptor antagonist as follows: REYATAZ 300 mg with ritonavir 100 mg once daily with food, 2 hours before and at least 10 hours following the administration of an H2‑receptor antagonist. Although not studied, similar results are expected with other H2‑receptor antagonists. The relevance of these data for HIV infected patients is unknown since the intragastric pH may be higher in this population. Therefore, the magnitude of this effect may be more pronounced. The mechanism of interaction is decreased solubility of atazanavir as intra-gastric pH increases with H2 blockers. Without Tenofovir For patients not taking tenofovir, if REYATAZ 300 mg/ritonavir 100 mg and H2‑receptor antagonists are co‑administered, a dose equivalent to famotidine 20 mg BID should not be exceeded. If a higher dose of an H2‑receptor antagonist is required (eg, famotidine 40 mg BID or equivalent) an increase of the REYATAZ/ritonavir dose from 300/100 mg to 400/100 mg can be considered. In HIV‑infected patients with atazanavir/ritonavir at the recommended dose 300/100 mg QD ‑ famotidine 20 mg BID atazanavir ↓0.82 (0.75, 1.01) ↓0.80 (0.68, 0.93) ↔0.99 (0.84, 1.18) ‑ famotidine 40 mg BID atazanavir ↓0.77 (0.68, 0.86) ↓0.77 (0.67, 0.88) ↓0.80 (0.69, 0.92) In Healthy volunteers with atazanavir/ritonavir at an increased dose of 400/100 mg QD ‑ famotidine 40 mg BID atazanavir ↔1.03 (0.86, 1.22) ↔1.02 (0.87, 1.18) ↓0.86 (0.68, 1.08) With Tenofovir 300 mg QD In HIV‑infected patients with atazanavir/ritonavir at the recommended dose of 300/100 mg QD For patients who are taking tenofovir, Co‑administration of REYATAZ/ritonavir in combination with tenofovir and an H2‑receptor antagonist should be avoided (see section 4.4). If the combination of REYATAZ/ritonavir with both tenofovir and an H2‑receptor antagonist is judged unavoidable, close clinical monitoring is recommended. A dose increase of REYATAZ to 400 mg with 100 mg of ritonavir may be considered but is still under evaluation. ‑ famotidine 20 mg BID atazanavir ↓0.79* (0.66, 0.96) ↓0.79* (0.64, 0.96) ↓0.81* (0.63, 1.05) ‑ famotidine 40 mg BID atazanavir ↓0.76* (0.64, 0.89) ↓0.77* (0.64, 0.92) ↓0.75* (0.53, 1.07) * When compared to atazanavir 300 mg QD with ritonavir 100 mg QD and tenofovir disoproxil fumarate 300 mg all as a single dose with food. When compared to atazanavir 300 mg with ritonavir 100 mg without tenofovir, atazanavir concentrations are expected to be additionally decreased by about 20%. The mechanism of interaction is decreased solubility of atazanavir as intra‑gastric pH increases with H2 blockers. Proton pump inhibitors Omeprazole 40 mg QD (atazanavir 400 mg QD with ritonavir 100 mg QD) atazanavir (am): 2 hr after omeprazole ↓0.39 (0.35, 0.45) ↓0.44 (0.38, 0.51) ↓0.35 (0.29, 0.41) Co-administration of REYATAZ/ritonavir with proton pump inhibitors is not recommended. If the combination of REYATAZ/ritonavir with a proton pump inhibitor is judged unavoidable, close clinical monitoring is recommended in combination with an increase in the dose of REYATAZ to 400 mg with 100 mg of ritonavir; doses of proton pump inhibitors comparable to omeprazole 20 mg should not be exceeded (see section 4.4). Omeprazole 20 mg QD (atazanavir 400 mg QD with ritonavir 100 mg QD) Omeprazole 20 mg QD (atazanavir 400 mg QD with ritonavir 100 mg QD) atazanavir (am): 1 hr after omeprazaoleomeprazole ↓0.70* (0.57, 0.86) ↓0.69* (0.58, 0.83) ↓0.69* (0.54, 0.88) * When compared to atazanavir 300 mg QD with ritonavir 100 mg QD The decrease in AUC, Cmax, and Cmin was not mitigated when an increased dose of REYATAZ/ritonavir (400/100 mg once daily) was temporally separated from omeprazole by 12 hours. Although not studied, similar results are expected with other proton pump inhibitors. This decrease in atazanavir exposure might negatively impact the efficacy of atazanavir. The mechanism of interaction is decreased solubility of atazanavir as intra‑gastric pH increases with proton pump inhibitors. 4.8 Undesirable effects REYATAZ has been evaluated for safety in combination therapy with other antiretroviral medicinal products in controlled clinical trials in 1,806 adult patients receiving REYATAZ 400 mg once daily (1,151 patients, 52 weeks median duration and 152 weeks maximum duration) or REYATAZ 300 mg with ritonavir 100 mg once daily (655 patients, 48 96°weeks median duration and 101108 weeks maximum duration). (.....) Laboratory abnormalities The most frequently reported laboratory abnormality in patients receiving regimens containing REYATAZ and one or more NRTIs was elevated total bilirubin reported predominantly as elevated indirect [unconjugated] bilirubin (8487% Grade 1, 2, 3, or 4). Grade 3 or 4 elevation of total bilirubin was noted in 35% (537% (6% Grade 4). Among experienced patients treated with REYATAZ 300 mg once daily with 100 mg ritonavir once daily for a median duration of 95 weeks, 53% had Grade 3‑4 total bilirubin elevations. Among naive patients treated with REYATAZ 300 mg once daily with 100 mg ritonavir once daily for a median duration of 4896 weeks, 3948% had Grade 3‑4 total bilirubin elevations (see section 4.4). Other marked clinical laboratory abnormalities (Grade 3 or 4) reported in ≥ 2% of patients receiving regimens containing REYATAZ and one or more NRTIs included: elevated creatine kinase (7%), elevated alanine aminotransferase/serum glutamic‑pyruvic transaminase (ALT/SGPT) (45%), low neutrophils (45%), elevated aspartate aminotransferase/serum glutamic‑oxaloacetic transaminase (AST/SGOT) (3%), and elevated lipase (23%). OneTwo percent of patients treated with REYATAZ experienced concurrent Grade 3‑4 ALT/AST and Grade 3‑4 total bilirubin elevations. 5.1 Pharmacodynamic properties Antiviral activity in vitro: atazanavir exhibits anti‑HIV‑1 activity (EC50 of 2 to 5 nM) in the absence of human serum against a variety of laboratory(including all clades tested) and clinical anti‑HIV isolates. Atazanavir has‑2 activity against HIV‑1 Group M subtype viruses A, B, C, D, AE, AG, F, G, and J isolates in cell culture. Atazanavir has activity against HIV‑2 isolates (EC50 of 1.9 to 32 nM). Combinations of atazanavir with stavudine, didanosine, lamivudine, zidovudine, nelfinavir, indinavir, ritonavir, saquinavir, amprenavir, did not result in antagonistic anti‑HIV activity or enhanced cytotoxic effects at the highest concentrations used for antiviral evaluation. Resistance Antiretroviral treatment naive patients In clinical trials of antiretroviral treatment naive patients treated with unboosted atazanavir, the I50L substitution, sometimes in combination with an A71V change, is the signature resistance substitution for atazanavir. An atazanavir resistance phenotype is expressed in all recombinant viral clones containing the I50L substitution in a variety of genetic backgrounds. Resistance levels to atazanavir ranged from 3.5‑ to 29‑fold. There was no without evidence of phenotypic cross‑resistance between atazanavir and amprenavir, with the presence resistance to other PIs. In clinical trials of antiretroviral treatment naive patients treated with boosted atazanavir, the I50L and I50Vsubstitution did not emerge in any patient without baseline PI substitutions yielding selective resistance to atazanavir and amprenavir, respectively. The N88S substitution has been rarely observed in patients with virologic failure on atazanavir treatment(with or without ritonavir). While it may contribute to decreased susceptibility to atazanavir when it occurs with other protease substitutions, in clinical studies N88S by itself does not always lead to phenotypic resistance to atazanavir or have a consistent impact on clinical efficacy. Table 2. De novo substitutions in treatment naive patients failing therapy with atazanavir + ritonavir (Study 138, 96 weeks) Frequency de novo PI substitution (n=26)a >20% none 10-20% none a Number of patients with paired genotypes classified as virological failures (HIV RNA ≥ 400 copies/ml). The M184I/V substitution emerged in 5/26 REYATAZ/ritonavir and 7/26 lopinavir/ritonavir virologic failure patients, respectively. Antiretroviral treatment experienced patients In antiretroviral treatment experienced patients from Studies 009, 043, and 045, 100 isolates from patients designated as virological failures on therapy that included either atazanavir, atazanavir + ritonavir, or atazanavir + saquinavir were determined to have developed resistance to atazanavir. Of the 60 isolates from patients treated with either atazanavir or atazanavir + ritonavir, 18 (30%) displayed the I50L phenotype previously described in naive patients. Table 3. De novo substitutions in treatment experienced patients failing therapy with atazanavir + ritonavir (Study 045, 48 weeks) Frequency de novo PI substitution (n=35)a,b >20% M36, M46, I54, A71, V82 10-20% L10, I15, K20, V32, E35, S37, F53, I62, G73, I84, L90 a Number of patients with paired genotypes classified as virological failures (HIV RNA ≥ 400 copies/ml). b Ten patients had baseline phenotypic resistance to atazanavir + ritonavir (fold change [FC]>5.2). FC susceptibility in cell culture relative to the wild-type reference was assayed using PhenoSenseTM (Monogram Biosciences, South San Francisco, California, USA) None of the de novo substitutions (see Table 3) are specific to atazanavir and may reflect re-emergence of archived resistance on atazanavir + ritonavir in Study 045 treatment-experienced population. The resistance in antiretroviral treatment experienced patients mainly occurs by accumulation of the primary and secondarymajor and minor resistance substitutions described previously to be involved in protease inhibitor resistance. These isolates developed higher levels of resistance to the other protease inhibitors. Cross‑resistance in vitro in viruses resistant to other protease inhibitors Atazanavir susceptibility was evaluated in 943 clinical isolates from patients without prior atazanavir exposure and exhibited a wide array of genotypic and phenotypic patterns. In vitro, there was a clear trend toward decreased susceptibility to atazanavir as isolates exhibited high resistance levels to multiple protease inhibitors. In general, susceptibility to atazanavir was retained (83% of isolates displayed < 2.5 fold change in EC50) among isolates resistant to no more than 2 protease inhibitors. Eighteen percent of isolates had 4 or more of the following 6 substitutions considered critical substitutions for protease inhibitors: positions L10, M46, I54, V82, I84, and L90. These isolates expressed a median fold change in EC50 relative to wildtype of 12.0 for atazanavir. Therefore, viral isolates having at least 4 of these specific mutations would be considered resistant for atazanavir. Clinical results In antiretroviral naive patients Study 138 is an international randomised, open‑label, multicenter, prospective trial of 883 antiretroviral treatment naïve patients comparing REYATAZ/ritonavir (300 mg/100 mg once daily) to lopinavir/ritonavir (400 mg/100 mg twice daily), each in combination with fixed dose tenofovir/emtricitabine (300 mg/200 mg tablets once daily). The mean baseline CD4 cell count was 214 cells/mm3 (range: 2 to 810 cells/ mm3) and mean baseline plasma HIV‑1 RNA was 4.94 log10 copies/ml (range: 2.6 to 5.88 log10 copies/ml). The REYATAZ/ritonavir arm hasshowed similar (non-inferior) antiviral efficacy compared to the lopinavir/ritonavir arm, as assessed by the proportion of patients with HIV RNA < 50 copies/ml at week 48: 78% of patients on REYATAZ/ritonavir compared to 76% on lopinavir/ritonavir (difference estimate of ATV/RTV-LPV/RTV: 1.7% [95% CI, -3.8%, 7.1%] according to the Confirmed Virologic Response (CVR) Non-Completer = Failure (NC = F) definition of response. In a per protocol analysis which excluded non-completers (i.e. patients who discontinued before the week 48 HIV RNA assessment) and patients with major protocol deviations, the proportion of patients with HIV RNA < 50 copies/ml at week 48 was 86% (338/392) for REYATAZ/ritonavir and 89% (332/372) for lopinavir/ritonavir (difference estimate of ATV/RTV-LPV/RTV: -3% [95% CI, -7.6%, 1.5%]. (Table 2: 4). Analyses of data through 96 weeks of treatment demonstrated durability of antiviral activity (Table 4). Table 4: Efficacy Outcomes at Week 48 (in Study 138) for the CVR (NC=F) analysis a Parameter REYATAZ/ritonaviraritonavirb (300 mg/100 mg once daily) n=440 lopinavir/ritonavirbLopinavir/ritonavirc (400 mg/100 mg twice daily) n=443 HIV RNA <50 copies/ml, % c All patients 78 76 Baseline Characteristics HIV RNA <100,000 copies/ml 82 (n=217d) 81 (n=218) ≥100,000 copies/ml 74 (n=223) 72 (n=225) CD4 count <50 cells/mm3 78 (n=58) 63 (n=48) 50 to <100 cells/mm3 76 (n=45) 69 (n=29) 100 to <200 cells/mm3 75 (n=106) 78 (n=134) ≥200 cells/mm3 80 (n=222) 80 (n=228) Week 48 Week 96 Week 48 Week 96 HIV RNA <50 copies/ml, % All patientsd 78 74 76 68 Difference estimate [95% CI]d Week 48: 1.7% [-3.8%, 7.1%] Week 96: 6.1% [0.3%, 12.0%] Per protocol analysise 86 (n=392f) 91 (n=352) 89 (n=372) 89 (n=331) Difference estimatee [95% CI] Week 48: -3% [-7.6%, 1.5%] Week 96: 2.2% [-2.3%, 6.7%] HIV RNA <50 copies/ml, % by Baseline Characteristicd HIV RNA <100,000 copies/ml 82 (n=217) 75 (n=217) 81 (n=218) 70 (n=218) ≥100,000 copies/ml 74 (n=223) 74 (n=223) 72 (n=225) 66 (n=225) CD4 count <50 cells/mm3 78 (n=58) 78 (n=58) 63 (n=48) 58 (n=48) 50 to <100 cells/mm3 76 (n=45) 71 (n=45) 69 (n=29) 69 (n=29) 100 to <200 cells/mm3 75 (n=106) 71 (n=106) 78 (n=134) 70 (n=134) ≥ 200 cells/mm3 80 (n=222) 76 (n=222) 80 (n=228) 69 (n=228) HIV RNA Mean Change from Baseline, log10 copies/ml All patients -3.09 (n=397) -3.13 (n=379) All patients -3.09 (n=397) -3.21 (n=360) -3.13 (n=379) -3.19 (n=340) CD4 Mean Change from Baseline, cells/mm3 All patients 203 (n=370) 268 (n=336) 219 (n=363) 290 (n=317) CD4 Mean Change from Baseline, cells/mm3 by Baseline Characteristic HIV RNA <100,000 copies/ml 179 (n=183) 243 (n=163) 194 (n=183) 267 (n=152) ≥100,000 copies/ml 227 (n=187) 291 (n=173) 245 (n=180) 310 (n=165) a Mean baseline CD4 cell count was 214 cells/mm3 (range 2 to 810 cells/mm3) and mean baseline plasma HIV-1 RNA was 4.94 log10 copies/ml (range 2.6 to 5.88 log10 copies/ml) b REYATAZ/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily). c Lopinavir/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily). d Intent-to-treat analysis, with missing values considered as failures. e Per protocol analysis: Excluding non-completers and patients with major protocol deviations. f Number of patients evaluable. In antiretroviral experienced patients Study 045 is a randomised, multicenter trial comparing REYATAZ/ritonavir (300/100 mg once daily) and REYATAZ/saquinavir (400/1,200 mg once daily), to lopinavir + ritonavir (400/100 mg fixed dose combination twice daily), each in combination with tenofovir (see sections 4.5 and 4.8) and one NRTI, in patients with virologic failure on two or more prior regimens containing at least one PI, NRTI, and NNRTI. For randomised patients, the mean time of prior antiretroviral exposure was 138 weeks for PIs, 281 weeks for NRTIs, and 85 weeks for NNRTIs. At baseline, 34% of patients were receiving a PI and 60% were receiving an NNRTI. Fifteen of 120 (13%) patients in the REYATAZ + ritonavir treatment arm and 17 of 123 (14%) patients in the lopinavir + ritonavir arm had four or more of the PI substitutions L10, M46, I54, V82, I84, and L90. Thirty‑two percent of patients in the study had a viral strain with fewer than two NRTI substitutions. The primary endpoint was the time‑averaged difference in change from baseline in HIV RNA through 48 weeks (Table 5). Table 5: Efficacy Outcomes at Week 48a and at Week 96 (Study 045) Parameter ATV/RTVb (300 mg/ 100 mg once daily) n=120 LPV/RTVc (400 mg/ 100 mg twice daily) n=123 Time-averaged difference ATV/RTV-LPV/RTV [97.5% CId] Week 48 Week 96 Week 48 Week 96 Week 48 Week 96 HIV RNA Mean Change from Baseline, log10 copies/ml All patients -1.93 (n=90 e) -2.29 (n=64) -1.87 (n=99) -2.08 (n=65) 0.13 [‑0.12, 0.39] 0.14 [‑0.13, 0.41] HIV RNA <50 copies/ml, %f (responder/evaluable) All patients 36 (43/120) 32 (38/120) 42 (52/123 35 (41/118) NA NA HIV RNA <50 copies/ml by select baseline PI substitutions,f, g % (responder/evaluable) 0-2 44 (28/63) 41 (26/63) 56 (32/57) 48 (26/54) NA NA 3 18 (2/11) 9 (1/11) 38 (6/16) 33 (5/15) NA NA ≥4 27 (12/45) 24 (11/45) 28 (14/50) 20 (10/49) NA NA CD4 Mean Change from Baseline, cells/mm3 All patients 203 (n=370) 219 (n=363) Baseline Characteristics HIV RNA <100,000 copies/ml 179 (n=183) 194 (n=183) ≥100,000 copies/ml 227 (n=187) 245 (n=180) All patients 110 (n=83) 122 (n=60) 121 (n=94) 154 (n=60) NA NA a REYATAZ/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily). b Lopinavir/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily). c Intent-to-treat analysis, with missing values considered as failures. d Number of patients evaluable. In antiretroviral experienced patients Study 045 is a randomised, multicenter trial comparing REYATAZ (300 mg once daily) with ritonavir (100 mg once daily) to REYATAZ (400 mg once daily) with saquinavir soft gelatine capsules (1,200 mg once daily), and to lopinavir + ritonavir (400/100 mg fixed dose combination twice daily), each in combination with tenofovir (see sections 4.5 and 4.8) and one NRTI, in 347 (of 358 randomised) patients with virologic failure on two or more prior regimens containing at least one PI, NRTI, and NNRTI. For randomised patients, the mean time of prior antiretroviral exposure was 138 weeks for PIs, 281 weeks for NRTIs, and 85 weeks for NNRTIs. At baseline, 34% of patients were receiving a PI and 60% were receiving an NNRTI. Fifteen of 120 (13%) patients in the REYATAZ + ritonavir treatment arm and 17 of 123 (14%) patients in the lopinavir + ritonavir arm had four or more of the PI substitutions L10, M46, I54, V82, I84, and L90. Thirty‑two percent of patients in the study had a viral strain with fewer than two NRTI substitutions. The mean baseline CD4 cell count was 337 cells/mm3 (range: 14 to 1,543 cells/mm3) and the mean baseline plasma HIV‑1 RNA level was 4.4 log10 copies/ml (range: 2.6 to 5.88 log10 copies/ml). The population included in this study was moderately pretreated. The primary endpoint was the time‑averaged difference in change from baseline in HIV RNA through 48 weeks. Through 48 weeks of treatment, the decreases from baseline in HIV RNA levels (primary endpoint) were 1.93 log10 copies/ml for REYATAZ + ritonavir and 1.87 log10 copies/ml for lopinavir + ritonavir. REYATAZ + ritonavir was similar (non‑inferior) to lopinavir + ritonavir on this efficacy measure (time‑averaged difference of 0.13, 97.5% confidenceb ATV/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily). c LPV/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily). d Confidence interval [‑0.12, 0.39]).. e Number of patients evaluable. f Intent-to-treat analysis, with missing values considered as failures. Responders on LPV/RTV who completed treatment before Week 96 are excluded from Week 96 analysis. The proportion of patients with HIV RNA < 400 copies/ml were 53% and 43% for ATV/RTV and 54% and 46% for LPV/RTV at weeks 48 and 96 respectively. g Select substitutions include any change at positions L10, K20, L24, V32, L33, M36, M46, G48, I50, I54, L63, A71, G73, V82, I84, and L90 (0-2, 3, 4 or more) at baseline. NA = not applicable. Through 48 weeks of treatment, the mean changes from baseline in HIV RNA levels for REYATAZ + ritonavir and lopinavir + ritonavir were similar (non‑inferior). Consistent results were obtained with the last observation carried forward method of analysis (time‑averaged difference of 0.11, 97.5% confidence interval [‑0.15, 0.36]). The proportions of patients with HIV RNA < 400 copies/ml in the REYATAZ + ritonavir arm and the lopinavir + ritonavir arm were 53% and 54%, respectively, by intent‑to‑treat analysis, with missing values considered as failures. The proportions of patients with HIV RNA < 50 copies/ml in the REYATAZ + ritonavir arm and the lopinavir + ritonavir arm were 36% and 42%, respectively. By as‑treated analysis, excluding missing values, the proportions of patients with HIV RNA < 400 copies/ml (< 50 copies/ml) in the REYATAZ + ritonavir arm and the lopinavir + ritonavir arm were 55% (40%) and 56% (46%), respectively. The mean increases from baseline in CD4 cell count were 110 cells/mm3 and 121 cells/mm3 in the REYATAZ + ritonavir and lopinavir + ritonavir arms, respectively. Analyses of data through 96 Through 96 weeks of treatment demonstrated durability of antiviral activity. Mean, mean HIV RNA changes from baseline at Week 96 (‑2.29 log10 copies/ml for REYATAZ + ritonavir and ‑2.08 log10 copies/ml for lopinavir + ritonavir, time‑averaged difference of 0.14, 97.5% confidence interval [‑0.13, 0.41]) met criteria for non‑inferiority based on observed cases. Consistent results were obtained with the last observation carried forward method of analysis. The proportions of patients with HIV RNA <400 copies/ml (<50 copies/ml) for REYATAZ + ritonavir were 43% (32%) and for lopinavir + ritonavir were 46% (35%). Patients completing treatment while in response after 48 weeks were censored. By as‑treated analysis, excluding missing values, the proportions of patients with HIV RNA <400 copies/ml (<50 copies/ml) for REYATAZ + ritonavir were 84% (72%) and for lopinavir + ritonavir were 82% (72%). It is important to note that at time of the 96‑week analysis, 48 % of patients overall remained on study. Through 48 weeks of treatment, two types of analyses were performed based on baseline genotypic mutations. The first consisted in assessing the HIV RNA change from baseline in the subgroup of patients with < or ≥ of 4 of the following set of mutations: 10, 20, 24, 32, 33, 36, 46, 48, 50, 54, 63, 71, 73, 82, 84 and 90. The second consisted in assessing the HIV RNA change from baseline in the subgroup of patients with < or ≥ of 4 of the following more specific set of mutations: 10, 46, 54, 82, 84, 90. In the analysis performed for patients with ≥ 4 protease gene mutations among the following set of mutations 10, 20, 24, 32, 33, 36, 46, 48, 50, 54, 63, 71, 73, 82, 84 and 90, the results significantly favoured the lopinavir + ritonavir arm. There were too few patients with ≥ 4 of the second more specific set of mutations (i.e. 10, 46, 54, 82, 84, 90) to assess the comparability of the REYATAZ + ritonavir and lopinavir + ritonavir regimens, but reduced virologic activity may be anticipated among patients with this resistance profile. REYATAZ + saquinavir was shown to be inferior to lopinavir + ritonavir. 5.2 Pharmacokinetic properties Special populations Impaired renal function: in healthy subjects, the renal elimination of unchanged atazanavir was approximately 7% of the administered dose. There are no pharmacokinetic data available on for REYATAZ with ritonavir in patients with renal insufficiency (see section 4.2); however, the impact of renal impairment on atazanavir elimination is anticipated to be minimal.. REYATAZ (without ritonavir) has been studied in adult patients with severe renal impairment (n=20), including those on haemodialysis, at multiple doses of 400 mg once daily. Although this study presented some limitations (i.e., unbound drug concentrations not studied), results suggested that the atazanavir pharmacokinetic parameters were decreased by 30% to 50% in patients undergoing haemodialysis compared to patients with normal renal function. The mechanism of this decrease is unknown. (See sections 4.2 and 4.4.) 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 02 March 2004 Date of latest renewal : 09 February: 02 March 2009 10. DATE OF REVISION OF THE TEXT 9th FebruaryJuly 2009 Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/http://www.emea.europa.eu
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Co‑administration of REYATAZ/ritonavir in combination with tenofovir and an H2‑receptor antagonist should be avoided (see section 4.5).
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ACID REDUCING AGENTS
H2‑Receptor antagonists
Famotidine 40 mg BID (atazanavir 300 mg QD with ritonavir 100 mg QD)
atazanavir
↓ 0.82 (0.75, 0.89)
(0.75, 0.89)
↓0.86 (0.79, 0.94)
(0.79, 0.94)
↓0.72 (0.64, 0.81)
(0.64, 0.81)
No dosage adjustment of REYATAZ/ ritonavir is required when co‑administered with an H2‑receptor antagonist, all as a single daily dose with food. Reductions in atazanavir concentrations may be avoided by temporal separation of REYATAZ and an H2‑receptor antagonist as follows: REYATAZ 300 mg with ritonavir 100 mg once daily with food, 2 hours before and at least 10 hours following the administration of an H2‑receptor antagonist.
Although not studied, similar results are expected with other H2‑receptor antagonists. The relevance of these data for HIV infected patients is unknown since the intragastric pH may be higher in this population. Therefore, the magnitude of this effect may be more pronounced. The mechanism of interaction is decreased solubility of atazanavir as intra-gastric pH increases with H2 blockers.
Without Tenofovir
For patients not taking tenofovir, if REYATAZ 300 mg/ritonavir 100 mg and H2‑receptor antagonists are co‑administered, a dose equivalent to famotidine 20 mg BID should not be exceeded. If a higher dose of an H2‑receptor antagonist is required (eg, famotidine 40 mg BID or equivalent) an increase of the REYATAZ/ritonavir dose from 300/100 mg to 400/100 mg can be considered.
In HIV‑infected patients with atazanavir/ritonavir at the recommended dose 300/100 mg QD
‑ famotidine 20 mg BID
↓0.82 (0.75, 1.01)
(0.75, 1.01)
↓0.80 (0.68, 0.93)
(0.68, 0.93)
↔0.99 (0.84, 1.18)
(0.84, 1.18)
‑ famotidine 40 mg BID
↓0.77 (0.68, 0.86)
(0.68, 0.86)
↓0.77 (0.67, 0.88)
(0.67, 0.88)
↓0.80 (0.69, 0.92)
(0.69, 0.92)
In Healthy volunteers with atazanavir/ritonavir at an increased dose of 400/100 mg QD
↔1.03 (0.86, 1.22)
(0.86, 1.22)
↔1.02 (0.87, 1.18)
(0.87, 1.18)
↓0.86 (0.68, 1.08)
(0.68, 1.08)
With Tenofovir 300 mg QD
In HIV‑infected patients with atazanavir/ritonavir at the recommended dose of 300/100 mg QD
For patients who are taking tenofovir, Co‑administration of REYATAZ/ritonavir in combination with tenofovir and an H2‑receptor antagonist should be avoided (see section 4.4). If the combination of REYATAZ/ritonavir with both tenofovir and an H2‑receptor antagonist is judged unavoidable, close clinical monitoring is recommended. A dose increase of REYATAZ to 400 mg with 100 mg of ritonavir may be considered but is still under evaluation.
Co‑administration of REYATAZ/ritonavir in combination with tenofovir and an H2‑receptor antagonist should be avoided (see section 4.4). If the combination of REYATAZ/ritonavir with both tenofovir and an H2‑receptor antagonist is judged unavoidable, close clinical monitoring is recommended. A dose increase of REYATAZ to 400 mg with 100 mg of ritonavir may be considered but is still under evaluation.
↓0.79* (0.66, 0.96)
(0.66, 0.96)
↓0.79* (0.64, 0.96)
(0.64, 0.96)
↓0.81* (0.63, 1.05)
(0.63, 1.05)
↓0.76* (0.64, 0.89)
(0.64, 0.89)
↓0.77* (0.64, 0.92)
(0.64, 0.92)
↓0.75* (0.53, 1.07)
(0.53, 1.07)
* When compared to atazanavir 300 mg QD with ritonavir 100 mg QD and tenofovir disoproxil fumarate 300 mg all as a single dose with food. When compared to atazanavir 300 mg with ritonavir 100 mg without tenofovir, atazanavir concentrations are expected to be additionally decreased by about 20%. The mechanism of interaction is decreased solubility of atazanavir as intra‑gastric pH increases with H2 blockers.
The mechanism of interaction is decreased solubility of atazanavir as intra‑gastric pH increases with H2 blockers.
Proton pump inhibitors
Omeprazole 40 mg QD (atazanavir 400 mg QD with ritonavir 100 mg QD)
atazanavir (am): 2 hr after omeprazole
↓0.39
(0.35, 0.45)
↓0.44
(0.38, 0.51)
↓0.35
(0.29, 0.41)
Co-administration of REYATAZ/ritonavir with proton pump inhibitors is not recommended. If the combination of REYATAZ/ritonavir with a proton pump inhibitor is judged unavoidable, close clinical monitoring is recommended in combination with an increase in the dose of REYATAZ to 400 mg with 100 mg of ritonavir; doses of proton pump inhibitors comparable to omeprazole 20 mg should not be exceeded (see section 4.4).
Omeprazole 20 mg QD (atazanavir 400 mg QD with ritonavir 100 mg QD) Omeprazole 20 mg QD (atazanavir 400 mg QD with ritonavir 100 mg QD)
Omeprazole 20 mg QD (atazanavir 400 mg QD with ritonavir 100 mg QD)
atazanavir (am): 1 hr after omeprazaoleomeprazole
↓0.70*
(0.57, 0.86)
↓0.69*
(0.58, 0.83)
(0.54, 0.88)
* When compared to atazanavir 300 mg QD with ritonavir 100 mg QD
The decrease in AUC, Cmax, and Cmin was not mitigated when an increased dose of REYATAZ/ritonavir (400/100 mg once daily) was temporally separated from omeprazole by 12 hours. Although not studied, similar results are expected with other proton pump inhibitors. This decrease in atazanavir exposure might negatively impact the efficacy of atazanavir. The mechanism of interaction is decreased solubility of atazanavir as intra‑gastric pH increases with proton pump inhibitors.
4.8 Undesirable effects
REYATAZ has been evaluated for safety in combination therapy with other antiretroviral medicinal products in controlled clinical trials in 1,806 adult patients receiving REYATAZ 400 mg once daily (1,151 patients, 52 weeks median duration and 152 weeks maximum duration) or REYATAZ 300 mg with ritonavir 100 mg once daily (655 patients, 48 96°weeks median duration and 101108 weeks maximum duration).
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Laboratory abnormalities
The most frequently reported laboratory abnormality in patients receiving regimens containing REYATAZ and one or more NRTIs was elevated total bilirubin reported predominantly as elevated indirect [unconjugated] bilirubin (8487% Grade 1, 2, 3, or 4). Grade 3 or 4 elevation of total bilirubin was noted in 35% (537% (6% Grade 4). Among experienced patients treated with REYATAZ 300 mg once daily with 100 mg ritonavir once daily for a median duration of 95 weeks, 53% had Grade 3‑4 total bilirubin elevations. Among naive patients treated with REYATAZ 300 mg once daily with 100 mg ritonavir once daily for a median duration of 4896 weeks, 3948% had Grade 3‑4 total bilirubin elevations (see section 4.4).
Other marked clinical laboratory abnormalities (Grade 3 or 4) reported in ≥ 2% of patients receiving regimens containing REYATAZ and one or more NRTIs included: elevated creatine kinase (7%), elevated alanine aminotransferase/serum glutamic‑pyruvic transaminase (ALT/SGPT) (45%), low neutrophils (45%), elevated aspartate aminotransferase/serum glutamic‑oxaloacetic transaminase (AST/SGOT) (3%), and elevated lipase (23%).
OneTwo percent of patients treated with REYATAZ experienced concurrent Grade 3‑4 ALT/AST and Grade 3‑4 total bilirubin elevations.
5.1 Pharmacodynamic properties
Antiviral activity in vitro: atazanavir exhibits anti‑HIV‑1 activity (EC50 of 2 to 5 nM) in the absence of human serum against a variety of laboratory(including all clades tested) and clinical anti‑HIV isolates. Atazanavir has‑2 activity against HIV‑1 Group M subtype viruses A, B, C, D, AE, AG, F, G, and J isolates in cell culture. Atazanavir has activity against HIV‑2 isolates (EC50 of 1.9 to 32 nM). Combinations of atazanavir with stavudine, didanosine, lamivudine, zidovudine, nelfinavir, indinavir, ritonavir, saquinavir, amprenavir, did not result in antagonistic anti‑HIV activity or enhanced cytotoxic effects at the highest concentrations used for antiviral evaluation. Resistance Antiretroviral treatment naive patients In clinical trials of antiretroviral treatment naive patients treated with unboosted atazanavir, the I50L substitution, sometimes in combination with an A71V change, is the signature resistance substitution for atazanavir. An atazanavir resistance phenotype is expressed in all recombinant viral clones containing the I50L substitution in a variety of genetic backgrounds. Resistance levels to atazanavir ranged from 3.5‑ to 29‑fold. There was no without evidence of phenotypic cross‑resistance between atazanavir and amprenavir, with the presence resistance to other PIs. In clinical trials of antiretroviral treatment naive patients treated with boosted atazanavir, the I50L and I50Vsubstitution did not emerge in any patient without baseline PI substitutions yielding selective resistance to atazanavir and amprenavir, respectively. The N88S substitution has been rarely observed in patients with virologic failure on atazanavir treatment(with or without ritonavir). While it may contribute to decreased susceptibility to atazanavir when it occurs with other protease substitutions, in clinical studies N88S by itself does not always lead to phenotypic resistance to atazanavir or have a consistent impact on clinical efficacy. Table 2. De novo substitutions in treatment naive patients failing therapy with atazanavir + ritonavir (Study 138, 96 weeks) Frequency de novo PI substitution (n=26)a >20% none 10-20% none a Number of patients with paired genotypes classified as virological failures (HIV RNA ≥ 400 copies/ml). The M184I/V substitution emerged in 5/26 REYATAZ/ritonavir and 7/26 lopinavir/ritonavir virologic failure patients, respectively. Antiretroviral treatment experienced patients In antiretroviral treatment experienced patients from Studies 009, 043, and 045, 100 isolates from patients designated as virological failures on therapy that included either atazanavir, atazanavir + ritonavir, or atazanavir + saquinavir were determined to have developed resistance to atazanavir. Of the 60 isolates from patients treated with either atazanavir or atazanavir + ritonavir, 18 (30%) displayed the I50L phenotype previously described in naive patients. Table 3. De novo substitutions in treatment experienced patients failing therapy with atazanavir + ritonavir (Study 045, 48 weeks) Frequency de novo PI substitution (n=35)a,b >20% M36, M46, I54, A71, V82 10-20% L10, I15, K20, V32, E35, S37, F53, I62, G73, I84, L90 a Number of patients with paired genotypes classified as virological failures (HIV RNA ≥ 400 copies/ml). b Ten patients had baseline phenotypic resistance to atazanavir + ritonavir (fold change [FC]>5.2). FC susceptibility in cell culture relative to the wild-type reference was assayed using PhenoSenseTM (Monogram Biosciences, South San Francisco, California, USA) None of the de novo substitutions (see Table 3) are specific to atazanavir and may reflect re-emergence of archived resistance on atazanavir + ritonavir in Study 045 treatment-experienced population. The resistance in antiretroviral treatment experienced patients mainly occurs by accumulation of the primary and secondarymajor and minor resistance substitutions described previously to be involved in protease inhibitor resistance. These isolates developed higher levels of resistance to the other protease inhibitors. Cross‑resistance in vitro in viruses resistant to other protease inhibitors Atazanavir susceptibility was evaluated in 943 clinical isolates from patients without prior atazanavir exposure and exhibited a wide array of genotypic and phenotypic patterns. In vitro, there was a clear trend toward decreased susceptibility to atazanavir as isolates exhibited high resistance levels to multiple protease inhibitors. In general, susceptibility to atazanavir was retained (83% of isolates displayed < 2.5 fold change in EC50) among isolates resistant to no more than 2 protease inhibitors. Eighteen percent of isolates had 4 or more of the following 6 substitutions considered critical substitutions for protease inhibitors: positions L10, M46, I54, V82, I84, and L90. These isolates expressed a median fold change in EC50 relative to wildtype of 12.0 for atazanavir. Therefore, viral isolates having at least 4 of these specific mutations would be considered resistant for atazanavir. Clinical results In antiretroviral naive patients Study 138 is an international randomised, open‑label, multicenter, prospective trial of 883 antiretroviral treatment naïve patients comparing REYATAZ/ritonavir (300 mg/100 mg once daily) to lopinavir/ritonavir (400 mg/100 mg twice daily), each in combination with fixed dose tenofovir/emtricitabine (300 mg/200 mg tablets once daily). The mean baseline CD4 cell count was 214 cells/mm3 (range: 2 to 810 cells/ mm3) and mean baseline plasma HIV‑1 RNA was 4.94 log10 copies/ml (range: 2.6 to 5.88 log10 copies/ml). The REYATAZ/ritonavir arm hasshowed similar (non-inferior) antiviral efficacy compared to the lopinavir/ritonavir arm, as assessed by the proportion of patients with HIV RNA < 50 copies/ml at week 48: 78% of patients on REYATAZ/ritonavir compared to 76% on lopinavir/ritonavir (difference estimate of ATV/RTV-LPV/RTV: 1.7% [95% CI, -3.8%, 7.1%] according to the Confirmed Virologic Response (CVR) Non-Completer = Failure (NC = F) definition of response. In a per protocol analysis which excluded non-completers (i.e. patients who discontinued before the week 48 HIV RNA assessment) and patients with major protocol deviations, the proportion of patients with HIV RNA < 50 copies/ml at week 48 was 86% (338/392) for REYATAZ/ritonavir and 89% (332/372) for lopinavir/ritonavir (difference estimate of ATV/RTV-LPV/RTV: -3% [95% CI, -7.6%, 1.5%]. (Table 2: 4). Analyses of data through 96 weeks of treatment demonstrated durability of antiviral activity (Table 4). Table 4: Efficacy Outcomes at Week 48 (in Study 138) for the CVR (NC=F) analysis a Parameter REYATAZ/ritonaviraritonavirb (300 mg/100 mg once daily) n=440 lopinavir/ritonavirbLopinavir/ritonavirc (400 mg/100 mg twice daily) n=443 HIV RNA <50 copies/ml, % c All patients 78 76 Baseline Characteristics HIV RNA <100,000 copies/ml 82 (n=217d) 81 (n=218) ≥100,000 copies/ml 74 (n=223) 72 (n=225) CD4 count <50 cells/mm3 78 (n=58) 63 (n=48) 50 to <100 cells/mm3 76 (n=45) 69 (n=29) 100 to <200 cells/mm3 75 (n=106) 78 (n=134) ≥200 cells/mm3 80 (n=222) 80 (n=228) Week 48 Week 96 Week 48 Week 96 HIV RNA <50 copies/ml, % All patientsd 78 74 76 68 Difference estimate [95% CI]d Week 48: 1.7% [-3.8%, 7.1%] Week 96: 6.1% [0.3%, 12.0%] Per protocol analysise 86 (n=392f) 91 (n=352) 89 (n=372) 89 (n=331) Difference estimatee [95% CI] Week 48: -3% [-7.6%, 1.5%] Week 96: 2.2% [-2.3%, 6.7%] HIV RNA <50 copies/ml, % by Baseline Characteristicd HIV RNA <100,000 copies/ml 82 (n=217) 75 (n=217) 81 (n=218) 70 (n=218) ≥100,000 copies/ml 74 (n=223) 74 (n=223) 72 (n=225) 66 (n=225) CD4 count <50 cells/mm3 78 (n=58) 78 (n=58) 63 (n=48) 58 (n=48) 50 to <100 cells/mm3 76 (n=45) 71 (n=45) 69 (n=29) 69 (n=29) 100 to <200 cells/mm3 75 (n=106) 71 (n=106) 78 (n=134) 70 (n=134) ≥ 200 cells/mm3 80 (n=222) 76 (n=222) 80 (n=228) 69 (n=228) HIV RNA Mean Change from Baseline, log10 copies/ml All patients -3.09 (n=397) -3.13 (n=379) All patients -3.09 (n=397) -3.21 (n=360) -3.13 (n=379) -3.19 (n=340) CD4 Mean Change from Baseline, cells/mm3 All patients 203 (n=370) 268 (n=336) 219 (n=363) 290 (n=317) CD4 Mean Change from Baseline, cells/mm3 by Baseline Characteristic HIV RNA <100,000 copies/ml 179 (n=183) 243 (n=163) 194 (n=183) 267 (n=152) ≥100,000 copies/ml 227 (n=187) 291 (n=173) 245 (n=180) 310 (n=165) a Mean baseline CD4 cell count was 214 cells/mm3 (range 2 to 810 cells/mm3) and mean baseline plasma HIV-1 RNA was 4.94 log10 copies/ml (range 2.6 to 5.88 log10 copies/ml) b REYATAZ/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily). c Lopinavir/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily). d Intent-to-treat analysis, with missing values considered as failures. e Per protocol analysis: Excluding non-completers and patients with major protocol deviations. f Number of patients evaluable. In antiretroviral experienced patients Study 045 is a randomised, multicenter trial comparing REYATAZ/ritonavir (300/100 mg once daily) and REYATAZ/saquinavir (400/1,200 mg once daily), to lopinavir + ritonavir (400/100 mg fixed dose combination twice daily), each in combination with tenofovir (see sections 4.5 and 4.8) and one NRTI, in patients with virologic failure on two or more prior regimens containing at least one PI, NRTI, and NNRTI. For randomised patients, the mean time of prior antiretroviral exposure was 138 weeks for PIs, 281 weeks for NRTIs, and 85 weeks for NNRTIs. At baseline, 34% of patients were receiving a PI and 60% were receiving an NNRTI. Fifteen of 120 (13%) patients in the REYATAZ + ritonavir treatment arm and 17 of 123 (14%) patients in the lopinavir + ritonavir arm had four or more of the PI substitutions L10, M46, I54, V82, I84, and L90. Thirty‑two percent of patients in the study had a viral strain with fewer than two NRTI substitutions. The primary endpoint was the time‑averaged difference in change from baseline in HIV RNA through 48 weeks (Table 5). Table 5: Efficacy Outcomes at Week 48a and at Week 96 (Study 045) Parameter ATV/RTVb (300 mg/ 100 mg once daily) n=120 LPV/RTVc (400 mg/ 100 mg twice daily) n=123 Time-averaged difference ATV/RTV-LPV/RTV [97.5% CId] Week 48 Week 96 Week 48 Week 96 Week 48 Week 96 HIV RNA Mean Change from Baseline, log10 copies/ml All patients -1.93 (n=90 e) -2.29 (n=64) -1.87 (n=99) -2.08 (n=65) 0.13 [‑0.12, 0.39] 0.14 [‑0.13, 0.41] HIV RNA <50 copies/ml, %f (responder/evaluable) All patients 36 (43/120) 32 (38/120) 42 (52/123 35 (41/118) NA NA HIV RNA <50 copies/ml by select baseline PI substitutions,f, g % (responder/evaluable) 0-2 44 (28/63) 41 (26/63) 56 (32/57) 48 (26/54) NA NA 3 18 (2/11) 9 (1/11) 38 (6/16) 33 (5/15) NA NA ≥4 27 (12/45) 24 (11/45) 28 (14/50) 20 (10/49) NA NA CD4 Mean Change from Baseline, cells/mm3 All patients 203 (n=370) 219 (n=363) Baseline Characteristics HIV RNA <100,000 copies/ml 179 (n=183) 194 (n=183) ≥100,000 copies/ml 227 (n=187) 245 (n=180) All patients 110 (n=83) 122 (n=60) 121 (n=94) 154 (n=60) NA NA a REYATAZ/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily). b Lopinavir/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily). c Intent-to-treat analysis, with missing values considered as failures. d Number of patients evaluable. In antiretroviral experienced patients Study 045 is a randomised, multicenter trial comparing REYATAZ (300 mg once daily) with ritonavir (100 mg once daily) to REYATAZ (400 mg once daily) with saquinavir soft gelatine capsules (1,200 mg once daily), and to lopinavir + ritonavir (400/100 mg fixed dose combination twice daily), each in combination with tenofovir (see sections 4.5 and 4.8) and one NRTI, in 347 (of 358 randomised) patients with virologic failure on two or more prior regimens containing at least one PI, NRTI, and NNRTI. For randomised patients, the mean time of prior antiretroviral exposure was 138 weeks for PIs, 281 weeks for NRTIs, and 85 weeks for NNRTIs. At baseline, 34% of patients were receiving a PI and 60% were receiving an NNRTI. Fifteen of 120 (13%) patients in the REYATAZ + ritonavir treatment arm and 17 of 123 (14%) patients in the lopinavir + ritonavir arm had four or more of the PI substitutions L10, M46, I54, V82, I84, and L90. Thirty‑two percent of patients in the study had a viral strain with fewer than two NRTI substitutions. The mean baseline CD4 cell count was 337 cells/mm3 (range: 14 to 1,543 cells/mm3) and the mean baseline plasma HIV‑1 RNA level was 4.4 log10 copies/ml (range: 2.6 to 5.88 log10 copies/ml). The population included in this study was moderately pretreated. The primary endpoint was the time‑averaged difference in change from baseline in HIV RNA through 48 weeks. Through 48 weeks of treatment, the decreases from baseline in HIV RNA levels (primary endpoint) were 1.93 log10 copies/ml for REYATAZ + ritonavir and 1.87 log10 copies/ml for lopinavir + ritonavir. REYATAZ + ritonavir was similar (non‑inferior) to lopinavir + ritonavir on this efficacy measure (time‑averaged difference of 0.13, 97.5% confidenceb ATV/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily). c LPV/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily). d Confidence interval [‑0.12, 0.39]).. e Number of patients evaluable. f Intent-to-treat analysis, with missing values considered as failures. Responders on LPV/RTV who completed treatment before Week 96 are excluded from Week 96 analysis. The proportion of patients with HIV RNA < 400 copies/ml were 53% and 43% for ATV/RTV and 54% and 46% for LPV/RTV at weeks 48 and 96 respectively. g Select substitutions include any change at positions L10, K20, L24, V32, L33, M36, M46, G48, I50, I54, L63, A71, G73, V82, I84, and L90 (0-2, 3, 4 or more) at baseline. NA = not applicable. Through 48 weeks of treatment, the mean changes from baseline in HIV RNA levels for REYATAZ + ritonavir and lopinavir + ritonavir were similar (non‑inferior). Consistent results were obtained with the last observation carried forward method of analysis (time‑averaged difference of 0.11, 97.5% confidence interval [‑0.15, 0.36]). The proportions of patients with HIV RNA < 400 copies/ml in the REYATAZ + ritonavir arm and the lopinavir + ritonavir arm were 53% and 54%, respectively, by intent‑to‑treat analysis, with missing values considered as failures. The proportions of patients with HIV RNA < 50 copies/ml in the REYATAZ + ritonavir arm and the lopinavir + ritonavir arm were 36% and 42%, respectively. By as‑treated analysis, excluding missing values, the proportions of patients with HIV RNA < 400 copies/ml (< 50 copies/ml) in the REYATAZ + ritonavir arm and the lopinavir + ritonavir arm were 55% (40%) and 56% (46%), respectively. The mean increases from baseline in CD4 cell count were 110 cells/mm3 and 121 cells/mm3 in the REYATAZ + ritonavir and lopinavir + ritonavir arms, respectively. Analyses of data through 96 Through 96 weeks of treatment demonstrated durability of antiviral activity. Mean, mean HIV RNA changes from baseline at Week 96 (‑2.29 log10 copies/ml for REYATAZ + ritonavir and ‑2.08 log10 copies/ml for lopinavir + ritonavir, time‑averaged difference of 0.14, 97.5% confidence interval [‑0.13, 0.41]) met criteria for non‑inferiority based on observed cases. Consistent results were obtained with the last observation carried forward method of analysis. The proportions of patients with HIV RNA <400 copies/ml (<50 copies/ml) for REYATAZ + ritonavir were 43% (32%) and for lopinavir + ritonavir were 46% (35%). Patients completing treatment while in response after 48 weeks were censored. By as‑treated analysis, excluding missing values, the proportions of patients with HIV RNA <400 copies/ml (<50 copies/ml) for REYATAZ + ritonavir were 84% (72%) and for lopinavir + ritonavir were 82% (72%). It is important to note that at time of the 96‑week analysis, 48 % of patients overall remained on study. Through 48 weeks of treatment, two types of analyses were performed based on baseline genotypic mutations. The first consisted in assessing the HIV RNA change from baseline in the subgroup of patients with < or ≥ of 4 of the following set of mutations: 10, 20, 24, 32, 33, 36, 46, 48, 50, 54, 63, 71, 73, 82, 84 and 90. The second consisted in assessing the HIV RNA change from baseline in the subgroup of patients with < or ≥ of 4 of the following more specific set of mutations: 10, 46, 54, 82, 84, 90. In the analysis performed for patients with ≥ 4 protease gene mutations among the following set of mutations 10, 20, 24, 32, 33, 36, 46, 48, 50, 54, 63, 71, 73, 82, 84 and 90, the results significantly favoured the lopinavir + ritonavir arm. There were too few patients with ≥ 4 of the second more specific set of mutations (i.e. 10, 46, 54, 82, 84, 90) to assess the comparability of the REYATAZ + ritonavir and lopinavir + ritonavir regimens, but reduced virologic activity may be anticipated among patients with this resistance profile. REYATAZ + saquinavir was shown to be inferior to lopinavir + ritonavir. 5.2 Pharmacokinetic properties Special populations Impaired renal function: in healthy subjects, the renal elimination of unchanged atazanavir was approximately 7% of the administered dose. There are no pharmacokinetic data available on for REYATAZ with ritonavir in patients with renal insufficiency (see section 4.2); however, the impact of renal impairment on atazanavir elimination is anticipated to be minimal.. REYATAZ (without ritonavir) has been studied in adult patients with severe renal impairment (n=20), including those on haemodialysis, at multiple doses of 400 mg once daily. Although this study presented some limitations (i.e., unbound drug concentrations not studied), results suggested that the atazanavir pharmacokinetic parameters were decreased by 30% to 50% in patients undergoing haemodialysis compared to patients with normal renal function. The mechanism of this decrease is unknown. (See sections 4.2 and 4.4.) 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 02 March 2004 Date of latest renewal : 09 February: 02 March 2009 10. DATE OF REVISION OF THE TEXT 9th FebruaryJuly 2009 Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/http://www.emea.europa.eu
Resistance Antiretroviral treatment naive patients In clinical trials of antiretroviral treatment naive patients treated with unboosted atazanavir, the I50L substitution, sometimes in combination with an A71V change, is the signature resistance substitution for atazanavir. An atazanavir resistance phenotype is expressed in all recombinant viral clones containing the I50L substitution in a variety of genetic backgrounds. Resistance levels to atazanavir ranged from 3.5‑ to 29‑fold. There was no without evidence of phenotypic cross‑resistance between atazanavir and amprenavir, with the presence resistance to other PIs. In clinical trials of antiretroviral treatment naive patients treated with boosted atazanavir, the I50L and I50Vsubstitution did not emerge in any patient without baseline PI substitutions yielding selective resistance to atazanavir and amprenavir, respectively. The N88S substitution has been rarely observed in patients with virologic failure on atazanavir treatment(with or without ritonavir). While it may contribute to decreased susceptibility to atazanavir when it occurs with other protease substitutions, in clinical studies N88S by itself does not always lead to phenotypic resistance to atazanavir or have a consistent impact on clinical efficacy. Table 2. De novo substitutions in treatment naive patients failing therapy with atazanavir + ritonavir (Study 138, 96 weeks) Frequency de novo PI substitution (n=26)a >20% none 10-20% none a Number of patients with paired genotypes classified as virological failures (HIV RNA ≥ 400 copies/ml). The M184I/V substitution emerged in 5/26 REYATAZ/ritonavir and 7/26 lopinavir/ritonavir virologic failure patients, respectively. Antiretroviral treatment experienced patients In antiretroviral treatment experienced patients from Studies 009, 043, and 045, 100 isolates from patients designated as virological failures on therapy that included either atazanavir, atazanavir + ritonavir, or atazanavir + saquinavir were determined to have developed resistance to atazanavir. Of the 60 isolates from patients treated with either atazanavir or atazanavir + ritonavir, 18 (30%) displayed the I50L phenotype previously described in naive patients. Table 3. De novo substitutions in treatment experienced patients failing therapy with atazanavir + ritonavir (Study 045, 48 weeks) Frequency de novo PI substitution (n=35)a,b >20% M36, M46, I54, A71, V82 10-20% L10, I15, K20, V32, E35, S37, F53, I62, G73, I84, L90 a Number of patients with paired genotypes classified as virological failures (HIV RNA ≥ 400 copies/ml). b Ten patients had baseline phenotypic resistance to atazanavir + ritonavir (fold change [FC]>5.2). FC susceptibility in cell culture relative to the wild-type reference was assayed using PhenoSenseTM (Monogram Biosciences, South San Francisco, California, USA) None of the de novo substitutions (see Table 3) are specific to atazanavir and may reflect re-emergence of archived resistance on atazanavir + ritonavir in Study 045 treatment-experienced population. The resistance in antiretroviral treatment experienced patients mainly occurs by accumulation of the primary and secondarymajor and minor resistance substitutions described previously to be involved in protease inhibitor resistance. These isolates developed higher levels of resistance to the other protease inhibitors. Cross‑resistance in vitro in viruses resistant to other protease inhibitors Atazanavir susceptibility was evaluated in 943 clinical isolates from patients without prior atazanavir exposure and exhibited a wide array of genotypic and phenotypic patterns. In vitro, there was a clear trend toward decreased susceptibility to atazanavir as isolates exhibited high resistance levels to multiple protease inhibitors. In general, susceptibility to atazanavir was retained (83% of isolates displayed < 2.5 fold change in EC50) among isolates resistant to no more than 2 protease inhibitors. Eighteen percent of isolates had 4 or more of the following 6 substitutions considered critical substitutions for protease inhibitors: positions L10, M46, I54, V82, I84, and L90. These isolates expressed a median fold change in EC50 relative to wildtype of 12.0 for atazanavir. Therefore, viral isolates having at least 4 of these specific mutations would be considered resistant for atazanavir. Clinical results In antiretroviral naive patients Study 138 is an international randomised, open‑label, multicenter, prospective trial of 883 antiretroviral treatment naïve patients comparing REYATAZ/ritonavir (300 mg/100 mg once daily) to lopinavir/ritonavir (400 mg/100 mg twice daily), each in combination with fixed dose tenofovir/emtricitabine (300 mg/200 mg tablets once daily). The mean baseline CD4 cell count was 214 cells/mm3 (range: 2 to 810 cells/ mm3) and mean baseline plasma HIV‑1 RNA was 4.94 log10 copies/ml (range: 2.6 to 5.88 log10 copies/ml). The REYATAZ/ritonavir arm hasshowed similar (non-inferior) antiviral efficacy compared to the lopinavir/ritonavir arm, as assessed by the proportion of patients with HIV RNA < 50 copies/ml at week 48: 78% of patients on REYATAZ/ritonavir compared to 76% on lopinavir/ritonavir (difference estimate of ATV/RTV-LPV/RTV: 1.7% [95% CI, -3.8%, 7.1%] according to the Confirmed Virologic Response (CVR) Non-Completer = Failure (NC = F) definition of response. In a per protocol analysis which excluded non-completers (i.e. patients who discontinued before the week 48 HIV RNA assessment) and patients with major protocol deviations, the proportion of patients with HIV RNA < 50 copies/ml at week 48 was 86% (338/392) for REYATAZ/ritonavir and 89% (332/372) for lopinavir/ritonavir (difference estimate of ATV/RTV-LPV/RTV: -3% [95% CI, -7.6%, 1.5%]. (Table 2: 4). Analyses of data through 96 weeks of treatment demonstrated durability of antiviral activity (Table 4). Table 4: Efficacy Outcomes at Week 48 (in Study 138) for the CVR (NC=F) analysis a Parameter REYATAZ/ritonaviraritonavirb (300 mg/100 mg once daily) n=440 lopinavir/ritonavirbLopinavir/ritonavirc (400 mg/100 mg twice daily) n=443 HIV RNA <50 copies/ml, % c All patients 78 76 Baseline Characteristics HIV RNA <100,000 copies/ml 82 (n=217d) 81 (n=218) ≥100,000 copies/ml 74 (n=223) 72 (n=225) CD4 count <50 cells/mm3 78 (n=58) 63 (n=48) 50 to <100 cells/mm3 76 (n=45) 69 (n=29) 100 to <200 cells/mm3 75 (n=106) 78 (n=134) ≥200 cells/mm3 80 (n=222) 80 (n=228) Week 48 Week 96 Week 48 Week 96 HIV RNA <50 copies/ml, % All patientsd 78 74 76 68 Difference estimate [95% CI]d Week 48: 1.7% [-3.8%, 7.1%] Week 96: 6.1% [0.3%, 12.0%] Per protocol analysise 86 (n=392f) 91 (n=352) 89 (n=372) 89 (n=331) Difference estimatee [95% CI] Week 48: -3% [-7.6%, 1.5%] Week 96: 2.2% [-2.3%, 6.7%] HIV RNA <50 copies/ml, % by Baseline Characteristicd HIV RNA <100,000 copies/ml 82 (n=217) 75 (n=217) 81 (n=218) 70 (n=218) ≥100,000 copies/ml 74 (n=223) 74 (n=223) 72 (n=225) 66 (n=225) CD4 count <50 cells/mm3 78 (n=58) 78 (n=58) 63 (n=48) 58 (n=48) 50 to <100 cells/mm3 76 (n=45) 71 (n=45) 69 (n=29) 69 (n=29) 100 to <200 cells/mm3 75 (n=106) 71 (n=106) 78 (n=134) 70 (n=134) ≥ 200 cells/mm3 80 (n=222) 76 (n=222) 80 (n=228) 69 (n=228) HIV RNA Mean Change from Baseline, log10 copies/ml All patients -3.09 (n=397) -3.13 (n=379) All patients -3.09 (n=397) -3.21 (n=360) -3.13 (n=379) -3.19 (n=340) CD4 Mean Change from Baseline, cells/mm3 All patients 203 (n=370) 268 (n=336) 219 (n=363) 290 (n=317) CD4 Mean Change from Baseline, cells/mm3 by Baseline Characteristic HIV RNA <100,000 copies/ml 179 (n=183) 243 (n=163) 194 (n=183) 267 (n=152) ≥100,000 copies/ml 227 (n=187) 291 (n=173) 245 (n=180) 310 (n=165) a Mean baseline CD4 cell count was 214 cells/mm3 (range 2 to 810 cells/mm3) and mean baseline plasma HIV-1 RNA was 4.94 log10 copies/ml (range 2.6 to 5.88 log10 copies/ml) b REYATAZ/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily). c Lopinavir/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily). d Intent-to-treat analysis, with missing values considered as failures. e Per protocol analysis: Excluding non-completers and patients with major protocol deviations. f Number of patients evaluable. In antiretroviral experienced patients Study 045 is a randomised, multicenter trial comparing REYATAZ/ritonavir (300/100 mg once daily) and REYATAZ/saquinavir (400/1,200 mg once daily), to lopinavir + ritonavir (400/100 mg fixed dose combination twice daily), each in combination with tenofovir (see sections 4.5 and 4.8) and one NRTI, in patients with virologic failure on two or more prior regimens containing at least one PI, NRTI, and NNRTI. For randomised patients, the mean time of prior antiretroviral exposure was 138 weeks for PIs, 281 weeks for NRTIs, and 85 weeks for NNRTIs. At baseline, 34% of patients were receiving a PI and 60% were receiving an NNRTI. Fifteen of 120 (13%) patients in the REYATAZ + ritonavir treatment arm and 17 of 123 (14%) patients in the lopinavir + ritonavir arm had four or more of the PI substitutions L10, M46, I54, V82, I84, and L90. Thirty‑two percent of patients in the study had a viral strain with fewer than two NRTI substitutions. The primary endpoint was the time‑averaged difference in change from baseline in HIV RNA through 48 weeks (Table 5). Table 5: Efficacy Outcomes at Week 48a and at Week 96 (Study 045) Parameter ATV/RTVb (300 mg/ 100 mg once daily) n=120 LPV/RTVc (400 mg/ 100 mg twice daily) n=123 Time-averaged difference ATV/RTV-LPV/RTV [97.5% CId] Week 48 Week 96 Week 48 Week 96 Week 48 Week 96 HIV RNA Mean Change from Baseline, log10 copies/ml All patients -1.93 (n=90 e) -2.29 (n=64) -1.87 (n=99) -2.08 (n=65) 0.13 [‑0.12, 0.39] 0.14 [‑0.13, 0.41] HIV RNA <50 copies/ml, %f (responder/evaluable) All patients 36 (43/120) 32 (38/120) 42 (52/123 35 (41/118) NA NA HIV RNA <50 copies/ml by select baseline PI substitutions,f, g % (responder/evaluable) 0-2 44 (28/63) 41 (26/63) 56 (32/57) 48 (26/54) NA NA 3 18 (2/11) 9 (1/11) 38 (6/16) 33 (5/15) NA NA ≥4 27 (12/45) 24 (11/45) 28 (14/50) 20 (10/49) NA NA CD4 Mean Change from Baseline, cells/mm3 All patients 203 (n=370) 219 (n=363) Baseline Characteristics HIV RNA <100,000 copies/ml 179 (n=183) 194 (n=183) ≥100,000 copies/ml 227 (n=187) 245 (n=180) All patients 110 (n=83) 122 (n=60) 121 (n=94) 154 (n=60) NA NA a REYATAZ/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily). b Lopinavir/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily). c Intent-to-treat analysis, with missing values considered as failures. d Number of patients evaluable. In antiretroviral experienced patients Study 045 is a randomised, multicenter trial comparing REYATAZ (300 mg once daily) with ritonavir (100 mg once daily) to REYATAZ (400 mg once daily) with saquinavir soft gelatine capsules (1,200 mg once daily), and to lopinavir + ritonavir (400/100 mg fixed dose combination twice daily), each in combination with tenofovir (see sections 4.5 and 4.8) and one NRTI, in 347 (of 358 randomised) patients with virologic failure on two or more prior regimens containing at least one PI, NRTI, and NNRTI. For randomised patients, the mean time of prior antiretroviral exposure was 138 weeks for PIs, 281 weeks for NRTIs, and 85 weeks for NNRTIs. At baseline, 34% of patients were receiving a PI and 60% were receiving an NNRTI. Fifteen of 120 (13%) patients in the REYATAZ + ritonavir treatment arm and 17 of 123 (14%) patients in the lopinavir + ritonavir arm had four or more of the PI substitutions L10, M46, I54, V82, I84, and L90. Thirty‑two percent of patients in the study had a viral strain with fewer than two NRTI substitutions. The mean baseline CD4 cell count was 337 cells/mm3 (range: 14 to 1,543 cells/mm3) and the mean baseline plasma HIV‑1 RNA level was 4.4 log10 copies/ml (range: 2.6 to 5.88 log10 copies/ml). The population included in this study was moderately pretreated. The primary endpoint was the time‑averaged difference in change from baseline in HIV RNA through 48 weeks. Through 48 weeks of treatment, the decreases from baseline in HIV RNA levels (primary endpoint) were 1.93 log10 copies/ml for REYATAZ + ritonavir and 1.87 log10 copies/ml for lopinavir + ritonavir. REYATAZ + ritonavir was similar (non‑inferior) to lopinavir + ritonavir on this efficacy measure (time‑averaged difference of 0.13, 97.5% confidenceb ATV/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily). c LPV/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily). d Confidence interval [‑0.12, 0.39]).. e Number of patients evaluable. f Intent-to-treat analysis, with missing values considered as failures. Responders on LPV/RTV who completed treatment before Week 96 are excluded from Week 96 analysis. The proportion of patients with HIV RNA < 400 copies/ml were 53% and 43% for ATV/RTV and 54% and 46% for LPV/RTV at weeks 48 and 96 respectively. g Select substitutions include any change at positions L10, K20, L24, V32, L33, M36, M46, G48, I50, I54, L63, A71, G73, V82, I84, and L90 (0-2, 3, 4 or more) at baseline. NA = not applicable. Through 48 weeks of treatment, the mean changes from baseline in HIV RNA levels for REYATAZ + ritonavir and lopinavir + ritonavir were similar (non‑inferior). Consistent results were obtained with the last observation carried forward method of analysis (time‑averaged difference of 0.11, 97.5% confidence interval [‑0.15, 0.36]). The proportions of patients with HIV RNA < 400 copies/ml in the REYATAZ + ritonavir arm and the lopinavir + ritonavir arm were 53% and 54%, respectively, by intent‑to‑treat analysis, with missing values considered as failures. The proportions of patients with HIV RNA < 50 copies/ml in the REYATAZ + ritonavir arm and the lopinavir + ritonavir arm were 36% and 42%, respectively. By as‑treated analysis, excluding missing values, the proportions of patients with HIV RNA < 400 copies/ml (< 50 copies/ml) in the REYATAZ + ritonavir arm and the lopinavir + ritonavir arm were 55% (40%) and 56% (46%), respectively. The mean increases from baseline in CD4 cell count were 110 cells/mm3 and 121 cells/mm3 in the REYATAZ + ritonavir and lopinavir + ritonavir arms, respectively. Analyses of data through 96 Through 96 weeks of treatment demonstrated durability of antiviral activity. Mean, mean HIV RNA changes from baseline at Week 96 (‑2.29 log10 copies/ml for REYATAZ + ritonavir and ‑2.08 log10 copies/ml for lopinavir + ritonavir, time‑averaged difference of 0.14, 97.5% confidence interval [‑0.13, 0.41]) met criteria for non‑inferiority based on observed cases. Consistent results were obtained with the last observation carried forward method of analysis. The proportions of patients with HIV RNA <400 copies/ml (<50 copies/ml) for REYATAZ + ritonavir were 43% (32%) and for lopinavir + ritonavir were 46% (35%). Patients completing treatment while in response after 48 weeks were censored. By as‑treated analysis, excluding missing values, the proportions of patients with HIV RNA <400 copies/ml (<50 copies/ml) for REYATAZ + ritonavir were 84% (72%) and for lopinavir + ritonavir were 82% (72%). It is important to note that at time of the 96‑week analysis, 48 % of patients overall remained on study. Through 48 weeks of treatment, two types of analyses were performed based on baseline genotypic mutations. The first consisted in assessing the HIV RNA change from baseline in the subgroup of patients with < or ≥ of 4 of the following set of mutations: 10, 20, 24, 32, 33, 36, 46, 48, 50, 54, 63, 71, 73, 82, 84 and 90. The second consisted in assessing the HIV RNA change from baseline in the subgroup of patients with < or ≥ of 4 of the following more specific set of mutations: 10, 46, 54, 82, 84, 90. In the analysis performed for patients with ≥ 4 protease gene mutations among the following set of mutations 10, 20, 24, 32, 33, 36, 46, 48, 50, 54, 63, 71, 73, 82, 84 and 90, the results significantly favoured the lopinavir + ritonavir arm. There were too few patients with ≥ 4 of the second more specific set of mutations (i.e. 10, 46, 54, 82, 84, 90) to assess the comparability of the REYATAZ + ritonavir and lopinavir + ritonavir regimens, but reduced virologic activity may be anticipated among patients with this resistance profile. REYATAZ + saquinavir was shown to be inferior to lopinavir + ritonavir. 5.2 Pharmacokinetic properties Special populations Impaired renal function: in healthy subjects, the renal elimination of unchanged atazanavir was approximately 7% of the administered dose. There are no pharmacokinetic data available on for REYATAZ with ritonavir in patients with renal insufficiency (see section 4.2); however, the impact of renal impairment on atazanavir elimination is anticipated to be minimal.. REYATAZ (without ritonavir) has been studied in adult patients with severe renal impairment (n=20), including those on haemodialysis, at multiple doses of 400 mg once daily. Although this study presented some limitations (i.e., unbound drug concentrations not studied), results suggested that the atazanavir pharmacokinetic parameters were decreased by 30% to 50% in patients undergoing haemodialysis compared to patients with normal renal function. The mechanism of this decrease is unknown. (See sections 4.2 and 4.4.) 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 02 March 2004 Date of latest renewal : 09 February: 02 March 2009 10. DATE OF REVISION OF THE TEXT 9th FebruaryJuly 2009 Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/http://www.emea.europa.eu
Resistance
Antiretroviral treatment naive patients
In clinical trials of antiretroviral treatment naive patients treated with unboosted atazanavir, the I50L substitution, sometimes in combination with an A71V change, is the signature resistance substitution for atazanavir. An atazanavir resistance phenotype is expressed in all recombinant viral clones containing the I50L substitution in a variety of genetic backgrounds. Resistance levels to atazanavir ranged from 3.5‑ to 29‑fold. There was no without evidence of phenotypic cross‑resistance between atazanavir and amprenavir, with the presence resistance to other PIs. In clinical trials of antiretroviral treatment naive patients treated with boosted atazanavir, the I50L and I50Vsubstitution did not emerge in any patient without baseline PI substitutions yielding selective resistance to atazanavir and amprenavir, respectively. The N88S substitution has been rarely observed in patients with virologic failure on atazanavir treatment(with or without ritonavir). While it may contribute to decreased susceptibility to atazanavir when it occurs with other protease substitutions, in clinical studies N88S by itself does not always lead to phenotypic resistance to atazanavir or have a consistent impact on clinical efficacy.
Table 2. De novo substitutions in treatment naive patients failing therapy with atazanavir + ritonavir (Study 138, 96 weeks)
Frequency
de novo PI substitution (n=26)a
>20%
none
10-20%
a Number of patients with paired genotypes classified as virological failures (HIV RNA ≥ 400 copies/ml).
The M184I/V substitution emerged in 5/26 REYATAZ/ritonavir and 7/26 lopinavir/ritonavir virologic failure patients, respectively.
Antiretroviral treatment experienced patients
In antiretroviral treatment experienced patients from Studies 009, 043, and 045, 100 isolates from patients designated as virological failures on therapy that included either atazanavir, atazanavir + ritonavir, or atazanavir + saquinavir were determined to have developed resistance to atazanavir. Of the 60 isolates from patients treated with either atazanavir or atazanavir + ritonavir, 18 (30%) displayed the I50L phenotype previously described in naive patients.
Table 3. De novo substitutions in treatment experienced patients failing therapy with atazanavir + ritonavir (Study 045, 48 weeks)
de novo PI substitution (n=35)a,b
M36, M46, I54, A71, V82
L10, I15, K20, V32, E35, S37, F53, I62, G73, I84, L90
a Number of patients with paired genotypes classified as virological failures (HIV RNA ≥ 400 copies/ml). b Ten patients had baseline phenotypic resistance to atazanavir + ritonavir (fold change [FC]>5.2). FC susceptibility in cell culture relative to the wild-type reference was assayed using PhenoSenseTM (Monogram Biosciences, South San Francisco, California, USA)
b Ten patients had baseline phenotypic resistance to atazanavir + ritonavir (fold change [FC]>5.2). FC susceptibility in cell culture relative to the wild-type reference was assayed using PhenoSenseTM (Monogram Biosciences, South San Francisco, California, USA)
None of the de novo substitutions (see Table 3) are specific to atazanavir and may reflect re-emergence of archived resistance on atazanavir + ritonavir in Study 045 treatment-experienced population.
The resistance in antiretroviral treatment experienced patients mainly occurs by accumulation of the primary and secondarymajor and minor resistance substitutions described previously to be involved in protease inhibitor resistance. These isolates developed higher levels of resistance to the other protease inhibitors.
Cross‑resistance in vitro in viruses resistant to other protease inhibitors
Atazanavir susceptibility was evaluated in 943 clinical isolates from patients without prior atazanavir exposure and exhibited a wide array of genotypic and phenotypic patterns. In vitro, there was a clear trend toward decreased susceptibility to atazanavir as isolates exhibited high resistance levels to multiple protease inhibitors. In general, susceptibility to atazanavir was retained (83% of isolates displayed < 2.5 fold change in EC50) among isolates resistant to no more than 2 protease inhibitors.
Eighteen percent of isolates had 4 or more of the following 6 substitutions considered critical substitutions for protease inhibitors: positions L10, M46, I54, V82, I84, and L90. These isolates expressed a median fold change in EC50 relative to wildtype of 12.0 for atazanavir. Therefore, viral isolates having at least 4 of these specific mutations would be considered resistant for atazanavir.
Clinical results
In antiretroviral naive patients
Study 138 is an international randomised, open‑label, multicenter, prospective trial of 883 antiretroviral treatment naïve patients comparing REYATAZ/ritonavir (300 mg/100 mg once daily) to lopinavir/ritonavir (400 mg/100 mg twice daily), each in combination with fixed dose tenofovir/emtricitabine (300 mg/200 mg tablets once daily). The mean baseline CD4 cell count was 214 cells/mm3 (range: 2 to 810 cells/ mm3) and mean baseline plasma HIV‑1 RNA was 4.94 log10 copies/ml (range: 2.6 to 5.88 log10 copies/ml). The REYATAZ/ritonavir arm hasshowed similar (non-inferior) antiviral efficacy compared to the lopinavir/ritonavir arm, as assessed by the proportion of patients with HIV RNA < 50 copies/ml at week 48: 78% of patients on REYATAZ/ritonavir compared to 76% on lopinavir/ritonavir (difference estimate of ATV/RTV-LPV/RTV: 1.7% [95% CI, -3.8%, 7.1%] according to the Confirmed Virologic Response (CVR) Non-Completer = Failure (NC = F) definition of response. In a per protocol analysis which excluded non-completers (i.e. patients who discontinued before the week 48 HIV RNA assessment) and patients with major protocol deviations, the proportion of patients with HIV RNA < 50 copies/ml at week 48 was 86% (338/392) for REYATAZ/ritonavir and 89% (332/372) for lopinavir/ritonavir (difference estimate of ATV/RTV-LPV/RTV: -3% [95% CI, -7.6%, 1.5%]. (Table 2: 4). Analyses of data through 96 weeks of treatment demonstrated durability of antiviral activity (Table 4). Table 4: Efficacy Outcomes at Week 48 (in Study 138) for the CVR (NC=F) analysis a Parameter REYATAZ/ritonaviraritonavirb (300 mg/100 mg once daily) n=440 lopinavir/ritonavirbLopinavir/ritonavirc (400 mg/100 mg twice daily) n=443 HIV RNA <50 copies/ml, % c All patients 78 76 Baseline Characteristics HIV RNA <100,000 copies/ml 82 (n=217d) 81 (n=218) ≥100,000 copies/ml 74 (n=223) 72 (n=225) CD4 count <50 cells/mm3 78 (n=58) 63 (n=48) 50 to <100 cells/mm3 76 (n=45) 69 (n=29) 100 to <200 cells/mm3 75 (n=106) 78 (n=134) ≥200 cells/mm3 80 (n=222) 80 (n=228) Week 48 Week 96 Week 48 Week 96 HIV RNA <50 copies/ml, % All patientsd 78 74 76 68 Difference estimate [95% CI]d Week 48: 1.7% [-3.8%, 7.1%] Week 96: 6.1% [0.3%, 12.0%] Per protocol analysise 86 (n=392f) 91 (n=352) 89 (n=372) 89 (n=331) Difference estimatee [95% CI] Week 48: -3% [-7.6%, 1.5%] Week 96: 2.2% [-2.3%, 6.7%] HIV RNA <50 copies/ml, % by Baseline Characteristicd HIV RNA <100,000 copies/ml 82 (n=217) 75 (n=217) 81 (n=218) 70 (n=218) ≥100,000 copies/ml 74 (n=223) 74 (n=223) 72 (n=225) 66 (n=225) CD4 count <50 cells/mm3 78 (n=58) 78 (n=58) 63 (n=48) 58 (n=48) 50 to <100 cells/mm3 76 (n=45) 71 (n=45) 69 (n=29) 69 (n=29) 100 to <200 cells/mm3 75 (n=106) 71 (n=106) 78 (n=134) 70 (n=134) ≥ 200 cells/mm3 80 (n=222) 76 (n=222) 80 (n=228) 69 (n=228) HIV RNA Mean Change from Baseline, log10 copies/ml All patients -3.09 (n=397) -3.13 (n=379) All patients -3.09 (n=397) -3.21 (n=360) -3.13 (n=379) -3.19 (n=340) CD4 Mean Change from Baseline, cells/mm3 All patients 203 (n=370) 268 (n=336) 219 (n=363) 290 (n=317) CD4 Mean Change from Baseline, cells/mm3 by Baseline Characteristic HIV RNA <100,000 copies/ml 179 (n=183) 243 (n=163) 194 (n=183) 267 (n=152) ≥100,000 copies/ml 227 (n=187) 291 (n=173) 245 (n=180) 310 (n=165) a Mean baseline CD4 cell count was 214 cells/mm3 (range 2 to 810 cells/mm3) and mean baseline plasma HIV-1 RNA was 4.94 log10 copies/ml (range 2.6 to 5.88 log10 copies/ml) b REYATAZ/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily). c Lopinavir/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily). d Intent-to-treat analysis, with missing values considered as failures. e Per protocol analysis: Excluding non-completers and patients with major protocol deviations. f Number of patients evaluable. In antiretroviral experienced patients Study 045 is a randomised, multicenter trial comparing REYATAZ/ritonavir (300/100 mg once daily) and REYATAZ/saquinavir (400/1,200 mg once daily), to lopinavir + ritonavir (400/100 mg fixed dose combination twice daily), each in combination with tenofovir (see sections 4.5 and 4.8) and one NRTI, in patients with virologic failure on two or more prior regimens containing at least one PI, NRTI, and NNRTI. For randomised patients, the mean time of prior antiretroviral exposure was 138 weeks for PIs, 281 weeks for NRTIs, and 85 weeks for NNRTIs. At baseline, 34% of patients were receiving a PI and 60% were receiving an NNRTI. Fifteen of 120 (13%) patients in the REYATAZ + ritonavir treatment arm and 17 of 123 (14%) patients in the lopinavir + ritonavir arm had four or more of the PI substitutions L10, M46, I54, V82, I84, and L90. Thirty‑two percent of patients in the study had a viral strain with fewer than two NRTI substitutions. The primary endpoint was the time‑averaged difference in change from baseline in HIV RNA through 48 weeks (Table 5). Table 5: Efficacy Outcomes at Week 48a and at Week 96 (Study 045) Parameter ATV/RTVb (300 mg/ 100 mg once daily) n=120 LPV/RTVc (400 mg/ 100 mg twice daily) n=123 Time-averaged difference ATV/RTV-LPV/RTV [97.5% CId] Week 48 Week 96 Week 48 Week 96 Week 48 Week 96 HIV RNA Mean Change from Baseline, log10 copies/ml All patients -1.93 (n=90 e) -2.29 (n=64) -1.87 (n=99) -2.08 (n=65) 0.13 [‑0.12, 0.39] 0.14 [‑0.13, 0.41] HIV RNA <50 copies/ml, %f (responder/evaluable) All patients 36 (43/120) 32 (38/120) 42 (52/123 35 (41/118) NA NA HIV RNA <50 copies/ml by select baseline PI substitutions,f, g % (responder/evaluable) 0-2 44 (28/63) 41 (26/63) 56 (32/57) 48 (26/54) NA NA 3 18 (2/11) 9 (1/11) 38 (6/16) 33 (5/15) NA NA ≥4 27 (12/45) 24 (11/45) 28 (14/50) 20 (10/49) NA NA CD4 Mean Change from Baseline, cells/mm3 All patients 203 (n=370) 219 (n=363) Baseline Characteristics HIV RNA <100,000 copies/ml 179 (n=183) 194 (n=183) ≥100,000 copies/ml 227 (n=187) 245 (n=180) All patients 110 (n=83) 122 (n=60) 121 (n=94) 154 (n=60) NA NA a REYATAZ/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily). b Lopinavir/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily). c Intent-to-treat analysis, with missing values considered as failures. d Number of patients evaluable. In antiretroviral experienced patients Study 045 is a randomised, multicenter trial comparing REYATAZ (300 mg once daily) with ritonavir (100 mg once daily) to REYATAZ (400 mg once daily) with saquinavir soft gelatine capsules (1,200 mg once daily), and to lopinavir + ritonavir (400/100 mg fixed dose combination twice daily), each in combination with tenofovir (see sections 4.5 and 4.8) and one NRTI, in 347 (of 358 randomised) patients with virologic failure on two or more prior regimens containing at least one PI, NRTI, and NNRTI. For randomised patients, the mean time of prior antiretroviral exposure was 138 weeks for PIs, 281 weeks for NRTIs, and 85 weeks for NNRTIs. At baseline, 34% of patients were receiving a PI and 60% were receiving an NNRTI. Fifteen of 120 (13%) patients in the REYATAZ + ritonavir treatment arm and 17 of 123 (14%) patients in the lopinavir + ritonavir arm had four or more of the PI substitutions L10, M46, I54, V82, I84, and L90. Thirty‑two percent of patients in the study had a viral strain with fewer than two NRTI substitutions. The mean baseline CD4 cell count was 337 cells/mm3 (range: 14 to 1,543 cells/mm3) and the mean baseline plasma HIV‑1 RNA level was 4.4 log10 copies/ml (range: 2.6 to 5.88 log10 copies/ml). The population included in this study was moderately pretreated. The primary endpoint was the time‑averaged difference in change from baseline in HIV RNA through 48 weeks. Through 48 weeks of treatment, the decreases from baseline in HIV RNA levels (primary endpoint) were 1.93 log10 copies/ml for REYATAZ + ritonavir and 1.87 log10 copies/ml for lopinavir + ritonavir. REYATAZ + ritonavir was similar (non‑inferior) to lopinavir + ritonavir on this efficacy measure (time‑averaged difference of 0.13, 97.5% confidenceb ATV/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily). c LPV/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily). d Confidence interval [‑0.12, 0.39]).. e Number of patients evaluable. f Intent-to-treat analysis, with missing values considered as failures. Responders on LPV/RTV who completed treatment before Week 96 are excluded from Week 96 analysis. The proportion of patients with HIV RNA < 400 copies/ml were 53% and 43% for ATV/RTV and 54% and 46% for LPV/RTV at weeks 48 and 96 respectively. g Select substitutions include any change at positions L10, K20, L24, V32, L33, M36, M46, G48, I50, I54, L63, A71, G73, V82, I84, and L90 (0-2, 3, 4 or more) at baseline. NA = not applicable. Through 48 weeks of treatment, the mean changes from baseline in HIV RNA levels for REYATAZ + ritonavir and lopinavir + ritonavir were similar (non‑inferior). Consistent results were obtained with the last observation carried forward method of analysis (time‑averaged difference of 0.11, 97.5% confidence interval [‑0.15, 0.36]). The proportions of patients with HIV RNA < 400 copies/ml in the REYATAZ + ritonavir arm and the lopinavir + ritonavir arm were 53% and 54%, respectively, by intent‑to‑treat analysis, with missing values considered as failures. The proportions of patients with HIV RNA < 50 copies/ml in the REYATAZ + ritonavir arm and the lopinavir + ritonavir arm were 36% and 42%, respectively. By as‑treated analysis, excluding missing values, the proportions of patients with HIV RNA < 400 copies/ml (< 50 copies/ml) in the REYATAZ + ritonavir arm and the lopinavir + ritonavir arm were 55% (40%) and 56% (46%), respectively. The mean increases from baseline in CD4 cell count were 110 cells/mm3 and 121 cells/mm3 in the REYATAZ + ritonavir and lopinavir + ritonavir arms, respectively. Analyses of data through 96 Through 96 weeks of treatment demonstrated durability of antiviral activity. Mean, mean HIV RNA changes from baseline at Week 96 (‑2.29 log10 copies/ml for REYATAZ + ritonavir and ‑2.08 log10 copies/ml for lopinavir + ritonavir, time‑averaged difference of 0.14, 97.5% confidence interval [‑0.13, 0.41]) met criteria for non‑inferiority based on observed cases. Consistent results were obtained with the last observation carried forward method of analysis. The proportions of patients with HIV RNA <400 copies/ml (<50 copies/ml) for REYATAZ + ritonavir were 43% (32%) and for lopinavir + ritonavir were 46% (35%). Patients completing treatment while in response after 48 weeks were censored. By as‑treated analysis, excluding missing values, the proportions of patients with HIV RNA <400 copies/ml (<50 copies/ml) for REYATAZ + ritonavir were 84% (72%) and for lopinavir + ritonavir were 82% (72%). It is important to note that at time of the 96‑week analysis, 48 % of patients overall remained on study. Through 48 weeks of treatment, two types of analyses were performed based on baseline genotypic mutations. The first consisted in assessing the HIV RNA change from baseline in the subgroup of patients with < or ≥ of 4 of the following set of mutations: 10, 20, 24, 32, 33, 36, 46, 48, 50, 54, 63, 71, 73, 82, 84 and 90. The second consisted in assessing the HIV RNA change from baseline in the subgroup of patients with < or ≥ of 4 of the following more specific set of mutations: 10, 46, 54, 82, 84, 90. In the analysis performed for patients with ≥ 4 protease gene mutations among the following set of mutations 10, 20, 24, 32, 33, 36, 46, 48, 50, 54, 63, 71, 73, 82, 84 and 90, the results significantly favoured the lopinavir + ritonavir arm. There were too few patients with ≥ 4 of the second more specific set of mutations (i.e. 10, 46, 54, 82, 84, 90) to assess the comparability of the REYATAZ + ritonavir and lopinavir + ritonavir regimens, but reduced virologic activity may be anticipated among patients with this resistance profile. REYATAZ + saquinavir was shown to be inferior to lopinavir + ritonavir. 5.2 Pharmacokinetic properties Special populations Impaired renal function: in healthy subjects, the renal elimination of unchanged atazanavir was approximately 7% of the administered dose. There are no pharmacokinetic data available on for REYATAZ with ritonavir in patients with renal insufficiency (see section 4.2); however, the impact of renal impairment on atazanavir elimination is anticipated to be minimal.. REYATAZ (without ritonavir) has been studied in adult patients with severe renal impairment (n=20), including those on haemodialysis, at multiple doses of 400 mg once daily. Although this study presented some limitations (i.e., unbound drug concentrations not studied), results suggested that the atazanavir pharmacokinetic parameters were decreased by 30% to 50% in patients undergoing haemodialysis compared to patients with normal renal function. The mechanism of this decrease is unknown. (See sections 4.2 and 4.4.) 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 02 March 2004 Date of latest renewal : 09 February: 02 March 2009 10. DATE OF REVISION OF THE TEXT 9th FebruaryJuly 2009 Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/http://www.emea.europa.eu
In a per protocol analysis which excluded non-completers (i.e. patients who discontinued before the week 48 HIV RNA assessment) and patients with major protocol deviations, the proportion of patients with HIV RNA < 50 copies/ml at week 48 was 86% (338/392) for REYATAZ/ritonavir and 89% (332/372) for lopinavir/ritonavir (difference estimate of ATV/RTV-LPV/RTV: -3% [95% CI, -7.6%, 1.5%]. (Table 2: 4). Analyses of data through 96 weeks of treatment demonstrated durability of antiviral activity (Table 4). Table 4: Efficacy Outcomes at Week 48 (in Study 138) for the CVR (NC=F) analysis a Parameter REYATAZ/ritonaviraritonavirb (300 mg/100 mg once daily) n=440 lopinavir/ritonavirbLopinavir/ritonavirc (400 mg/100 mg twice daily) n=443 HIV RNA <50 copies/ml, % c All patients 78 76 Baseline Characteristics HIV RNA <100,000 copies/ml 82 (n=217d) 81 (n=218) ≥100,000 copies/ml 74 (n=223) 72 (n=225) CD4 count <50 cells/mm3 78 (n=58) 63 (n=48) 50 to <100 cells/mm3 76 (n=45) 69 (n=29) 100 to <200 cells/mm3 75 (n=106) 78 (n=134) ≥200 cells/mm3 80 (n=222) 80 (n=228) Week 48 Week 96 Week 48 Week 96 HIV RNA <50 copies/ml, % All patientsd 78 74 76 68 Difference estimate [95% CI]d Week 48: 1.7% [-3.8%, 7.1%] Week 96: 6.1% [0.3%, 12.0%] Per protocol analysise 86 (n=392f) 91 (n=352) 89 (n=372) 89 (n=331) Difference estimatee [95% CI] Week 48: -3% [-7.6%, 1.5%] Week 96: 2.2% [-2.3%, 6.7%] HIV RNA <50 copies/ml, % by Baseline Characteristicd HIV RNA <100,000 copies/ml 82 (n=217) 75 (n=217) 81 (n=218) 70 (n=218) ≥100,000 copies/ml 74 (n=223) 74 (n=223) 72 (n=225) 66 (n=225) CD4 count <50 cells/mm3 78 (n=58) 78 (n=58) 63 (n=48) 58 (n=48) 50 to <100 cells/mm3 76 (n=45) 71 (n=45) 69 (n=29) 69 (n=29) 100 to <200 cells/mm3 75 (n=106) 71 (n=106) 78 (n=134) 70 (n=134) ≥ 200 cells/mm3 80 (n=222) 76 (n=222) 80 (n=228) 69 (n=228) HIV RNA Mean Change from Baseline, log10 copies/ml All patients -3.09 (n=397) -3.13 (n=379) All patients -3.09 (n=397) -3.21 (n=360) -3.13 (n=379) -3.19 (n=340) CD4 Mean Change from Baseline, cells/mm3 All patients 203 (n=370) 268 (n=336) 219 (n=363) 290 (n=317) CD4 Mean Change from Baseline, cells/mm3 by Baseline Characteristic HIV RNA <100,000 copies/ml 179 (n=183) 243 (n=163) 194 (n=183) 267 (n=152) ≥100,000 copies/ml 227 (n=187) 291 (n=173) 245 (n=180) 310 (n=165) a Mean baseline CD4 cell count was 214 cells/mm3 (range 2 to 810 cells/mm3) and mean baseline plasma HIV-1 RNA was 4.94 log10 copies/ml (range 2.6 to 5.88 log10 copies/ml) b REYATAZ/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily). c Lopinavir/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily). d Intent-to-treat analysis, with missing values considered as failures. e Per protocol analysis: Excluding non-completers and patients with major protocol deviations. f Number of patients evaluable. In antiretroviral experienced patients Study 045 is a randomised, multicenter trial comparing REYATAZ/ritonavir (300/100 mg once daily) and REYATAZ/saquinavir (400/1,200 mg once daily), to lopinavir + ritonavir (400/100 mg fixed dose combination twice daily), each in combination with tenofovir (see sections 4.5 and 4.8) and one NRTI, in patients with virologic failure on two or more prior regimens containing at least one PI, NRTI, and NNRTI. For randomised patients, the mean time of prior antiretroviral exposure was 138 weeks for PIs, 281 weeks for NRTIs, and 85 weeks for NNRTIs. At baseline, 34% of patients were receiving a PI and 60% were receiving an NNRTI. Fifteen of 120 (13%) patients in the REYATAZ + ritonavir treatment arm and 17 of 123 (14%) patients in the lopinavir + ritonavir arm had four or more of the PI substitutions L10, M46, I54, V82, I84, and L90. Thirty‑two percent of patients in the study had a viral strain with fewer than two NRTI substitutions. The primary endpoint was the time‑averaged difference in change from baseline in HIV RNA through 48 weeks (Table 5). Table 5: Efficacy Outcomes at Week 48a and at Week 96 (Study 045) Parameter ATV/RTVb (300 mg/ 100 mg once daily) n=120 LPV/RTVc (400 mg/ 100 mg twice daily) n=123 Time-averaged difference ATV/RTV-LPV/RTV [97.5% CId] Week 48 Week 96 Week 48 Week 96 Week 48 Week 96 HIV RNA Mean Change from Baseline, log10 copies/ml All patients -1.93 (n=90 e) -2.29 (n=64) -1.87 (n=99) -2.08 (n=65) 0.13 [‑0.12, 0.39] 0.14 [‑0.13, 0.41] HIV RNA <50 copies/ml, %f (responder/evaluable) All patients 36 (43/120) 32 (38/120) 42 (52/123 35 (41/118) NA NA HIV RNA <50 copies/ml by select baseline PI substitutions,f, g % (responder/evaluable) 0-2 44 (28/63) 41 (26/63) 56 (32/57) 48 (26/54) NA NA 3 18 (2/11) 9 (1/11) 38 (6/16) 33 (5/15) NA NA ≥4 27 (12/45) 24 (11/45) 28 (14/50) 20 (10/49) NA NA CD4 Mean Change from Baseline, cells/mm3 All patients 203 (n=370) 219 (n=363) Baseline Characteristics HIV RNA <100,000 copies/ml 179 (n=183) 194 (n=183) ≥100,000 copies/ml 227 (n=187) 245 (n=180) All patients 110 (n=83) 122 (n=60) 121 (n=94) 154 (n=60) NA NA a REYATAZ/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily). b Lopinavir/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily). c Intent-to-treat analysis, with missing values considered as failures. d Number of patients evaluable. In antiretroviral experienced patients Study 045 is a randomised, multicenter trial comparing REYATAZ (300 mg once daily) with ritonavir (100 mg once daily) to REYATAZ (400 mg once daily) with saquinavir soft gelatine capsules (1,200 mg once daily), and to lopinavir + ritonavir (400/100 mg fixed dose combination twice daily), each in combination with tenofovir (see sections 4.5 and 4.8) and one NRTI, in 347 (of 358 randomised) patients with virologic failure on two or more prior regimens containing at least one PI, NRTI, and NNRTI. For randomised patients, the mean time of prior antiretroviral exposure was 138 weeks for PIs, 281 weeks for NRTIs, and 85 weeks for NNRTIs. At baseline, 34% of patients were receiving a PI and 60% were receiving an NNRTI. Fifteen of 120 (13%) patients in the REYATAZ + ritonavir treatment arm and 17 of 123 (14%) patients in the lopinavir + ritonavir arm had four or more of the PI substitutions L10, M46, I54, V82, I84, and L90. Thirty‑two percent of patients in the study had a viral strain with fewer than two NRTI substitutions. The mean baseline CD4 cell count was 337 cells/mm3 (range: 14 to 1,543 cells/mm3) and the mean baseline plasma HIV‑1 RNA level was 4.4 log10 copies/ml (range: 2.6 to 5.88 log10 copies/ml). The population included in this study was moderately pretreated. The primary endpoint was the time‑averaged difference in change from baseline in HIV RNA through 48 weeks. Through 48 weeks of treatment, the decreases from baseline in HIV RNA levels (primary endpoint) were 1.93 log10 copies/ml for REYATAZ + ritonavir and 1.87 log10 copies/ml for lopinavir + ritonavir. REYATAZ + ritonavir was similar (non‑inferior) to lopinavir + ritonavir on this efficacy measure (time‑averaged difference of 0.13, 97.5% confidenceb ATV/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily). c LPV/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily). d Confidence interval [‑0.12, 0.39]).. e Number of patients evaluable. f Intent-to-treat analysis, with missing values considered as failures. Responders on LPV/RTV who completed treatment before Week 96 are excluded from Week 96 analysis. The proportion of patients with HIV RNA < 400 copies/ml were 53% and 43% for ATV/RTV and 54% and 46% for LPV/RTV at weeks 48 and 96 respectively. g Select substitutions include any change at positions L10, K20, L24, V32, L33, M36, M46, G48, I50, I54, L63, A71, G73, V82, I84, and L90 (0-2, 3, 4 or more) at baseline. NA = not applicable. Through 48 weeks of treatment, the mean changes from baseline in HIV RNA levels for REYATAZ + ritonavir and lopinavir + ritonavir were similar (non‑inferior). Consistent results were obtained with the last observation carried forward method of analysis (time‑averaged difference of 0.11, 97.5% confidence interval [‑0.15, 0.36]). The proportions of patients with HIV RNA < 400 copies/ml in the REYATAZ + ritonavir arm and the lopinavir + ritonavir arm were 53% and 54%, respectively, by intent‑to‑treat analysis, with missing values considered as failures. The proportions of patients with HIV RNA < 50 copies/ml in the REYATAZ + ritonavir arm and the lopinavir + ritonavir arm were 36% and 42%, respectively. By as‑treated analysis, excluding missing values, the proportions of patients with HIV RNA < 400 copies/ml (< 50 copies/ml) in the REYATAZ + ritonavir arm and the lopinavir + ritonavir arm were 55% (40%) and 56% (46%), respectively. The mean increases from baseline in CD4 cell count were 110 cells/mm3 and 121 cells/mm3 in the REYATAZ + ritonavir and lopinavir + ritonavir arms, respectively. Analyses of data through 96 Through 96 weeks of treatment demonstrated durability of antiviral activity. Mean, mean HIV RNA changes from baseline at Week 96 (‑2.29 log10 copies/ml for REYATAZ + ritonavir and ‑2.08 log10 copies/ml for lopinavir + ritonavir, time‑averaged difference of 0.14, 97.5% confidence interval [‑0.13, 0.41]) met criteria for non‑inferiority based on observed cases. Consistent results were obtained with the last observation carried forward method of analysis. The proportions of patients with HIV RNA <400 copies/ml (<50 copies/ml) for REYATAZ + ritonavir were 43% (32%) and for lopinavir + ritonavir were 46% (35%). Patients completing treatment while in response after 48 weeks were censored. By as‑treated analysis, excluding missing values, the proportions of patients with HIV RNA <400 copies/ml (<50 copies/ml) for REYATAZ + ritonavir were 84% (72%) and for lopinavir + ritonavir were 82% (72%). It is important to note that at time of the 96‑week analysis, 48 % of patients overall remained on study. Through 48 weeks of treatment, two types of analyses were performed based on baseline genotypic mutations. The first consisted in assessing the HIV RNA change from baseline in the subgroup of patients with < or ≥ of 4 of the following set of mutations: 10, 20, 24, 32, 33, 36, 46, 48, 50, 54, 63, 71, 73, 82, 84 and 90. The second consisted in assessing the HIV RNA change from baseline in the subgroup of patients with < or ≥ of 4 of the following more specific set of mutations: 10, 46, 54, 82, 84, 90. In the analysis performed for patients with ≥ 4 protease gene mutations among the following set of mutations 10, 20, 24, 32, 33, 36, 46, 48, 50, 54, 63, 71, 73, 82, 84 and 90, the results significantly favoured the lopinavir + ritonavir arm. There were too few patients with ≥ 4 of the second more specific set of mutations (i.e. 10, 46, 54, 82, 84, 90) to assess the comparability of the REYATAZ + ritonavir and lopinavir + ritonavir regimens, but reduced virologic activity may be anticipated among patients with this resistance profile. REYATAZ + saquinavir was shown to be inferior to lopinavir + ritonavir. 5.2 Pharmacokinetic properties Special populations Impaired renal function: in healthy subjects, the renal elimination of unchanged atazanavir was approximately 7% of the administered dose. There are no pharmacokinetic data available on for REYATAZ with ritonavir in patients with renal insufficiency (see section 4.2); however, the impact of renal impairment on atazanavir elimination is anticipated to be minimal.. REYATAZ (without ritonavir) has been studied in adult patients with severe renal impairment (n=20), including those on haemodialysis, at multiple doses of 400 mg once daily. Although this study presented some limitations (i.e., unbound drug concentrations not studied), results suggested that the atazanavir pharmacokinetic parameters were decreased by 30% to 50% in patients undergoing haemodialysis compared to patients with normal renal function. The mechanism of this decrease is unknown. (See sections 4.2 and 4.4.) 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 02 March 2004 Date of latest renewal : 09 February: 02 March 2009 10. DATE OF REVISION OF THE TEXT 9th FebruaryJuly 2009 Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/http://www.emea.europa.eu
(Table 2: 4). Analyses of data through 96 weeks of treatment demonstrated durability of antiviral activity (Table 4). Table 4: Efficacy Outcomes at Week 48 (in Study 138) for the CVR (NC=F) analysis a Parameter REYATAZ/ritonaviraritonavirb (300 mg/100 mg once daily) n=440 lopinavir/ritonavirbLopinavir/ritonavirc (400 mg/100 mg twice daily) n=443 HIV RNA <50 copies/ml, % c All patients 78 76 Baseline Characteristics HIV RNA <100,000 copies/ml 82 (n=217d) 81 (n=218) ≥100,000 copies/ml 74 (n=223) 72 (n=225) CD4 count <50 cells/mm3 78 (n=58) 63 (n=48) 50 to <100 cells/mm3 76 (n=45) 69 (n=29) 100 to <200 cells/mm3 75 (n=106) 78 (n=134) ≥200 cells/mm3 80 (n=222) 80 (n=228) Week 48 Week 96 Week 48 Week 96 HIV RNA <50 copies/ml, % All patientsd 78 74 76 68 Difference estimate [95% CI]d Week 48: 1.7% [-3.8%, 7.1%] Week 96: 6.1% [0.3%, 12.0%] Per protocol analysise 86 (n=392f) 91 (n=352) 89 (n=372) 89 (n=331) Difference estimatee [95% CI] Week 48: -3% [-7.6%, 1.5%] Week 96: 2.2% [-2.3%, 6.7%] HIV RNA <50 copies/ml, % by Baseline Characteristicd HIV RNA <100,000 copies/ml 82 (n=217) 75 (n=217) 81 (n=218) 70 (n=218) ≥100,000 copies/ml 74 (n=223) 74 (n=223) 72 (n=225) 66 (n=225) CD4 count <50 cells/mm3 78 (n=58) 78 (n=58) 63 (n=48) 58 (n=48) 50 to <100 cells/mm3 76 (n=45) 71 (n=45) 69 (n=29) 69 (n=29) 100 to <200 cells/mm3 75 (n=106) 71 (n=106) 78 (n=134) 70 (n=134) ≥ 200 cells/mm3 80 (n=222) 76 (n=222) 80 (n=228) 69 (n=228) HIV RNA Mean Change from Baseline, log10 copies/ml All patients -3.09 (n=397) -3.13 (n=379) All patients -3.09 (n=397) -3.21 (n=360) -3.13 (n=379) -3.19 (n=340) CD4 Mean Change from Baseline, cells/mm3 All patients 203 (n=370) 268 (n=336) 219 (n=363) 290 (n=317) CD4 Mean Change from Baseline, cells/mm3 by Baseline Characteristic HIV RNA <100,000 copies/ml 179 (n=183) 243 (n=163) 194 (n=183) 267 (n=152) ≥100,000 copies/ml 227 (n=187) 291 (n=173) 245 (n=180) 310 (n=165) a Mean baseline CD4 cell count was 214 cells/mm3 (range 2 to 810 cells/mm3) and mean baseline plasma HIV-1 RNA was 4.94 log10 copies/ml (range 2.6 to 5.88 log10 copies/ml) b REYATAZ/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily). c Lopinavir/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily). d Intent-to-treat analysis, with missing values considered as failures. e Per protocol analysis: Excluding non-completers and patients with major protocol deviations. f Number of patients evaluable. In antiretroviral experienced patients Study 045 is a randomised, multicenter trial comparing REYATAZ/ritonavir (300/100 mg once daily) and REYATAZ/saquinavir (400/1,200 mg once daily), to lopinavir + ritonavir (400/100 mg fixed dose combination twice daily), each in combination with tenofovir (see sections 4.5 and 4.8) and one NRTI, in patients with virologic failure on two or more prior regimens containing at least one PI, NRTI, and NNRTI. For randomised patients, the mean time of prior antiretroviral exposure was 138 weeks for PIs, 281 weeks for NRTIs, and 85 weeks for NNRTIs. At baseline, 34% of patients were receiving a PI and 60% were receiving an NNRTI. Fifteen of 120 (13%) patients in the REYATAZ + ritonavir treatment arm and 17 of 123 (14%) patients in the lopinavir + ritonavir arm had four or more of the PI substitutions L10, M46, I54, V82, I84, and L90. Thirty‑two percent of patients in the study had a viral strain with fewer than two NRTI substitutions. The primary endpoint was the time‑averaged difference in change from baseline in HIV RNA through 48 weeks (Table 5). Table 5: Efficacy Outcomes at Week 48a and at Week 96 (Study 045) Parameter ATV/RTVb (300 mg/ 100 mg once daily) n=120 LPV/RTVc (400 mg/ 100 mg twice daily) n=123 Time-averaged difference ATV/RTV-LPV/RTV [97.5% CId] Week 48 Week 96 Week 48 Week 96 Week 48 Week 96 HIV RNA Mean Change from Baseline, log10 copies/ml All patients -1.93 (n=90 e) -2.29 (n=64) -1.87 (n=99) -2.08 (n=65) 0.13 [‑0.12, 0.39] 0.14 [‑0.13, 0.41] HIV RNA <50 copies/ml, %f (responder/evaluable) All patients 36 (43/120) 32 (38/120) 42 (52/123 35 (41/118) NA NA HIV RNA <50 copies/ml by select baseline PI substitutions,f, g % (responder/evaluable) 0-2 44 (28/63) 41 (26/63) 56 (32/57) 48 (26/54) NA NA 3 18 (2/11) 9 (1/11) 38 (6/16) 33 (5/15) NA NA ≥4 27 (12/45) 24 (11/45) 28 (14/50) 20 (10/49) NA NA CD4 Mean Change from Baseline, cells/mm3 All patients 203 (n=370) 219 (n=363) Baseline Characteristics HIV RNA <100,000 copies/ml 179 (n=183) 194 (n=183) ≥100,000 copies/ml 227 (n=187) 245 (n=180) All patients 110 (n=83) 122 (n=60) 121 (n=94) 154 (n=60) NA NA a REYATAZ/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily). b Lopinavir/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily). c Intent-to-treat analysis, with missing values considered as failures. d Number of patients evaluable. In antiretroviral experienced patients Study 045 is a randomised, multicenter trial comparing REYATAZ (300 mg once daily) with ritonavir (100 mg once daily) to REYATAZ (400 mg once daily) with saquinavir soft gelatine capsules (1,200 mg once daily), and to lopinavir + ritonavir (400/100 mg fixed dose combination twice daily), each in combination with tenofovir (see sections 4.5 and 4.8) and one NRTI, in 347 (of 358 randomised) patients with virologic failure on two or more prior regimens containing at least one PI, NRTI, and NNRTI. For randomised patients, the mean time of prior antiretroviral exposure was 138 weeks for PIs, 281 weeks for NRTIs, and 85 weeks for NNRTIs. At baseline, 34% of patients were receiving a PI and 60% were receiving an NNRTI. Fifteen of 120 (13%) patients in the REYATAZ + ritonavir treatment arm and 17 of 123 (14%) patients in the lopinavir + ritonavir arm had four or more of the PI substitutions L10, M46, I54, V82, I84, and L90. Thirty‑two percent of patients in the study had a viral strain with fewer than two NRTI substitutions. The mean baseline CD4 cell count was 337 cells/mm3 (range: 14 to 1,543 cells/mm3) and the mean baseline plasma HIV‑1 RNA level was 4.4 log10 copies/ml (range: 2.6 to 5.88 log10 copies/ml). The population included in this study was moderately pretreated. The primary endpoint was the time‑averaged difference in change from baseline in HIV RNA through 48 weeks. Through 48 weeks of treatment, the decreases from baseline in HIV RNA levels (primary endpoint) were 1.93 log10 copies/ml for REYATAZ + ritonavir and 1.87 log10 copies/ml for lopinavir + ritonavir. REYATAZ + ritonavir was similar (non‑inferior) to lopinavir + ritonavir on this efficacy measure (time‑averaged difference of 0.13, 97.5% confidenceb ATV/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily). c LPV/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily). d Confidence interval [‑0.12, 0.39]).. e Number of patients evaluable. f Intent-to-treat analysis, with missing values considered as failures. Responders on LPV/RTV who completed treatment before Week 96 are excluded from Week 96 analysis. The proportion of patients with HIV RNA < 400 copies/ml were 53% and 43% for ATV/RTV and 54% and 46% for LPV/RTV at weeks 48 and 96 respectively. g Select substitutions include any change at positions L10, K20, L24, V32, L33, M36, M46, G48, I50, I54, L63, A71, G73, V82, I84, and L90 (0-2, 3, 4 or more) at baseline. NA = not applicable. Through 48 weeks of treatment, the mean changes from baseline in HIV RNA levels for REYATAZ + ritonavir and lopinavir + ritonavir were similar (non‑inferior). Consistent results were obtained with the last observation carried forward method of analysis (time‑averaged difference of 0.11, 97.5% confidence interval [‑0.15, 0.36]). The proportions of patients with HIV RNA < 400 copies/ml in the REYATAZ + ritonavir arm and the lopinavir + ritonavir arm were 53% and 54%, respectively, by intent‑to‑treat analysis, with missing values considered as failures. The proportions of patients with HIV RNA < 50 copies/ml in the REYATAZ + ritonavir arm and the lopinavir + ritonavir arm were 36% and 42%, respectively. By as‑treated analysis, excluding missing values, the proportions of patients with HIV RNA < 400 copies/ml (< 50 copies/ml) in the REYATAZ + ritonavir arm and the lopinavir + ritonavir arm were 55% (40%) and 56% (46%), respectively. The mean increases from baseline in CD4 cell count were 110 cells/mm3 and 121 cells/mm3 in the REYATAZ + ritonavir and lopinavir + ritonavir arms, respectively. Analyses of data through 96 Through 96 weeks of treatment demonstrated durability of antiviral activity. Mean, mean HIV RNA changes from baseline at Week 96 (‑2.29 log10 copies/ml for REYATAZ + ritonavir and ‑2.08 log10 copies/ml for lopinavir + ritonavir, time‑averaged difference of 0.14, 97.5% confidence interval [‑0.13, 0.41]) met criteria for non‑inferiority based on observed cases. Consistent results were obtained with the last observation carried forward method of analysis. The proportions of patients with HIV RNA <400 copies/ml (<50 copies/ml) for REYATAZ + ritonavir were 43% (32%) and for lopinavir + ritonavir were 46% (35%). Patients completing treatment while in response after 48 weeks were censored. By as‑treated analysis, excluding missing values, the proportions of patients with HIV RNA <400 copies/ml (<50 copies/ml) for REYATAZ + ritonavir were 84% (72%) and for lopinavir + ritonavir were 82% (72%). It is important to note that at time of the 96‑week analysis, 48 % of patients overall remained on study. Through 48 weeks of treatment, two types of analyses were performed based on baseline genotypic mutations. The first consisted in assessing the HIV RNA change from baseline in the subgroup of patients with < or ≥ of 4 of the following set of mutations: 10, 20, 24, 32, 33, 36, 46, 48, 50, 54, 63, 71, 73, 82, 84 and 90. The second consisted in assessing the HIV RNA change from baseline in the subgroup of patients with < or ≥ of 4 of the following more specific set of mutations: 10, 46, 54, 82, 84, 90. In the analysis performed for patients with ≥ 4 protease gene mutations among the following set of mutations 10, 20, 24, 32, 33, 36, 46, 48, 50, 54, 63, 71, 73, 82, 84 and 90, the results significantly favoured the lopinavir + ritonavir arm. There were too few patients with ≥ 4 of the second more specific set of mutations (i.e. 10, 46, 54, 82, 84, 90) to assess the comparability of the REYATAZ + ritonavir and lopinavir + ritonavir regimens, but reduced virologic activity may be anticipated among patients with this resistance profile. REYATAZ + saquinavir was shown to be inferior to lopinavir + ritonavir. 5.2 Pharmacokinetic properties Special populations Impaired renal function: in healthy subjects, the renal elimination of unchanged atazanavir was approximately 7% of the administered dose. There are no pharmacokinetic data available on for REYATAZ with ritonavir in patients with renal insufficiency (see section 4.2); however, the impact of renal impairment on atazanavir elimination is anticipated to be minimal.. REYATAZ (without ritonavir) has been studied in adult patients with severe renal impairment (n=20), including those on haemodialysis, at multiple doses of 400 mg once daily. Although this study presented some limitations (i.e., unbound drug concentrations not studied), results suggested that the atazanavir pharmacokinetic parameters were decreased by 30% to 50% in patients undergoing haemodialysis compared to patients with normal renal function. The mechanism of this decrease is unknown. (See sections 4.2 and 4.4.) 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 02 March 2004 Date of latest renewal : 09 February: 02 March 2009 10. DATE OF REVISION OF THE TEXT 9th FebruaryJuly 2009 Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/http://www.emea.europa.eu
Analyses of data through 96 weeks of treatment demonstrated durability of antiviral activity (Table 4).
Table 4: Efficacy Outcomes at Week 48 (in Study 138) for the CVR (NC=F) analysis a Parameter REYATAZ/ritonaviraritonavirb (300 mg/100 mg once daily) n=440 lopinavir/ritonavirbLopinavir/ritonavirc (400 mg/100 mg twice daily) n=443 HIV RNA <50 copies/ml, % c All patients 78 76 Baseline Characteristics HIV RNA <100,000 copies/ml 82 (n=217d) 81 (n=218) ≥100,000 copies/ml 74 (n=223) 72 (n=225) CD4 count <50 cells/mm3 78 (n=58) 63 (n=48) 50 to <100 cells/mm3 76 (n=45) 69 (n=29) 100 to <200 cells/mm3 75 (n=106) 78 (n=134) ≥200 cells/mm3 80 (n=222) 80 (n=228) Week 48 Week 96 Week 48 Week 96 HIV RNA <50 copies/ml, % All patientsd 78 74 76 68 Difference estimate [95% CI]d Week 48: 1.7% [-3.8%, 7.1%] Week 96: 6.1% [0.3%, 12.0%] Per protocol analysise 86 (n=392f) 91 (n=352) 89 (n=372) 89 (n=331) Difference estimatee [95% CI] Week 48: -3% [-7.6%, 1.5%] Week 96: 2.2% [-2.3%, 6.7%] HIV RNA <50 copies/ml, % by Baseline Characteristicd HIV RNA <100,000 copies/ml 82 (n=217) 75 (n=217) 81 (n=218) 70 (n=218) ≥100,000 copies/ml 74 (n=223) 74 (n=223) 72 (n=225) 66 (n=225) CD4 count <50 cells/mm3 78 (n=58) 78 (n=58) 63 (n=48) 58 (n=48) 50 to <100 cells/mm3 76 (n=45) 71 (n=45) 69 (n=29) 69 (n=29) 100 to <200 cells/mm3 75 (n=106) 71 (n=106) 78 (n=134) 70 (n=134) ≥ 200 cells/mm3 80 (n=222) 76 (n=222) 80 (n=228) 69 (n=228) HIV RNA Mean Change from Baseline, log10 copies/ml All patients -3.09 (n=397) -3.13 (n=379) All patients -3.09 (n=397) -3.21 (n=360) -3.13 (n=379) -3.19 (n=340) CD4 Mean Change from Baseline, cells/mm3 All patients 203 (n=370) 268 (n=336) 219 (n=363) 290 (n=317) CD4 Mean Change from Baseline, cells/mm3 by Baseline Characteristic HIV RNA <100,000 copies/ml 179 (n=183) 243 (n=163) 194 (n=183) 267 (n=152) ≥100,000 copies/ml 227 (n=187) 291 (n=173) 245 (n=180) 310 (n=165) a Mean baseline CD4 cell count was 214 cells/mm3 (range 2 to 810 cells/mm3) and mean baseline plasma HIV-1 RNA was 4.94 log10 copies/ml (range 2.6 to 5.88 log10 copies/ml) b REYATAZ/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily). c Lopinavir/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily). d Intent-to-treat analysis, with missing values considered as failures. e Per protocol analysis: Excluding non-completers and patients with major protocol deviations. f Number of patients evaluable. In antiretroviral experienced patients Study 045 is a randomised, multicenter trial comparing REYATAZ/ritonavir (300/100 mg once daily) and REYATAZ/saquinavir (400/1,200 mg once daily), to lopinavir + ritonavir (400/100 mg fixed dose combination twice daily), each in combination with tenofovir (see sections 4.5 and 4.8) and one NRTI, in patients with virologic failure on two or more prior regimens containing at least one PI, NRTI, and NNRTI. For randomised patients, the mean time of prior antiretroviral exposure was 138 weeks for PIs, 281 weeks for NRTIs, and 85 weeks for NNRTIs. At baseline, 34% of patients were receiving a PI and 60% were receiving an NNRTI. Fifteen of 120 (13%) patients in the REYATAZ + ritonavir treatment arm and 17 of 123 (14%) patients in the lopinavir + ritonavir arm had four or more of the PI substitutions L10, M46, I54, V82, I84, and L90. Thirty‑two percent of patients in the study had a viral strain with fewer than two NRTI substitutions. The primary endpoint was the time‑averaged difference in change from baseline in HIV RNA through 48 weeks (Table 5). Table 5: Efficacy Outcomes at Week 48a and at Week 96 (Study 045) Parameter ATV/RTVb (300 mg/ 100 mg once daily) n=120 LPV/RTVc (400 mg/ 100 mg twice daily) n=123 Time-averaged difference ATV/RTV-LPV/RTV [97.5% CId] Week 48 Week 96 Week 48 Week 96 Week 48 Week 96 HIV RNA Mean Change from Baseline, log10 copies/ml All patients -1.93 (n=90 e) -2.29 (n=64) -1.87 (n=99) -2.08 (n=65) 0.13 [‑0.12, 0.39] 0.14 [‑0.13, 0.41] HIV RNA <50 copies/ml, %f (responder/evaluable) All patients 36 (43/120) 32 (38/120) 42 (52/123 35 (41/118) NA NA HIV RNA <50 copies/ml by select baseline PI substitutions,f, g % (responder/evaluable) 0-2 44 (28/63) 41 (26/63) 56 (32/57) 48 (26/54) NA NA 3 18 (2/11) 9 (1/11) 38 (6/16) 33 (5/15) NA NA ≥4 27 (12/45) 24 (11/45) 28 (14/50) 20 (10/49) NA NA CD4 Mean Change from Baseline, cells/mm3 All patients 203 (n=370) 219 (n=363) Baseline Characteristics HIV RNA <100,000 copies/ml 179 (n=183) 194 (n=183) ≥100,000 copies/ml 227 (n=187) 245 (n=180) All patients 110 (n=83) 122 (n=60) 121 (n=94) 154 (n=60) NA NA a REYATAZ/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily). b Lopinavir/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily). c Intent-to-treat analysis, with missing values considered as failures. d Number of patients evaluable. In antiretroviral experienced patients Study 045 is a randomised, multicenter trial comparing REYATAZ (300 mg once daily) with ritonavir (100 mg once daily) to REYATAZ (400 mg once daily) with saquinavir soft gelatine capsules (1,200 mg once daily), and to lopinavir + ritonavir (400/100 mg fixed dose combination twice daily), each in combination with tenofovir (see sections 4.5 and 4.8) and one NRTI, in 347 (of 358 randomised) patients with virologic failure on two or more prior regimens containing at least one PI, NRTI, and NNRTI. For randomised patients, the mean time of prior antiretroviral exposure was 138 weeks for PIs, 281 weeks for NRTIs, and 85 weeks for NNRTIs. At baseline, 34% of patients were receiving a PI and 60% were receiving an NNRTI. Fifteen of 120 (13%) patients in the REYATAZ + ritonavir treatment arm and 17 of 123 (14%) patients in the lopinavir + ritonavir arm had four or more of the PI substitutions L10, M46, I54, V82, I84, and L90. Thirty‑two percent of patients in the study had a viral strain with fewer than two NRTI substitutions. The mean baseline CD4 cell count was 337 cells/mm3 (range: 14 to 1,543 cells/mm3) and the mean baseline plasma HIV‑1 RNA level was 4.4 log10 copies/ml (range: 2.6 to 5.88 log10 copies/ml). The population included in this study was moderately pretreated. The primary endpoint was the time‑averaged difference in change from baseline in HIV RNA through 48 weeks. Through 48 weeks of treatment, the decreases from baseline in HIV RNA levels (primary endpoint) were 1.93 log10 copies/ml for REYATAZ + ritonavir and 1.87 log10 copies/ml for lopinavir + ritonavir. REYATAZ + ritonavir was similar (non‑inferior) to lopinavir + ritonavir on this efficacy measure (time‑averaged difference of 0.13, 97.5% confidenceb ATV/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily). c LPV/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily). d Confidence interval [‑0.12, 0.39]).. e Number of patients evaluable. f Intent-to-treat analysis, with missing values considered as failures. Responders on LPV/RTV who completed treatment before Week 96 are excluded from Week 96 analysis. The proportion of patients with HIV RNA < 400 copies/ml were 53% and 43% for ATV/RTV and 54% and 46% for LPV/RTV at weeks 48 and 96 respectively. g Select substitutions include any change at positions L10, K20, L24, V32, L33, M36, M46, G48, I50, I54, L63, A71, G73, V82, I84, and L90 (0-2, 3, 4 or more) at baseline. NA = not applicable. Through 48 weeks of treatment, the mean changes from baseline in HIV RNA levels for REYATAZ + ritonavir and lopinavir + ritonavir were similar (non‑inferior). Consistent results were obtained with the last observation carried forward method of analysis (time‑averaged difference of 0.11, 97.5% confidence interval [‑0.15, 0.36]). The proportions of patients with HIV RNA < 400 copies/ml in the REYATAZ + ritonavir arm and the lopinavir + ritonavir arm were 53% and 54%, respectively, by intent‑to‑treat analysis, with missing values considered as failures. The proportions of patients with HIV RNA < 50 copies/ml in the REYATAZ + ritonavir arm and the lopinavir + ritonavir arm were 36% and 42%, respectively. By as‑treated analysis, excluding missing values, the proportions of patients with HIV RNA < 400 copies/ml (< 50 copies/ml) in the REYATAZ + ritonavir arm and the lopinavir + ritonavir arm were 55% (40%) and 56% (46%), respectively. The mean increases from baseline in CD4 cell count were 110 cells/mm3 and 121 cells/mm3 in the REYATAZ + ritonavir and lopinavir + ritonavir arms, respectively. Analyses of data through 96 Through 96 weeks of treatment demonstrated durability of antiviral activity. Mean, mean HIV RNA changes from baseline at Week 96 (‑2.29 log10 copies/ml for REYATAZ + ritonavir and ‑2.08 log10 copies/ml for lopinavir + ritonavir, time‑averaged difference of 0.14, 97.5% confidence interval [‑0.13, 0.41]) met criteria for non‑inferiority based on observed cases. Consistent results were obtained with the last observation carried forward method of analysis. The proportions of patients with HIV RNA <400 copies/ml (<50 copies/ml) for REYATAZ + ritonavir were 43% (32%) and for lopinavir + ritonavir were 46% (35%). Patients completing treatment while in response after 48 weeks were censored. By as‑treated analysis, excluding missing values, the proportions of patients with HIV RNA <400 copies/ml (<50 copies/ml) for REYATAZ + ritonavir were 84% (72%) and for lopinavir + ritonavir were 82% (72%). It is important to note that at time of the 96‑week analysis, 48 % of patients overall remained on study. Through 48 weeks of treatment, two types of analyses were performed based on baseline genotypic mutations. The first consisted in assessing the HIV RNA change from baseline in the subgroup of patients with < or ≥ of 4 of the following set of mutations: 10, 20, 24, 32, 33, 36, 46, 48, 50, 54, 63, 71, 73, 82, 84 and 90. The second consisted in assessing the HIV RNA change from baseline in the subgroup of patients with < or ≥ of 4 of the following more specific set of mutations: 10, 46, 54, 82, 84, 90. In the analysis performed for patients with ≥ 4 protease gene mutations among the following set of mutations 10, 20, 24, 32, 33, 36, 46, 48, 50, 54, 63, 71, 73, 82, 84 and 90, the results significantly favoured the lopinavir + ritonavir arm. There were too few patients with ≥ 4 of the second more specific set of mutations (i.e. 10, 46, 54, 82, 84, 90) to assess the comparability of the REYATAZ + ritonavir and lopinavir + ritonavir regimens, but reduced virologic activity may be anticipated among patients with this resistance profile. REYATAZ + saquinavir was shown to be inferior to lopinavir + ritonavir. 5.2 Pharmacokinetic properties Special populations Impaired renal function: in healthy subjects, the renal elimination of unchanged atazanavir was approximately 7% of the administered dose. There are no pharmacokinetic data available on for REYATAZ with ritonavir in patients with renal insufficiency (see section 4.2); however, the impact of renal impairment on atazanavir elimination is anticipated to be minimal.. REYATAZ (without ritonavir) has been studied in adult patients with severe renal impairment (n=20), including those on haemodialysis, at multiple doses of 400 mg once daily. Although this study presented some limitations (i.e., unbound drug concentrations not studied), results suggested that the atazanavir pharmacokinetic parameters were decreased by 30% to 50% in patients undergoing haemodialysis compared to patients with normal renal function. The mechanism of this decrease is unknown. (See sections 4.2 and 4.4.) 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 02 March 2004 Date of latest renewal : 09 February: 02 March 2009 10. DATE OF REVISION OF THE TEXT 9th FebruaryJuly 2009 Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/http://www.emea.europa.eu
Parameter
REYATAZ/ritonaviraritonavirb (300 mg/100 mg once daily) n=440
n=440
lopinavir/ritonavirbLopinavir/ritonavirc (400 mg/100 mg twice daily) n=443
n=443
HIV RNA <50 copies/ml, % c
All patients
78
76
Baseline Characteristics
HIV RNA <100,000 copies/ml
82 (n=217d)
81 (n=218)
≥100,000 copies/ml
74 (n=223)
72 (n=225)
CD4 count <50 cells/mm3
78 (n=58)
63 (n=48)
50 to <100 cells/mm3
76 (n=45)
69 (n=29)
100 to <200 cells/mm3
75 (n=106)
78 (n=134)
≥200 cells/mm3
80 (n=222)
80 (n=228)
Week 48
Week 96
HIV RNA <50 copies/ml, %
All patientsd
74
68
Difference estimate
[95% CI]d
Week 48: 1.7% [-3.8%, 7.1%]
Week 96: 6.1% [0.3%, 12.0%]
Per protocol analysise
86
(n=392f)
91
(n=352)
89
(n=372)
(n=331)
Difference estimatee
[95% CI]
Week 48: -3% [-7.6%, 1.5%]
Week 96: 2.2% [-2.3%, 6.7%]
HIV RNA <50 copies/ml, % by Baseline Characteristicd
82 (n=217)
75 (n=217)
70 (n=218)
66 (n=225)
58 (n=48)
71 (n=45)
71 (n=106)
70 (n=134)
≥ 200 cells/mm3
76 (n=222)
69 (n=228)
HIV RNA Mean Change from Baseline, log10 copies/ml
-3.09 (n=397)
-3.13 (n=379)
-3.21 (n=360)
-3.19 (n=340)
CD4 Mean Change from Baseline, cells/mm3
203 (n=370)
268 (n=336)
219 (n=363)
290 (n=317)
CD4 Mean Change from Baseline, cells/mm3 by Baseline Characteristic
179 (n=183)
243 (n=163)
194 (n=183)
267 (n=152)
227 (n=187)
291 (n=173)
245 (n=180)
310 (n=165)
a Mean baseline CD4 cell count was 214 cells/mm3 (range 2 to 810 cells/mm3) and mean baseline plasma HIV-1 RNA was 4.94 log10 copies/ml (range 2.6 to 5.88 log10 copies/ml) b REYATAZ/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily). c Lopinavir/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily). d Intent-to-treat analysis, with missing values considered as failures. e Per protocol analysis: Excluding non-completers and patients with major protocol deviations. f Number of patients evaluable. In antiretroviral experienced patients Study 045 is a randomised, multicenter trial comparing REYATAZ/ritonavir (300/100 mg once daily) and REYATAZ/saquinavir (400/1,200 mg once daily), to lopinavir + ritonavir (400/100 mg fixed dose combination twice daily), each in combination with tenofovir (see sections 4.5 and 4.8) and one NRTI, in patients with virologic failure on two or more prior regimens containing at least one PI, NRTI, and NNRTI. For randomised patients, the mean time of prior antiretroviral exposure was 138 weeks for PIs, 281 weeks for NRTIs, and 85 weeks for NNRTIs. At baseline, 34% of patients were receiving a PI and 60% were receiving an NNRTI. Fifteen of 120 (13%) patients in the REYATAZ + ritonavir treatment arm and 17 of 123 (14%) patients in the lopinavir + ritonavir arm had four or more of the PI substitutions L10, M46, I54, V82, I84, and L90. Thirty‑two percent of patients in the study had a viral strain with fewer than two NRTI substitutions. The primary endpoint was the time‑averaged difference in change from baseline in HIV RNA through 48 weeks (Table 5). Table 5: Efficacy Outcomes at Week 48a and at Week 96 (Study 045) Parameter ATV/RTVb (300 mg/ 100 mg once daily) n=120 LPV/RTVc (400 mg/ 100 mg twice daily) n=123 Time-averaged difference ATV/RTV-LPV/RTV [97.5% CId] Week 48 Week 96 Week 48 Week 96 Week 48 Week 96 HIV RNA Mean Change from Baseline, log10 copies/ml All patients -1.93 (n=90 e) -2.29 (n=64) -1.87 (n=99) -2.08 (n=65) 0.13 [‑0.12, 0.39] 0.14 [‑0.13, 0.41] HIV RNA <50 copies/ml, %f (responder/evaluable) All patients 36 (43/120) 32 (38/120) 42 (52/123 35 (41/118) NA NA HIV RNA <50 copies/ml by select baseline PI substitutions,f, g % (responder/evaluable) 0-2 44 (28/63) 41 (26/63) 56 (32/57) 48 (26/54) NA NA 3 18 (2/11) 9 (1/11) 38 (6/16) 33 (5/15) NA NA ≥4 27 (12/45) 24 (11/45) 28 (14/50) 20 (10/49) NA NA CD4 Mean Change from Baseline, cells/mm3 All patients 203 (n=370) 219 (n=363) Baseline Characteristics HIV RNA <100,000 copies/ml 179 (n=183) 194 (n=183) ≥100,000 copies/ml 227 (n=187) 245 (n=180) All patients 110 (n=83) 122 (n=60) 121 (n=94) 154 (n=60) NA NA a REYATAZ/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily). b Lopinavir/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily). c Intent-to-treat analysis, with missing values considered as failures. d Number of patients evaluable. In antiretroviral experienced patients Study 045 is a randomised, multicenter trial comparing REYATAZ (300 mg once daily) with ritonavir (100 mg once daily) to REYATAZ (400 mg once daily) with saquinavir soft gelatine capsules (1,200 mg once daily), and to lopinavir + ritonavir (400/100 mg fixed dose combination twice daily), each in combination with tenofovir (see sections 4.5 and 4.8) and one NRTI, in 347 (of 358 randomised) patients with virologic failure on two or more prior regimens containing at least one PI, NRTI, and NNRTI. For randomised patients, the mean time of prior antiretroviral exposure was 138 weeks for PIs, 281 weeks for NRTIs, and 85 weeks for NNRTIs. At baseline, 34% of patients were receiving a PI and 60% were receiving an NNRTI. Fifteen of 120 (13%) patients in the REYATAZ + ritonavir treatment arm and 17 of 123 (14%) patients in the lopinavir + ritonavir arm had four or more of the PI substitutions L10, M46, I54, V82, I84, and L90. Thirty‑two percent of patients in the study had a viral strain with fewer than two NRTI substitutions. The mean baseline CD4 cell count was 337 cells/mm3 (range: 14 to 1,543 cells/mm3) and the mean baseline plasma HIV‑1 RNA level was 4.4 log10 copies/ml (range: 2.6 to 5.88 log10 copies/ml). The population included in this study was moderately pretreated. The primary endpoint was the time‑averaged difference in change from baseline in HIV RNA through 48 weeks. Through 48 weeks of treatment, the decreases from baseline in HIV RNA levels (primary endpoint) were 1.93 log10 copies/ml for REYATAZ + ritonavir and 1.87 log10 copies/ml for lopinavir + ritonavir. REYATAZ + ritonavir was similar (non‑inferior) to lopinavir + ritonavir on this efficacy measure (time‑averaged difference of 0.13, 97.5% confidenceb ATV/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily). c LPV/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily). d Confidence interval [‑0.12, 0.39]).. e Number of patients evaluable. f Intent-to-treat analysis, with missing values considered as failures. Responders on LPV/RTV who completed treatment before Week 96 are excluded from Week 96 analysis. The proportion of patients with HIV RNA < 400 copies/ml were 53% and 43% for ATV/RTV and 54% and 46% for LPV/RTV at weeks 48 and 96 respectively. g Select substitutions include any change at positions L10, K20, L24, V32, L33, M36, M46, G48, I50, I54, L63, A71, G73, V82, I84, and L90 (0-2, 3, 4 or more) at baseline. NA = not applicable. Through 48 weeks of treatment, the mean changes from baseline in HIV RNA levels for REYATAZ + ritonavir and lopinavir + ritonavir were similar (non‑inferior). Consistent results were obtained with the last observation carried forward method of analysis (time‑averaged difference of 0.11, 97.5% confidence interval [‑0.15, 0.36]). The proportions of patients with HIV RNA < 400 copies/ml in the REYATAZ + ritonavir arm and the lopinavir + ritonavir arm were 53% and 54%, respectively, by intent‑to‑treat analysis, with missing values considered as failures. The proportions of patients with HIV RNA < 50 copies/ml in the REYATAZ + ritonavir arm and the lopinavir + ritonavir arm were 36% and 42%, respectively. By as‑treated analysis, excluding missing values, the proportions of patients with HIV RNA < 400 copies/ml (< 50 copies/ml) in the REYATAZ + ritonavir arm and the lopinavir + ritonavir arm were 55% (40%) and 56% (46%), respectively. The mean increases from baseline in CD4 cell count were 110 cells/mm3 and 121 cells/mm3 in the REYATAZ + ritonavir and lopinavir + ritonavir arms, respectively. Analyses of data through 96 Through 96 weeks of treatment demonstrated durability of antiviral activity. Mean, mean HIV RNA changes from baseline at Week 96 (‑2.29 log10 copies/ml for REYATAZ + ritonavir and ‑2.08 log10 copies/ml for lopinavir + ritonavir, time‑averaged difference of 0.14, 97.5% confidence interval [‑0.13, 0.41]) met criteria for non‑inferiority based on observed cases. Consistent results were obtained with the last observation carried forward method of analysis. The proportions of patients with HIV RNA <400 copies/ml (<50 copies/ml) for REYATAZ + ritonavir were 43% (32%) and for lopinavir + ritonavir were 46% (35%). Patients completing treatment while in response after 48 weeks were censored. By as‑treated analysis, excluding missing values, the proportions of patients with HIV RNA <400 copies/ml (<50 copies/ml) for REYATAZ + ritonavir were 84% (72%) and for lopinavir + ritonavir were 82% (72%). It is important to note that at time of the 96‑week analysis, 48 % of patients overall remained on study. Through 48 weeks of treatment, two types of analyses were performed based on baseline genotypic mutations. The first consisted in assessing the HIV RNA change from baseline in the subgroup of patients with < or ≥ of 4 of the following set of mutations: 10, 20, 24, 32, 33, 36, 46, 48, 50, 54, 63, 71, 73, 82, 84 and 90. The second consisted in assessing the HIV RNA change from baseline in the subgroup of patients with < or ≥ of 4 of the following more specific set of mutations: 10, 46, 54, 82, 84, 90. In the analysis performed for patients with ≥ 4 protease gene mutations among the following set of mutations 10, 20, 24, 32, 33, 36, 46, 48, 50, 54, 63, 71, 73, 82, 84 and 90, the results significantly favoured the lopinavir + ritonavir arm. There were too few patients with ≥ 4 of the second more specific set of mutations (i.e. 10, 46, 54, 82, 84, 90) to assess the comparability of the REYATAZ + ritonavir and lopinavir + ritonavir regimens, but reduced virologic activity may be anticipated among patients with this resistance profile. REYATAZ + saquinavir was shown to be inferior to lopinavir + ritonavir. 5.2 Pharmacokinetic properties Special populations Impaired renal function: in healthy subjects, the renal elimination of unchanged atazanavir was approximately 7% of the administered dose. There are no pharmacokinetic data available on for REYATAZ with ritonavir in patients with renal insufficiency (see section 4.2); however, the impact of renal impairment on atazanavir elimination is anticipated to be minimal.. REYATAZ (without ritonavir) has been studied in adult patients with severe renal impairment (n=20), including those on haemodialysis, at multiple doses of 400 mg once daily. Although this study presented some limitations (i.e., unbound drug concentrations not studied), results suggested that the atazanavir pharmacokinetic parameters were decreased by 30% to 50% in patients undergoing haemodialysis compared to patients with normal renal function. The mechanism of this decrease is unknown. (See sections 4.2 and 4.4.) 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 02 March 2004 Date of latest renewal : 09 February: 02 March 2009 10. DATE OF REVISION OF THE TEXT 9th FebruaryJuly 2009 Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/http://www.emea.europa.eu
b REYATAZ/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily). c Lopinavir/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily). d Intent-to-treat analysis, with missing values considered as failures. e Per protocol analysis: Excluding non-completers and patients with major protocol deviations. f Number of patients evaluable. In antiretroviral experienced patients Study 045 is a randomised, multicenter trial comparing REYATAZ/ritonavir (300/100 mg once daily) and REYATAZ/saquinavir (400/1,200 mg once daily), to lopinavir + ritonavir (400/100 mg fixed dose combination twice daily), each in combination with tenofovir (see sections 4.5 and 4.8) and one NRTI, in patients with virologic failure on two or more prior regimens containing at least one PI, NRTI, and NNRTI. For randomised patients, the mean time of prior antiretroviral exposure was 138 weeks for PIs, 281 weeks for NRTIs, and 85 weeks for NNRTIs. At baseline, 34% of patients were receiving a PI and 60% were receiving an NNRTI. Fifteen of 120 (13%) patients in the REYATAZ + ritonavir treatment arm and 17 of 123 (14%) patients in the lopinavir + ritonavir arm had four or more of the PI substitutions L10, M46, I54, V82, I84, and L90. Thirty‑two percent of patients in the study had a viral strain with fewer than two NRTI substitutions. The primary endpoint was the time‑averaged difference in change from baseline in HIV RNA through 48 weeks (Table 5). Table 5: Efficacy Outcomes at Week 48a and at Week 96 (Study 045) Parameter ATV/RTVb (300 mg/ 100 mg once daily) n=120 LPV/RTVc (400 mg/ 100 mg twice daily) n=123 Time-averaged difference ATV/RTV-LPV/RTV [97.5% CId] Week 48 Week 96 Week 48 Week 96 Week 48 Week 96 HIV RNA Mean Change from Baseline, log10 copies/ml All patients -1.93 (n=90 e) -2.29 (n=64) -1.87 (n=99) -2.08 (n=65) 0.13 [‑0.12, 0.39] 0.14 [‑0.13, 0.41] HIV RNA <50 copies/ml, %f (responder/evaluable) All patients 36 (43/120) 32 (38/120) 42 (52/123 35 (41/118) NA NA HIV RNA <50 copies/ml by select baseline PI substitutions,f, g % (responder/evaluable) 0-2 44 (28/63) 41 (26/63) 56 (32/57) 48 (26/54) NA NA 3 18 (2/11) 9 (1/11) 38 (6/16) 33 (5/15) NA NA ≥4 27 (12/45) 24 (11/45) 28 (14/50) 20 (10/49) NA NA CD4 Mean Change from Baseline, cells/mm3 All patients 203 (n=370) 219 (n=363) Baseline Characteristics HIV RNA <100,000 copies/ml 179 (n=183) 194 (n=183) ≥100,000 copies/ml 227 (n=187) 245 (n=180) All patients 110 (n=83) 122 (n=60) 121 (n=94) 154 (n=60) NA NA a REYATAZ/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily). b Lopinavir/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily). c Intent-to-treat analysis, with missing values considered as failures. d Number of patients evaluable. In antiretroviral experienced patients Study 045 is a randomised, multicenter trial comparing REYATAZ (300 mg once daily) with ritonavir (100 mg once daily) to REYATAZ (400 mg once daily) with saquinavir soft gelatine capsules (1,200 mg once daily), and to lopinavir + ritonavir (400/100 mg fixed dose combination twice daily), each in combination with tenofovir (see sections 4.5 and 4.8) and one NRTI, in 347 (of 358 randomised) patients with virologic failure on two or more prior regimens containing at least one PI, NRTI, and NNRTI. For randomised patients, the mean time of prior antiretroviral exposure was 138 weeks for PIs, 281 weeks for NRTIs, and 85 weeks for NNRTIs. At baseline, 34% of patients were receiving a PI and 60% were receiving an NNRTI. Fifteen of 120 (13%) patients in the REYATAZ + ritonavir treatment arm and 17 of 123 (14%) patients in the lopinavir + ritonavir arm had four or more of the PI substitutions L10, M46, I54, V82, I84, and L90. Thirty‑two percent of patients in the study had a viral strain with fewer than two NRTI substitutions. The mean baseline CD4 cell count was 337 cells/mm3 (range: 14 to 1,543 cells/mm3) and the mean baseline plasma HIV‑1 RNA level was 4.4 log10 copies/ml (range: 2.6 to 5.88 log10 copies/ml). The population included in this study was moderately pretreated. The primary endpoint was the time‑averaged difference in change from baseline in HIV RNA through 48 weeks. Through 48 weeks of treatment, the decreases from baseline in HIV RNA levels (primary endpoint) were 1.93 log10 copies/ml for REYATAZ + ritonavir and 1.87 log10 copies/ml for lopinavir + ritonavir. REYATAZ + ritonavir was similar (non‑inferior) to lopinavir + ritonavir on this efficacy measure (time‑averaged difference of 0.13, 97.5% confidenceb ATV/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily). c LPV/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily). d Confidence interval [‑0.12, 0.39]).. e Number of patients evaluable. f Intent-to-treat analysis, with missing values considered as failures. Responders on LPV/RTV who completed treatment before Week 96 are excluded from Week 96 analysis. The proportion of patients with HIV RNA < 400 copies/ml were 53% and 43% for ATV/RTV and 54% and 46% for LPV/RTV at weeks 48 and 96 respectively. g Select substitutions include any change at positions L10, K20, L24, V32, L33, M36, M46, G48, I50, I54, L63, A71, G73, V82, I84, and L90 (0-2, 3, 4 or more) at baseline. NA = not applicable. Through 48 weeks of treatment, the mean changes from baseline in HIV RNA levels for REYATAZ + ritonavir and lopinavir + ritonavir were similar (non‑inferior). Consistent results were obtained with the last observation carried forward method of analysis (time‑averaged difference of 0.11, 97.5% confidence interval [‑0.15, 0.36]). The proportions of patients with HIV RNA < 400 copies/ml in the REYATAZ + ritonavir arm and the lopinavir + ritonavir arm were 53% and 54%, respectively, by intent‑to‑treat analysis, with missing values considered as failures. The proportions of patients with HIV RNA < 50 copies/ml in the REYATAZ + ritonavir arm and the lopinavir + ritonavir arm were 36% and 42%, respectively. By as‑treated analysis, excluding missing values, the proportions of patients with HIV RNA < 400 copies/ml (< 50 copies/ml) in the REYATAZ + ritonavir arm and the lopinavir + ritonavir arm were 55% (40%) and 56% (46%), respectively. The mean increases from baseline in CD4 cell count were 110 cells/mm3 and 121 cells/mm3 in the REYATAZ + ritonavir and lopinavir + ritonavir arms, respectively. Analyses of data through 96 Through 96 weeks of treatment demonstrated durability of antiviral activity. Mean, mean HIV RNA changes from baseline at Week 96 (‑2.29 log10 copies/ml for REYATAZ + ritonavir and ‑2.08 log10 copies/ml for lopinavir + ritonavir, time‑averaged difference of 0.14, 97.5% confidence interval [‑0.13, 0.41]) met criteria for non‑inferiority based on observed cases. Consistent results were obtained with the last observation carried forward method of analysis. The proportions of patients with HIV RNA <400 copies/ml (<50 copies/ml) for REYATAZ + ritonavir were 43% (32%) and for lopinavir + ritonavir were 46% (35%). Patients completing treatment while in response after 48 weeks were censored. By as‑treated analysis, excluding missing values, the proportions of patients with HIV RNA <400 copies/ml (<50 copies/ml) for REYATAZ + ritonavir were 84% (72%) and for lopinavir + ritonavir were 82% (72%). It is important to note that at time of the 96‑week analysis, 48 % of patients overall remained on study. Through 48 weeks of treatment, two types of analyses were performed based on baseline genotypic mutations. The first consisted in assessing the HIV RNA change from baseline in the subgroup of patients with < or ≥ of 4 of the following set of mutations: 10, 20, 24, 32, 33, 36, 46, 48, 50, 54, 63, 71, 73, 82, 84 and 90. The second consisted in assessing the HIV RNA change from baseline in the subgroup of patients with < or ≥ of 4 of the following more specific set of mutations: 10, 46, 54, 82, 84, 90. In the analysis performed for patients with ≥ 4 protease gene mutations among the following set of mutations 10, 20, 24, 32, 33, 36, 46, 48, 50, 54, 63, 71, 73, 82, 84 and 90, the results significantly favoured the lopinavir + ritonavir arm. There were too few patients with ≥ 4 of the second more specific set of mutations (i.e. 10, 46, 54, 82, 84, 90) to assess the comparability of the REYATAZ + ritonavir and lopinavir + ritonavir regimens, but reduced virologic activity may be anticipated among patients with this resistance profile. REYATAZ + saquinavir was shown to be inferior to lopinavir + ritonavir. 5.2 Pharmacokinetic properties Special populations Impaired renal function: in healthy subjects, the renal elimination of unchanged atazanavir was approximately 7% of the administered dose. There are no pharmacokinetic data available on for REYATAZ with ritonavir in patients with renal insufficiency (see section 4.2); however, the impact of renal impairment on atazanavir elimination is anticipated to be minimal.. REYATAZ (without ritonavir) has been studied in adult patients with severe renal impairment (n=20), including those on haemodialysis, at multiple doses of 400 mg once daily. Although this study presented some limitations (i.e., unbound drug concentrations not studied), results suggested that the atazanavir pharmacokinetic parameters were decreased by 30% to 50% in patients undergoing haemodialysis compared to patients with normal renal function. The mechanism of this decrease is unknown. (See sections 4.2 and 4.4.) 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 02 March 2004 Date of latest renewal : 09 February: 02 March 2009 10. DATE OF REVISION OF THE TEXT 9th FebruaryJuly 2009 Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/http://www.emea.europa.eu
c Lopinavir/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily). d Intent-to-treat analysis, with missing values considered as failures. e Per protocol analysis: Excluding non-completers and patients with major protocol deviations. f Number of patients evaluable. In antiretroviral experienced patients Study 045 is a randomised, multicenter trial comparing REYATAZ/ritonavir (300/100 mg once daily) and REYATAZ/saquinavir (400/1,200 mg once daily), to lopinavir + ritonavir (400/100 mg fixed dose combination twice daily), each in combination with tenofovir (see sections 4.5 and 4.8) and one NRTI, in patients with virologic failure on two or more prior regimens containing at least one PI, NRTI, and NNRTI. For randomised patients, the mean time of prior antiretroviral exposure was 138 weeks for PIs, 281 weeks for NRTIs, and 85 weeks for NNRTIs. At baseline, 34% of patients were receiving a PI and 60% were receiving an NNRTI. Fifteen of 120 (13%) patients in the REYATAZ + ritonavir treatment arm and 17 of 123 (14%) patients in the lopinavir + ritonavir arm had four or more of the PI substitutions L10, M46, I54, V82, I84, and L90. Thirty‑two percent of patients in the study had a viral strain with fewer than two NRTI substitutions. The primary endpoint was the time‑averaged difference in change from baseline in HIV RNA through 48 weeks (Table 5). Table 5: Efficacy Outcomes at Week 48a and at Week 96 (Study 045) Parameter ATV/RTVb (300 mg/ 100 mg once daily) n=120 LPV/RTVc (400 mg/ 100 mg twice daily) n=123 Time-averaged difference ATV/RTV-LPV/RTV [97.5% CId] Week 48 Week 96 Week 48 Week 96 Week 48 Week 96 HIV RNA Mean Change from Baseline, log10 copies/ml All patients -1.93 (n=90 e) -2.29 (n=64) -1.87 (n=99) -2.08 (n=65) 0.13 [‑0.12, 0.39] 0.14 [‑0.13, 0.41] HIV RNA <50 copies/ml, %f (responder/evaluable) All patients 36 (43/120) 32 (38/120) 42 (52/123 35 (41/118) NA NA HIV RNA <50 copies/ml by select baseline PI substitutions,f, g % (responder/evaluable) 0-2 44 (28/63) 41 (26/63) 56 (32/57) 48 (26/54) NA NA 3 18 (2/11) 9 (1/11) 38 (6/16) 33 (5/15) NA NA ≥4 27 (12/45) 24 (11/45) 28 (14/50) 20 (10/49) NA NA CD4 Mean Change from Baseline, cells/mm3 All patients 203 (n=370) 219 (n=363) Baseline Characteristics HIV RNA <100,000 copies/ml 179 (n=183) 194 (n=183) ≥100,000 copies/ml 227 (n=187) 245 (n=180) All patients 110 (n=83) 122 (n=60) 121 (n=94) 154 (n=60) NA NA a REYATAZ/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily). b Lopinavir/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily). c Intent-to-treat analysis, with missing values considered as failures. d Number of patients evaluable. In antiretroviral experienced patients Study 045 is a randomised, multicenter trial comparing REYATAZ (300 mg once daily) with ritonavir (100 mg once daily) to REYATAZ (400 mg once daily) with saquinavir soft gelatine capsules (1,200 mg once daily), and to lopinavir + ritonavir (400/100 mg fixed dose combination twice daily), each in combination with tenofovir (see sections 4.5 and 4.8) and one NRTI, in 347 (of 358 randomised) patients with virologic failure on two or more prior regimens containing at least one PI, NRTI, and NNRTI. For randomised patients, the mean time of prior antiretroviral exposure was 138 weeks for PIs, 281 weeks for NRTIs, and 85 weeks for NNRTIs. At baseline, 34% of patients were receiving a PI and 60% were receiving an NNRTI. Fifteen of 120 (13%) patients in the REYATAZ + ritonavir treatment arm and 17 of 123 (14%) patients in the lopinavir + ritonavir arm had four or more of the PI substitutions L10, M46, I54, V82, I84, and L90. Thirty‑two percent of patients in the study had a viral strain with fewer than two NRTI substitutions. The mean baseline CD4 cell count was 337 cells/mm3 (range: 14 to 1,543 cells/mm3) and the mean baseline plasma HIV‑1 RNA level was 4.4 log10 copies/ml (range: 2.6 to 5.88 log10 copies/ml). The population included in this study was moderately pretreated. The primary endpoint was the time‑averaged difference in change from baseline in HIV RNA through 48 weeks. Through 48 weeks of treatment, the decreases from baseline in HIV RNA levels (primary endpoint) were 1.93 log10 copies/ml for REYATAZ + ritonavir and 1.87 log10 copies/ml for lopinavir + ritonavir. REYATAZ + ritonavir was similar (non‑inferior) to lopinavir + ritonavir on this efficacy measure (time‑averaged difference of 0.13, 97.5% confidenceb ATV/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily). c LPV/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily). d Confidence interval [‑0.12, 0.39]).. e Number of patients evaluable. f Intent-to-treat analysis, with missing values considered as failures. Responders on LPV/RTV who completed treatment before Week 96 are excluded from Week 96 analysis. The proportion of patients with HIV RNA < 400 copies/ml were 53% and 43% for ATV/RTV and 54% and 46% for LPV/RTV at weeks 48 and 96 respectively. g Select substitutions include any change at positions L10, K20, L24, V32, L33, M36, M46, G48, I50, I54, L63, A71, G73, V82, I84, and L90 (0-2, 3, 4 or more) at baseline. NA = not applicable. Through 48 weeks of treatment, the mean changes from baseline in HIV RNA levels for REYATAZ + ritonavir and lopinavir + ritonavir were similar (non‑inferior). Consistent results were obtained with the last observation carried forward method of analysis (time‑averaged difference of 0.11, 97.5% confidence interval [‑0.15, 0.36]). The proportions of patients with HIV RNA < 400 copies/ml in the REYATAZ + ritonavir arm and the lopinavir + ritonavir arm were 53% and 54%, respectively, by intent‑to‑treat analysis, with missing values considered as failures. The proportions of patients with HIV RNA < 50 copies/ml in the REYATAZ + ritonavir arm and the lopinavir + ritonavir arm were 36% and 42%, respectively. By as‑treated analysis, excluding missing values, the proportions of patients with HIV RNA < 400 copies/ml (< 50 copies/ml) in the REYATAZ + ritonavir arm and the lopinavir + ritonavir arm were 55% (40%) and 56% (46%), respectively. The mean increases from baseline in CD4 cell count were 110 cells/mm3 and 121 cells/mm3 in the REYATAZ + ritonavir and lopinavir + ritonavir arms, respectively. Analyses of data through 96 Through 96 weeks of treatment demonstrated durability of antiviral activity. Mean, mean HIV RNA changes from baseline at Week 96 (‑2.29 log10 copies/ml for REYATAZ + ritonavir and ‑2.08 log10 copies/ml for lopinavir + ritonavir, time‑averaged difference of 0.14, 97.5% confidence interval [‑0.13, 0.41]) met criteria for non‑inferiority based on observed cases. Consistent results were obtained with the last observation carried forward method of analysis. The proportions of patients with HIV RNA <400 copies/ml (<50 copies/ml) for REYATAZ + ritonavir were 43% (32%) and for lopinavir + ritonavir were 46% (35%). Patients completing treatment while in response after 48 weeks were censored. By as‑treated analysis, excluding missing values, the proportions of patients with HIV RNA <400 copies/ml (<50 copies/ml) for REYATAZ + ritonavir were 84% (72%) and for lopinavir + ritonavir were 82% (72%). It is important to note that at time of the 96‑week analysis, 48 % of patients overall remained on study. Through 48 weeks of treatment, two types of analyses were performed based on baseline genotypic mutations. The first consisted in assessing the HIV RNA change from baseline in the subgroup of patients with < or ≥ of 4 of the following set of mutations: 10, 20, 24, 32, 33, 36, 46, 48, 50, 54, 63, 71, 73, 82, 84 and 90. The second consisted in assessing the HIV RNA change from baseline in the subgroup of patients with < or ≥ of 4 of the following more specific set of mutations: 10, 46, 54, 82, 84, 90. In the analysis performed for patients with ≥ 4 protease gene mutations among the following set of mutations 10, 20, 24, 32, 33, 36, 46, 48, 50, 54, 63, 71, 73, 82, 84 and 90, the results significantly favoured the lopinavir + ritonavir arm. There were too few patients with ≥ 4 of the second more specific set of mutations (i.e. 10, 46, 54, 82, 84, 90) to assess the comparability of the REYATAZ + ritonavir and lopinavir + ritonavir regimens, but reduced virologic activity may be anticipated among patients with this resistance profile. REYATAZ + saquinavir was shown to be inferior to lopinavir + ritonavir. 5.2 Pharmacokinetic properties Special populations Impaired renal function: in healthy subjects, the renal elimination of unchanged atazanavir was approximately 7% of the administered dose. There are no pharmacokinetic data available on for REYATAZ with ritonavir in patients with renal insufficiency (see section 4.2); however, the impact of renal impairment on atazanavir elimination is anticipated to be minimal.. REYATAZ (without ritonavir) has been studied in adult patients with severe renal impairment (n=20), including those on haemodialysis, at multiple doses of 400 mg once daily. Although this study presented some limitations (i.e., unbound drug concentrations not studied), results suggested that the atazanavir pharmacokinetic parameters were decreased by 30% to 50% in patients undergoing haemodialysis compared to patients with normal renal function. The mechanism of this decrease is unknown. (See sections 4.2 and 4.4.) 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 02 March 2004 Date of latest renewal : 09 February: 02 March 2009 10. DATE OF REVISION OF THE TEXT 9th FebruaryJuly 2009 Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/http://www.emea.europa.eu
d Intent-to-treat analysis, with missing values considered as failures. e Per protocol analysis: Excluding non-completers and patients with major protocol deviations. f Number of patients evaluable. In antiretroviral experienced patients Study 045 is a randomised, multicenter trial comparing REYATAZ/ritonavir (300/100 mg once daily) and REYATAZ/saquinavir (400/1,200 mg once daily), to lopinavir + ritonavir (400/100 mg fixed dose combination twice daily), each in combination with tenofovir (see sections 4.5 and 4.8) and one NRTI, in patients with virologic failure on two or more prior regimens containing at least one PI, NRTI, and NNRTI. For randomised patients, the mean time of prior antiretroviral exposure was 138 weeks for PIs, 281 weeks for NRTIs, and 85 weeks for NNRTIs. At baseline, 34% of patients were receiving a PI and 60% were receiving an NNRTI. Fifteen of 120 (13%) patients in the REYATAZ + ritonavir treatment arm and 17 of 123 (14%) patients in the lopinavir + ritonavir arm had four or more of the PI substitutions L10, M46, I54, V82, I84, and L90. Thirty‑two percent of patients in the study had a viral strain with fewer than two NRTI substitutions. The primary endpoint was the time‑averaged difference in change from baseline in HIV RNA through 48 weeks (Table 5). Table 5: Efficacy Outcomes at Week 48a and at Week 96 (Study 045) Parameter ATV/RTVb (300 mg/ 100 mg once daily) n=120 LPV/RTVc (400 mg/ 100 mg twice daily) n=123 Time-averaged difference ATV/RTV-LPV/RTV [97.5% CId] Week 48 Week 96 Week 48 Week 96 Week 48 Week 96 HIV RNA Mean Change from Baseline, log10 copies/ml All patients -1.93 (n=90 e) -2.29 (n=64) -1.87 (n=99) -2.08 (n=65) 0.13 [‑0.12, 0.39] 0.14 [‑0.13, 0.41] HIV RNA <50 copies/ml, %f (responder/evaluable) All patients 36 (43/120) 32 (38/120) 42 (52/123 35 (41/118) NA NA HIV RNA <50 copies/ml by select baseline PI substitutions,f, g % (responder/evaluable) 0-2 44 (28/63) 41 (26/63) 56 (32/57) 48 (26/54) NA NA 3 18 (2/11) 9 (1/11) 38 (6/16) 33 (5/15) NA NA ≥4 27 (12/45) 24 (11/45) 28 (14/50) 20 (10/49) NA NA CD4 Mean Change from Baseline, cells/mm3 All patients 203 (n=370) 219 (n=363) Baseline Characteristics HIV RNA <100,000 copies/ml 179 (n=183) 194 (n=183) ≥100,000 copies/ml 227 (n=187) 245 (n=180) All patients 110 (n=83) 122 (n=60) 121 (n=94) 154 (n=60) NA NA a REYATAZ/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily). b Lopinavir/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily). c Intent-to-treat analysis, with missing values considered as failures. d Number of patients evaluable. In antiretroviral experienced patients Study 045 is a randomised, multicenter trial comparing REYATAZ (300 mg once daily) with ritonavir (100 mg once daily) to REYATAZ (400 mg once daily) with saquinavir soft gelatine capsules (1,200 mg once daily), and to lopinavir + ritonavir (400/100 mg fixed dose combination twice daily), each in combination with tenofovir (see sections 4.5 and 4.8) and one NRTI, in 347 (of 358 randomised) patients with virologic failure on two or more prior regimens containing at least one PI, NRTI, and NNRTI. For randomised patients, the mean time of prior antiretroviral exposure was 138 weeks for PIs, 281 weeks for NRTIs, and 85 weeks for NNRTIs. At baseline, 34% of patients were receiving a PI and 60% were receiving an NNRTI. Fifteen of 120 (13%) patients in the REYATAZ + ritonavir treatment arm and 17 of 123 (14%) patients in the lopinavir + ritonavir arm had four or more of the PI substitutions L10, M46, I54, V82, I84, and L90. Thirty‑two percent of patients in the study had a viral strain with fewer than two NRTI substitutions. The mean baseline CD4 cell count was 337 cells/mm3 (range: 14 to 1,543 cells/mm3) and the mean baseline plasma HIV‑1 RNA level was 4.4 log10 copies/ml (range: 2.6 to 5.88 log10 copies/ml). The population included in this study was moderately pretreated. The primary endpoint was the time‑averaged difference in change from baseline in HIV RNA through 48 weeks. Through 48 weeks of treatment, the decreases from baseline in HIV RNA levels (primary endpoint) were 1.93 log10 copies/ml for REYATAZ + ritonavir and 1.87 log10 copies/ml for lopinavir + ritonavir. REYATAZ + ritonavir was similar (non‑inferior) to lopinavir + ritonavir on this efficacy measure (time‑averaged difference of 0.13, 97.5% confidenceb ATV/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily). c LPV/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily). d Confidence interval [‑0.12, 0.39]).. e Number of patients evaluable. f Intent-to-treat analysis, with missing values considered as failures. Responders on LPV/RTV who completed treatment before Week 96 are excluded from Week 96 analysis. The proportion of patients with HIV RNA < 400 copies/ml were 53% and 43% for ATV/RTV and 54% and 46% for LPV/RTV at weeks 48 and 96 respectively. g Select substitutions include any change at positions L10, K20, L24, V32, L33, M36, M46, G48, I50, I54, L63, A71, G73, V82, I84, and L90 (0-2, 3, 4 or more) at baseline. NA = not applicable. Through 48 weeks of treatment, the mean changes from baseline in HIV RNA levels for REYATAZ + ritonavir and lopinavir + ritonavir were similar (non‑inferior). Consistent results were obtained with the last observation carried forward method of analysis (time‑averaged difference of 0.11, 97.5% confidence interval [‑0.15, 0.36]). The proportions of patients with HIV RNA < 400 copies/ml in the REYATAZ + ritonavir arm and the lopinavir + ritonavir arm were 53% and 54%, respectively, by intent‑to‑treat analysis, with missing values considered as failures. The proportions of patients with HIV RNA < 50 copies/ml in the REYATAZ + ritonavir arm and the lopinavir + ritonavir arm were 36% and 42%, respectively. By as‑treated analysis, excluding missing values, the proportions of patients with HIV RNA < 400 copies/ml (< 50 copies/ml) in the REYATAZ + ritonavir arm and the lopinavir + ritonavir arm were 55% (40%) and 56% (46%), respectively. The mean increases from baseline in CD4 cell count were 110 cells/mm3 and 121 cells/mm3 in the REYATAZ + ritonavir and lopinavir + ritonavir arms, respectively. Analyses of data through 96 Through 96 weeks of treatment demonstrated durability of antiviral activity. Mean, mean HIV RNA changes from baseline at Week 96 (‑2.29 log10 copies/ml for REYATAZ + ritonavir and ‑2.08 log10 copies/ml for lopinavir + ritonavir, time‑averaged difference of 0.14, 97.5% confidence interval [‑0.13, 0.41]) met criteria for non‑inferiority based on observed cases. Consistent results were obtained with the last observation carried forward method of analysis. The proportions of patients with HIV RNA <400 copies/ml (<50 copies/ml) for REYATAZ + ritonavir were 43% (32%) and for lopinavir + ritonavir were 46% (35%). Patients completing treatment while in response after 48 weeks were censored. By as‑treated analysis, excluding missing values, the proportions of patients with HIV RNA <400 copies/ml (<50 copies/ml) for REYATAZ + ritonavir were 84% (72%) and for lopinavir + ritonavir were 82% (72%). It is important to note that at time of the 96‑week analysis, 48 % of patients overall remained on study. Through 48 weeks of treatment, two types of analyses were performed based on baseline genotypic mutations. The first consisted in assessing the HIV RNA change from baseline in the subgroup of patients with < or ≥ of 4 of the following set of mutations: 10, 20, 24, 32, 33, 36, 46, 48, 50, 54, 63, 71, 73, 82, 84 and 90. The second consisted in assessing the HIV RNA change from baseline in the subgroup of patients with < or ≥ of 4 of the following more specific set of mutations: 10, 46, 54, 82, 84, 90. In the analysis performed for patients with ≥ 4 protease gene mutations among the following set of mutations 10, 20, 24, 32, 33, 36, 46, 48, 50, 54, 63, 71, 73, 82, 84 and 90, the results significantly favoured the lopinavir + ritonavir arm. There were too few patients with ≥ 4 of the second more specific set of mutations (i.e. 10, 46, 54, 82, 84, 90) to assess the comparability of the REYATAZ + ritonavir and lopinavir + ritonavir regimens, but reduced virologic activity may be anticipated among patients with this resistance profile. REYATAZ + saquinavir was shown to be inferior to lopinavir + ritonavir. 5.2 Pharmacokinetic properties Special populations Impaired renal function: in healthy subjects, the renal elimination of unchanged atazanavir was approximately 7% of the administered dose. There are no pharmacokinetic data available on for REYATAZ with ritonavir in patients with renal insufficiency (see section 4.2); however, the impact of renal impairment on atazanavir elimination is anticipated to be minimal.. REYATAZ (without ritonavir) has been studied in adult patients with severe renal impairment (n=20), including those on haemodialysis, at multiple doses of 400 mg once daily. Although this study presented some limitations (i.e., unbound drug concentrations not studied), results suggested that the atazanavir pharmacokinetic parameters were decreased by 30% to 50% in patients undergoing haemodialysis compared to patients with normal renal function. The mechanism of this decrease is unknown. (See sections 4.2 and 4.4.) 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 02 March 2004 Date of latest renewal : 09 February: 02 March 2009 10. DATE OF REVISION OF THE TEXT 9th FebruaryJuly 2009 Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/http://www.emea.europa.eu
e Per protocol analysis: Excluding non-completers and patients with major protocol deviations. f Number of patients evaluable. In antiretroviral experienced patients Study 045 is a randomised, multicenter trial comparing REYATAZ/ritonavir (300/100 mg once daily) and REYATAZ/saquinavir (400/1,200 mg once daily), to lopinavir + ritonavir (400/100 mg fixed dose combination twice daily), each in combination with tenofovir (see sections 4.5 and 4.8) and one NRTI, in patients with virologic failure on two or more prior regimens containing at least one PI, NRTI, and NNRTI. For randomised patients, the mean time of prior antiretroviral exposure was 138 weeks for PIs, 281 weeks for NRTIs, and 85 weeks for NNRTIs. At baseline, 34% of patients were receiving a PI and 60% were receiving an NNRTI. Fifteen of 120 (13%) patients in the REYATAZ + ritonavir treatment arm and 17 of 123 (14%) patients in the lopinavir + ritonavir arm had four or more of the PI substitutions L10, M46, I54, V82, I84, and L90. Thirty‑two percent of patients in the study had a viral strain with fewer than two NRTI substitutions. The primary endpoint was the time‑averaged difference in change from baseline in HIV RNA through 48 weeks (Table 5). Table 5: Efficacy Outcomes at Week 48a and at Week 96 (Study 045) Parameter ATV/RTVb (300 mg/ 100 mg once daily) n=120 LPV/RTVc (400 mg/ 100 mg twice daily) n=123 Time-averaged difference ATV/RTV-LPV/RTV [97.5% CId] Week 48 Week 96 Week 48 Week 96 Week 48 Week 96 HIV RNA Mean Change from Baseline, log10 copies/ml All patients -1.93 (n=90 e) -2.29 (n=64) -1.87 (n=99) -2.08 (n=65) 0.13 [‑0.12, 0.39] 0.14 [‑0.13, 0.41] HIV RNA <50 copies/ml, %f (responder/evaluable) All patients 36 (43/120) 32 (38/120) 42 (52/123 35 (41/118) NA NA HIV RNA <50 copies/ml by select baseline PI substitutions,f, g % (responder/evaluable) 0-2 44 (28/63) 41 (26/63) 56 (32/57) 48 (26/54) NA NA 3 18 (2/11) 9 (1/11) 38 (6/16) 33 (5/15) NA NA ≥4 27 (12/45) 24 (11/45) 28 (14/50) 20 (10/49) NA NA CD4 Mean Change from Baseline, cells/mm3 All patients 203 (n=370) 219 (n=363) Baseline Characteristics HIV RNA <100,000 copies/ml 179 (n=183) 194 (n=183) ≥100,000 copies/ml 227 (n=187) 245 (n=180) All patients 110 (n=83) 122 (n=60) 121 (n=94) 154 (n=60) NA NA a REYATAZ/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily). b Lopinavir/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily). c Intent-to-treat analysis, with missing values considered as failures. d Number of patients evaluable. In antiretroviral experienced patients Study 045 is a randomised, multicenter trial comparing REYATAZ (300 mg once daily) with ritonavir (100 mg once daily) to REYATAZ (400 mg once daily) with saquinavir soft gelatine capsules (1,200 mg once daily), and to lopinavir + ritonavir (400/100 mg fixed dose combination twice daily), each in combination with tenofovir (see sections 4.5 and 4.8) and one NRTI, in 347 (of 358 randomised) patients with virologic failure on two or more prior regimens containing at least one PI, NRTI, and NNRTI. For randomised patients, the mean time of prior antiretroviral exposure was 138 weeks for PIs, 281 weeks for NRTIs, and 85 weeks for NNRTIs. At baseline, 34% of patients were receiving a PI and 60% were receiving an NNRTI. Fifteen of 120 (13%) patients in the REYATAZ + ritonavir treatment arm and 17 of 123 (14%) patients in the lopinavir + ritonavir arm had four or more of the PI substitutions L10, M46, I54, V82, I84, and L90. Thirty‑two percent of patients in the study had a viral strain with fewer than two NRTI substitutions. The mean baseline CD4 cell count was 337 cells/mm3 (range: 14 to 1,543 cells/mm3) and the mean baseline plasma HIV‑1 RNA level was 4.4 log10 copies/ml (range: 2.6 to 5.88 log10 copies/ml). The population included in this study was moderately pretreated. The primary endpoint was the time‑averaged difference in change from baseline in HIV RNA through 48 weeks. Through 48 weeks of treatment, the decreases from baseline in HIV RNA levels (primary endpoint) were 1.93 log10 copies/ml for REYATAZ + ritonavir and 1.87 log10 copies/ml for lopinavir + ritonavir. REYATAZ + ritonavir was similar (non‑inferior) to lopinavir + ritonavir on this efficacy measure (time‑averaged difference of 0.13, 97.5% confidenceb ATV/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily). c LPV/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily). d Confidence interval [‑0.12, 0.39]).. e Number of patients evaluable. f Intent-to-treat analysis, with missing values considered as failures. Responders on LPV/RTV who completed treatment before Week 96 are excluded from Week 96 analysis. The proportion of patients with HIV RNA < 400 copies/ml were 53% and 43% for ATV/RTV and 54% and 46% for LPV/RTV at weeks 48 and 96 respectively. g Select substitutions include any change at positions L10, K20, L24, V32, L33, M36, M46, G48, I50, I54, L63, A71, G73, V82, I84, and L90 (0-2, 3, 4 or more) at baseline. NA = not applicable. Through 48 weeks of treatment, the mean changes from baseline in HIV RNA levels for REYATAZ + ritonavir and lopinavir + ritonavir were similar (non‑inferior). Consistent results were obtained with the last observation carried forward method of analysis (time‑averaged difference of 0.11, 97.5% confidence interval [‑0.15, 0.36]). The proportions of patients with HIV RNA < 400 copies/ml in the REYATAZ + ritonavir arm and the lopinavir + ritonavir arm were 53% and 54%, respectively, by intent‑to‑treat analysis, with missing values considered as failures. The proportions of patients with HIV RNA < 50 copies/ml in the REYATAZ + ritonavir arm and the lopinavir + ritonavir arm were 36% and 42%, respectively. By as‑treated analysis, excluding missing values, the proportions of patients with HIV RNA < 400 copies/ml (< 50 copies/ml) in the REYATAZ + ritonavir arm and the lopinavir + ritonavir arm were 55% (40%) and 56% (46%), respectively. The mean increases from baseline in CD4 cell count were 110 cells/mm3 and 121 cells/mm3 in the REYATAZ + ritonavir and lopinavir + ritonavir arms, respectively. Analyses of data through 96 Through 96 weeks of treatment demonstrated durability of antiviral activity. Mean, mean HIV RNA changes from baseline at Week 96 (‑2.29 log10 copies/ml for REYATAZ + ritonavir and ‑2.08 log10 copies/ml for lopinavir + ritonavir, time‑averaged difference of 0.14, 97.5% confidence interval [‑0.13, 0.41]) met criteria for non‑inferiority based on observed cases. Consistent results were obtained with the last observation carried forward method of analysis. The proportions of patients with HIV RNA <400 copies/ml (<50 copies/ml) for REYATAZ + ritonavir were 43% (32%) and for lopinavir + ritonavir were 46% (35%). Patients completing treatment while in response after 48 weeks were censored. By as‑treated analysis, excluding missing values, the proportions of patients with HIV RNA <400 copies/ml (<50 copies/ml) for REYATAZ + ritonavir were 84% (72%) and for lopinavir + ritonavir were 82% (72%). It is important to note that at time of the 96‑week analysis, 48 % of patients overall remained on study. Through 48 weeks of treatment, two types of analyses were performed based on baseline genotypic mutations. The first consisted in assessing the HIV RNA change from baseline in the subgroup of patients with < or ≥ of 4 of the following set of mutations: 10, 20, 24, 32, 33, 36, 46, 48, 50, 54, 63, 71, 73, 82, 84 and 90. The second consisted in assessing the HIV RNA change from baseline in the subgroup of patients with < or ≥ of 4 of the following more specific set of mutations: 10, 46, 54, 82, 84, 90. In the analysis performed for patients with ≥ 4 protease gene mutations among the following set of mutations 10, 20, 24, 32, 33, 36, 46, 48, 50, 54, 63, 71, 73, 82, 84 and 90, the results significantly favoured the lopinavir + ritonavir arm. There were too few patients with ≥ 4 of the second more specific set of mutations (i.e. 10, 46, 54, 82, 84, 90) to assess the comparability of the REYATAZ + ritonavir and lopinavir + ritonavir regimens, but reduced virologic activity may be anticipated among patients with this resistance profile. REYATAZ + saquinavir was shown to be inferior to lopinavir + ritonavir. 5.2 Pharmacokinetic properties Special populations Impaired renal function: in healthy subjects, the renal elimination of unchanged atazanavir was approximately 7% of the administered dose. There are no pharmacokinetic data available on for REYATAZ with ritonavir in patients with renal insufficiency (see section 4.2); however, the impact of renal impairment on atazanavir elimination is anticipated to be minimal.. REYATAZ (without ritonavir) has been studied in adult patients with severe renal impairment (n=20), including those on haemodialysis, at multiple doses of 400 mg once daily. Although this study presented some limitations (i.e., unbound drug concentrations not studied), results suggested that the atazanavir pharmacokinetic parameters were decreased by 30% to 50% in patients undergoing haemodialysis compared to patients with normal renal function. The mechanism of this decrease is unknown. (See sections 4.2 and 4.4.) 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 02 March 2004 Date of latest renewal : 09 February: 02 March 2009 10. DATE OF REVISION OF THE TEXT 9th FebruaryJuly 2009 Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/http://www.emea.europa.eu
f Number of patients evaluable. In antiretroviral experienced patients Study 045 is a randomised, multicenter trial comparing REYATAZ/ritonavir (300/100 mg once daily) and REYATAZ/saquinavir (400/1,200 mg once daily), to lopinavir + ritonavir (400/100 mg fixed dose combination twice daily), each in combination with tenofovir (see sections 4.5 and 4.8) and one NRTI, in patients with virologic failure on two or more prior regimens containing at least one PI, NRTI, and NNRTI. For randomised patients, the mean time of prior antiretroviral exposure was 138 weeks for PIs, 281 weeks for NRTIs, and 85 weeks for NNRTIs. At baseline, 34% of patients were receiving a PI and 60% were receiving an NNRTI. Fifteen of 120 (13%) patients in the REYATAZ + ritonavir treatment arm and 17 of 123 (14%) patients in the lopinavir + ritonavir arm had four or more of the PI substitutions L10, M46, I54, V82, I84, and L90. Thirty‑two percent of patients in the study had a viral strain with fewer than two NRTI substitutions. The primary endpoint was the time‑averaged difference in change from baseline in HIV RNA through 48 weeks (Table 5). Table 5: Efficacy Outcomes at Week 48a and at Week 96 (Study 045) Parameter ATV/RTVb (300 mg/ 100 mg once daily) n=120 LPV/RTVc (400 mg/ 100 mg twice daily) n=123 Time-averaged difference ATV/RTV-LPV/RTV [97.5% CId] Week 48 Week 96 Week 48 Week 96 Week 48 Week 96 HIV RNA Mean Change from Baseline, log10 copies/ml All patients -1.93 (n=90 e) -2.29 (n=64) -1.87 (n=99) -2.08 (n=65) 0.13 [‑0.12, 0.39] 0.14 [‑0.13, 0.41] HIV RNA <50 copies/ml, %f (responder/evaluable) All patients 36 (43/120) 32 (38/120) 42 (52/123 35 (41/118) NA NA HIV RNA <50 copies/ml by select baseline PI substitutions,f, g % (responder/evaluable) 0-2 44 (28/63) 41 (26/63) 56 (32/57) 48 (26/54) NA NA 3 18 (2/11) 9 (1/11) 38 (6/16) 33 (5/15) NA NA ≥4 27 (12/45) 24 (11/45) 28 (14/50) 20 (10/49) NA NA CD4 Mean Change from Baseline, cells/mm3 All patients 203 (n=370) 219 (n=363) Baseline Characteristics HIV RNA <100,000 copies/ml 179 (n=183) 194 (n=183) ≥100,000 copies/ml 227 (n=187) 245 (n=180) All patients 110 (n=83) 122 (n=60) 121 (n=94) 154 (n=60) NA NA a REYATAZ/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily). b Lopinavir/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily). c Intent-to-treat analysis, with missing values considered as failures. d Number of patients evaluable. In antiretroviral experienced patients Study 045 is a randomised, multicenter trial comparing REYATAZ (300 mg once daily) with ritonavir (100 mg once daily) to REYATAZ (400 mg once daily) with saquinavir soft gelatine capsules (1,200 mg once daily), and to lopinavir + ritonavir (400/100 mg fixed dose combination twice daily), each in combination with tenofovir (see sections 4.5 and 4.8) and one NRTI, in 347 (of 358 randomised) patients with virologic failure on two or more prior regimens containing at least one PI, NRTI, and NNRTI. For randomised patients, the mean time of prior antiretroviral exposure was 138 weeks for PIs, 281 weeks for NRTIs, and 85 weeks for NNRTIs. At baseline, 34% of patients were receiving a PI and 60% were receiving an NNRTI. Fifteen of 120 (13%) patients in the REYATAZ + ritonavir treatment arm and 17 of 123 (14%) patients in the lopinavir + ritonavir arm had four or more of the PI substitutions L10, M46, I54, V82, I84, and L90. Thirty‑two percent of patients in the study had a viral strain with fewer than two NRTI substitutions. The mean baseline CD4 cell count was 337 cells/mm3 (range: 14 to 1,543 cells/mm3) and the mean baseline plasma HIV‑1 RNA level was 4.4 log10 copies/ml (range: 2.6 to 5.88 log10 copies/ml). The population included in this study was moderately pretreated. The primary endpoint was the time‑averaged difference in change from baseline in HIV RNA through 48 weeks. Through 48 weeks of treatment, the decreases from baseline in HIV RNA levels (primary endpoint) were 1.93 log10 copies/ml for REYATAZ + ritonavir and 1.87 log10 copies/ml for lopinavir + ritonavir. REYATAZ + ritonavir was similar (non‑inferior) to lopinavir + ritonavir on this efficacy measure (time‑averaged difference of 0.13, 97.5% confidenceb ATV/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily). c LPV/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily). d Confidence interval [‑0.12, 0.39]).. e Number of patients evaluable. f Intent-to-treat analysis, with missing values considered as failures. Responders on LPV/RTV who completed treatment before Week 96 are excluded from Week 96 analysis. The proportion of patients with HIV RNA < 400 copies/ml were 53% and 43% for ATV/RTV and 54% and 46% for LPV/RTV at weeks 48 and 96 respectively. g Select substitutions include any change at positions L10, K20, L24, V32, L33, M36, M46, G48, I50, I54, L63, A71, G73, V82, I84, and L90 (0-2, 3, 4 or more) at baseline. NA = not applicable. Through 48 weeks of treatment, the mean changes from baseline in HIV RNA levels for REYATAZ + ritonavir and lopinavir + ritonavir were similar (non‑inferior). Consistent results were obtained with the last observation carried forward method of analysis (time‑averaged difference of 0.11, 97.5% confidence interval [‑0.15, 0.36]). The proportions of patients with HIV RNA < 400 copies/ml in the REYATAZ + ritonavir arm and the lopinavir + ritonavir arm were 53% and 54%, respectively, by intent‑to‑treat analysis, with missing values considered as failures. The proportions of patients with HIV RNA < 50 copies/ml in the REYATAZ + ritonavir arm and the lopinavir + ritonavir arm were 36% and 42%, respectively. By as‑treated analysis, excluding missing values, the proportions of patients with HIV RNA < 400 copies/ml (< 50 copies/ml) in the REYATAZ + ritonavir arm and the lopinavir + ritonavir arm were 55% (40%) and 56% (46%), respectively. The mean increases from baseline in CD4 cell count were 110 cells/mm3 and 121 cells/mm3 in the REYATAZ + ritonavir and lopinavir + ritonavir arms, respectively. Analyses of data through 96 Through 96 weeks of treatment demonstrated durability of antiviral activity. Mean, mean HIV RNA changes from baseline at Week 96 (‑2.29 log10 copies/ml for REYATAZ + ritonavir and ‑2.08 log10 copies/ml for lopinavir + ritonavir, time‑averaged difference of 0.14, 97.5% confidence interval [‑0.13, 0.41]) met criteria for non‑inferiority based on observed cases. Consistent results were obtained with the last observation carried forward method of analysis. The proportions of patients with HIV RNA <400 copies/ml (<50 copies/ml) for REYATAZ + ritonavir were 43% (32%) and for lopinavir + ritonavir were 46% (35%). Patients completing treatment while in response after 48 weeks were censored. By as‑treated analysis, excluding missing values, the proportions of patients with HIV RNA <400 copies/ml (<50 copies/ml) for REYATAZ + ritonavir were 84% (72%) and for lopinavir + ritonavir were 82% (72%). It is important to note that at time of the 96‑week analysis, 48 % of patients overall remained on study. Through 48 weeks of treatment, two types of analyses were performed based on baseline genotypic mutations. The first consisted in assessing the HIV RNA change from baseline in the subgroup of patients with < or ≥ of 4 of the following set of mutations: 10, 20, 24, 32, 33, 36, 46, 48, 50, 54, 63, 71, 73, 82, 84 and 90. The second consisted in assessing the HIV RNA change from baseline in the subgroup of patients with < or ≥ of 4 of the following more specific set of mutations: 10, 46, 54, 82, 84, 90. In the analysis performed for patients with ≥ 4 protease gene mutations among the following set of mutations 10, 20, 24, 32, 33, 36, 46, 48, 50, 54, 63, 71, 73, 82, 84 and 90, the results significantly favoured the lopinavir + ritonavir arm. There were too few patients with ≥ 4 of the second more specific set of mutations (i.e. 10, 46, 54, 82, 84, 90) to assess the comparability of the REYATAZ + ritonavir and lopinavir + ritonavir regimens, but reduced virologic activity may be anticipated among patients with this resistance profile. REYATAZ + saquinavir was shown to be inferior to lopinavir + ritonavir. 5.2 Pharmacokinetic properties Special populations Impaired renal function: in healthy subjects, the renal elimination of unchanged atazanavir was approximately 7% of the administered dose. There are no pharmacokinetic data available on for REYATAZ with ritonavir in patients with renal insufficiency (see section 4.2); however, the impact of renal impairment on atazanavir elimination is anticipated to be minimal.. REYATAZ (without ritonavir) has been studied in adult patients with severe renal impairment (n=20), including those on haemodialysis, at multiple doses of 400 mg once daily. Although this study presented some limitations (i.e., unbound drug concentrations not studied), results suggested that the atazanavir pharmacokinetic parameters were decreased by 30% to 50% in patients undergoing haemodialysis compared to patients with normal renal function. The mechanism of this decrease is unknown. (See sections 4.2 and 4.4.) 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 02 March 2004 Date of latest renewal : 09 February: 02 March 2009 10. DATE OF REVISION OF THE TEXT 9th FebruaryJuly 2009 Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/http://www.emea.europa.eu
In antiretroviral experienced patients
Study 045 is a randomised, multicenter trial comparing REYATAZ/ritonavir (300/100 mg once daily) and REYATAZ/saquinavir (400/1,200 mg once daily), to lopinavir + ritonavir (400/100 mg fixed dose combination twice daily), each in combination with tenofovir (see sections 4.5 and 4.8) and one NRTI, in patients with virologic failure on two or more prior regimens containing at least one PI, NRTI, and NNRTI. For randomised patients, the mean time of prior antiretroviral exposure was 138 weeks for PIs, 281 weeks for NRTIs, and 85 weeks for NNRTIs. At baseline, 34% of patients were receiving a PI and 60% were receiving an NNRTI. Fifteen of 120 (13%) patients in the REYATAZ + ritonavir treatment arm and 17 of 123 (14%) patients in the lopinavir + ritonavir arm had four or more of the PI substitutions L10, M46, I54, V82, I84, and L90. Thirty‑two percent of patients in the study had a viral strain with fewer than two NRTI substitutions.
The primary endpoint was the time‑averaged difference in change from baseline in HIV RNA through 48 weeks (Table 5).
Table 5: Efficacy Outcomes at Week 48a and at Week 96 (Study 045)
ATV/RTVb (300 mg/ 100 mg once daily)
n=120
LPV/RTVc (400 mg/ 100 mg twice daily)
n=123
Time-averaged difference ATV/RTV-LPV/RTV
[97.5% CId]
-1.93
(n=90 e)
-2.29 (n=64)
-1.87 (n=99)
-2.08 (n=65)
0.13
[‑0.12, 0.39]
0.14
[‑0.13, 0.41]
HIV RNA <50 copies/ml, %f (responder/evaluable)
36 (43/120)
32 (38/120)
42 (52/123
35 (41/118)
NA
HIV RNA <50 copies/ml by select baseline PI substitutions,f, g % (responder/evaluable)
0-2
44 (28/63)
41 (26/63)
56 (32/57)
48 (26/54)
3
18 (2/11)
9 (1/11)
38 (6/16)
33 (5/15)
≥4
27 (12/45)
24 (11/45)
28 (14/50)
20 (10/49)
110 (n=83)
122 (n=60)
121 (n=94)
154 (n=60)
a REYATAZ/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily). b Lopinavir/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily). c Intent-to-treat analysis, with missing values considered as failures. d Number of patients evaluable. In antiretroviral experienced patients Study 045 is a randomised, multicenter trial comparing REYATAZ (300 mg once daily) with ritonavir (100 mg once daily) to REYATAZ (400 mg once daily) with saquinavir soft gelatine capsules (1,200 mg once daily), and to lopinavir + ritonavir (400/100 mg fixed dose combination twice daily), each in combination with tenofovir (see sections 4.5 and 4.8) and one NRTI, in 347 (of 358 randomised) patients with virologic failure on two or more prior regimens containing at least one PI, NRTI, and NNRTI. For randomised patients, the mean time of prior antiretroviral exposure was 138 weeks for PIs, 281 weeks for NRTIs, and 85 weeks for NNRTIs. At baseline, 34% of patients were receiving a PI and 60% were receiving an NNRTI. Fifteen of 120 (13%) patients in the REYATAZ + ritonavir treatment arm and 17 of 123 (14%) patients in the lopinavir + ritonavir arm had four or more of the PI substitutions L10, M46, I54, V82, I84, and L90. Thirty‑two percent of patients in the study had a viral strain with fewer than two NRTI substitutions. The mean baseline CD4 cell count was 337 cells/mm3 (range: 14 to 1,543 cells/mm3) and the mean baseline plasma HIV‑1 RNA level was 4.4 log10 copies/ml (range: 2.6 to 5.88 log10 copies/ml). The population included in this study was moderately pretreated. The primary endpoint was the time‑averaged difference in change from baseline in HIV RNA through 48 weeks. Through 48 weeks of treatment, the decreases from baseline in HIV RNA levels (primary endpoint) were 1.93 log10 copies/ml for REYATAZ + ritonavir and 1.87 log10 copies/ml for lopinavir + ritonavir. REYATAZ + ritonavir was similar (non‑inferior) to lopinavir + ritonavir on this efficacy measure (time‑averaged difference of 0.13, 97.5% confidenceb ATV/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily). c LPV/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily). d Confidence interval [‑0.12, 0.39]).. e Number of patients evaluable. f Intent-to-treat analysis, with missing values considered as failures. Responders on LPV/RTV who completed treatment before Week 96 are excluded from Week 96 analysis. The proportion of patients with HIV RNA < 400 copies/ml were 53% and 43% for ATV/RTV and 54% and 46% for LPV/RTV at weeks 48 and 96 respectively. g Select substitutions include any change at positions L10, K20, L24, V32, L33, M36, M46, G48, I50, I54, L63, A71, G73, V82, I84, and L90 (0-2, 3, 4 or more) at baseline. NA = not applicable. Through 48 weeks of treatment, the mean changes from baseline in HIV RNA levels for REYATAZ + ritonavir and lopinavir + ritonavir were similar (non‑inferior). Consistent results were obtained with the last observation carried forward method of analysis (time‑averaged difference of 0.11, 97.5% confidence interval [‑0.15, 0.36]). The proportions of patients with HIV RNA < 400 copies/ml in the REYATAZ + ritonavir arm and the lopinavir + ritonavir arm were 53% and 54%, respectively, by intent‑to‑treat analysis, with missing values considered as failures. The proportions of patients with HIV RNA < 50 copies/ml in the REYATAZ + ritonavir arm and the lopinavir + ritonavir arm were 36% and 42%, respectively. By as‑treated analysis, excluding missing values, the proportions of patients with HIV RNA < 400 copies/ml (< 50 copies/ml) in the REYATAZ + ritonavir arm and the lopinavir + ritonavir arm were 55% (40%) and 56% (46%), respectively. The mean increases from baseline in CD4 cell count were 110 cells/mm3 and 121 cells/mm3 in the REYATAZ + ritonavir and lopinavir + ritonavir arms, respectively. Analyses of data through 96 Through 96 weeks of treatment demonstrated durability of antiviral activity. Mean, mean HIV RNA changes from baseline at Week 96 (‑2.29 log10 copies/ml for REYATAZ + ritonavir and ‑2.08 log10 copies/ml for lopinavir + ritonavir, time‑averaged difference of 0.14, 97.5% confidence interval [‑0.13, 0.41]) met criteria for non‑inferiority based on observed cases. Consistent results were obtained with the last observation carried forward method of analysis. The proportions of patients with HIV RNA <400 copies/ml (<50 copies/ml) for REYATAZ + ritonavir were 43% (32%) and for lopinavir + ritonavir were 46% (35%). Patients completing treatment while in response after 48 weeks were censored. By as‑treated analysis, excluding missing values, the proportions of patients with HIV RNA <400 copies/ml (<50 copies/ml) for REYATAZ + ritonavir were 84% (72%) and for lopinavir + ritonavir were 82% (72%). It is important to note that at time of the 96‑week analysis, 48 % of patients overall remained on study. Through 48 weeks of treatment, two types of analyses were performed based on baseline genotypic mutations. The first consisted in assessing the HIV RNA change from baseline in the subgroup of patients with < or ≥ of 4 of the following set of mutations: 10, 20, 24, 32, 33, 36, 46, 48, 50, 54, 63, 71, 73, 82, 84 and 90. The second consisted in assessing the HIV RNA change from baseline in the subgroup of patients with < or ≥ of 4 of the following more specific set of mutations: 10, 46, 54, 82, 84, 90. In the analysis performed for patients with ≥ 4 protease gene mutations among the following set of mutations 10, 20, 24, 32, 33, 36, 46, 48, 50, 54, 63, 71, 73, 82, 84 and 90, the results significantly favoured the lopinavir + ritonavir arm. There were too few patients with ≥ 4 of the second more specific set of mutations (i.e. 10, 46, 54, 82, 84, 90) to assess the comparability of the REYATAZ + ritonavir and lopinavir + ritonavir regimens, but reduced virologic activity may be anticipated among patients with this resistance profile. REYATAZ + saquinavir was shown to be inferior to lopinavir + ritonavir. 5.2 Pharmacokinetic properties Special populations Impaired renal function: in healthy subjects, the renal elimination of unchanged atazanavir was approximately 7% of the administered dose. There are no pharmacokinetic data available on for REYATAZ with ritonavir in patients with renal insufficiency (see section 4.2); however, the impact of renal impairment on atazanavir elimination is anticipated to be minimal.. REYATAZ (without ritonavir) has been studied in adult patients with severe renal impairment (n=20), including those on haemodialysis, at multiple doses of 400 mg once daily. Although this study presented some limitations (i.e., unbound drug concentrations not studied), results suggested that the atazanavir pharmacokinetic parameters were decreased by 30% to 50% in patients undergoing haemodialysis compared to patients with normal renal function. The mechanism of this decrease is unknown. (See sections 4.2 and 4.4.) 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 02 March 2004 Date of latest renewal : 09 February: 02 March 2009 10. DATE OF REVISION OF THE TEXT 9th FebruaryJuly 2009 Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/http://www.emea.europa.eu
b Lopinavir/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily). c Intent-to-treat analysis, with missing values considered as failures. d Number of patients evaluable. In antiretroviral experienced patients Study 045 is a randomised, multicenter trial comparing REYATAZ (300 mg once daily) with ritonavir (100 mg once daily) to REYATAZ (400 mg once daily) with saquinavir soft gelatine capsules (1,200 mg once daily), and to lopinavir + ritonavir (400/100 mg fixed dose combination twice daily), each in combination with tenofovir (see sections 4.5 and 4.8) and one NRTI, in 347 (of 358 randomised) patients with virologic failure on two or more prior regimens containing at least one PI, NRTI, and NNRTI. For randomised patients, the mean time of prior antiretroviral exposure was 138 weeks for PIs, 281 weeks for NRTIs, and 85 weeks for NNRTIs. At baseline, 34% of patients were receiving a PI and 60% were receiving an NNRTI. Fifteen of 120 (13%) patients in the REYATAZ + ritonavir treatment arm and 17 of 123 (14%) patients in the lopinavir + ritonavir arm had four or more of the PI substitutions L10, M46, I54, V82, I84, and L90. Thirty‑two percent of patients in the study had a viral strain with fewer than two NRTI substitutions. The mean baseline CD4 cell count was 337 cells/mm3 (range: 14 to 1,543 cells/mm3) and the mean baseline plasma HIV‑1 RNA level was 4.4 log10 copies/ml (range: 2.6 to 5.88 log10 copies/ml). The population included in this study was moderately pretreated. The primary endpoint was the time‑averaged difference in change from baseline in HIV RNA through 48 weeks. Through 48 weeks of treatment, the decreases from baseline in HIV RNA levels (primary endpoint) were 1.93 log10 copies/ml for REYATAZ + ritonavir and 1.87 log10 copies/ml for lopinavir + ritonavir. REYATAZ + ritonavir was similar (non‑inferior) to lopinavir + ritonavir on this efficacy measure (time‑averaged difference of 0.13, 97.5% confidenceb ATV/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily). c LPV/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily). d Confidence interval [‑0.12, 0.39]).. e Number of patients evaluable. f Intent-to-treat analysis, with missing values considered as failures. Responders on LPV/RTV who completed treatment before Week 96 are excluded from Week 96 analysis. The proportion of patients with HIV RNA < 400 copies/ml were 53% and 43% for ATV/RTV and 54% and 46% for LPV/RTV at weeks 48 and 96 respectively. g Select substitutions include any change at positions L10, K20, L24, V32, L33, M36, M46, G48, I50, I54, L63, A71, G73, V82, I84, and L90 (0-2, 3, 4 or more) at baseline. NA = not applicable. Through 48 weeks of treatment, the mean changes from baseline in HIV RNA levels for REYATAZ + ritonavir and lopinavir + ritonavir were similar (non‑inferior). Consistent results were obtained with the last observation carried forward method of analysis (time‑averaged difference of 0.11, 97.5% confidence interval [‑0.15, 0.36]). The proportions of patients with HIV RNA < 400 copies/ml in the REYATAZ + ritonavir arm and the lopinavir + ritonavir arm were 53% and 54%, respectively, by intent‑to‑treat analysis, with missing values considered as failures. The proportions of patients with HIV RNA < 50 copies/ml in the REYATAZ + ritonavir arm and the lopinavir + ritonavir arm were 36% and 42%, respectively. By as‑treated analysis, excluding missing values, the proportions of patients with HIV RNA < 400 copies/ml (< 50 copies/ml) in the REYATAZ + ritonavir arm and the lopinavir + ritonavir arm were 55% (40%) and 56% (46%), respectively. The mean increases from baseline in CD4 cell count were 110 cells/mm3 and 121 cells/mm3 in the REYATAZ + ritonavir and lopinavir + ritonavir arms, respectively. Analyses of data through 96 Through 96 weeks of treatment demonstrated durability of antiviral activity. Mean, mean HIV RNA changes from baseline at Week 96 (‑2.29 log10 copies/ml for REYATAZ + ritonavir and ‑2.08 log10 copies/ml for lopinavir + ritonavir, time‑averaged difference of 0.14, 97.5% confidence interval [‑0.13, 0.41]) met criteria for non‑inferiority based on observed cases. Consistent results were obtained with the last observation carried forward method of analysis. The proportions of patients with HIV RNA <400 copies/ml (<50 copies/ml) for REYATAZ + ritonavir were 43% (32%) and for lopinavir + ritonavir were 46% (35%). Patients completing treatment while in response after 48 weeks were censored. By as‑treated analysis, excluding missing values, the proportions of patients with HIV RNA <400 copies/ml (<50 copies/ml) for REYATAZ + ritonavir were 84% (72%) and for lopinavir + ritonavir were 82% (72%). It is important to note that at time of the 96‑week analysis, 48 % of patients overall remained on study. Through 48 weeks of treatment, two types of analyses were performed based on baseline genotypic mutations. The first consisted in assessing the HIV RNA change from baseline in the subgroup of patients with < or ≥ of 4 of the following set of mutations: 10, 20, 24, 32, 33, 36, 46, 48, 50, 54, 63, 71, 73, 82, 84 and 90. The second consisted in assessing the HIV RNA change from baseline in the subgroup of patients with < or ≥ of 4 of the following more specific set of mutations: 10, 46, 54, 82, 84, 90. In the analysis performed for patients with ≥ 4 protease gene mutations among the following set of mutations 10, 20, 24, 32, 33, 36, 46, 48, 50, 54, 63, 71, 73, 82, 84 and 90, the results significantly favoured the lopinavir + ritonavir arm. There were too few patients with ≥ 4 of the second more specific set of mutations (i.e. 10, 46, 54, 82, 84, 90) to assess the comparability of the REYATAZ + ritonavir and lopinavir + ritonavir regimens, but reduced virologic activity may be anticipated among patients with this resistance profile. REYATAZ + saquinavir was shown to be inferior to lopinavir + ritonavir. 5.2 Pharmacokinetic properties Special populations Impaired renal function: in healthy subjects, the renal elimination of unchanged atazanavir was approximately 7% of the administered dose. There are no pharmacokinetic data available on for REYATAZ with ritonavir in patients with renal insufficiency (see section 4.2); however, the impact of renal impairment on atazanavir elimination is anticipated to be minimal.. REYATAZ (without ritonavir) has been studied in adult patients with severe renal impairment (n=20), including those on haemodialysis, at multiple doses of 400 mg once daily. Although this study presented some limitations (i.e., unbound drug concentrations not studied), results suggested that the atazanavir pharmacokinetic parameters were decreased by 30% to 50% in patients undergoing haemodialysis compared to patients with normal renal function. The mechanism of this decrease is unknown. (See sections 4.2 and 4.4.) 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 02 March 2004 Date of latest renewal : 09 February: 02 March 2009 10. DATE OF REVISION OF THE TEXT 9th FebruaryJuly 2009 Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/http://www.emea.europa.eu
c Intent-to-treat analysis, with missing values considered as failures. d Number of patients evaluable. In antiretroviral experienced patients Study 045 is a randomised, multicenter trial comparing REYATAZ (300 mg once daily) with ritonavir (100 mg once daily) to REYATAZ (400 mg once daily) with saquinavir soft gelatine capsules (1,200 mg once daily), and to lopinavir + ritonavir (400/100 mg fixed dose combination twice daily), each in combination with tenofovir (see sections 4.5 and 4.8) and one NRTI, in 347 (of 358 randomised) patients with virologic failure on two or more prior regimens containing at least one PI, NRTI, and NNRTI. For randomised patients, the mean time of prior antiretroviral exposure was 138 weeks for PIs, 281 weeks for NRTIs, and 85 weeks for NNRTIs. At baseline, 34% of patients were receiving a PI and 60% were receiving an NNRTI. Fifteen of 120 (13%) patients in the REYATAZ + ritonavir treatment arm and 17 of 123 (14%) patients in the lopinavir + ritonavir arm had four or more of the PI substitutions L10, M46, I54, V82, I84, and L90. Thirty‑two percent of patients in the study had a viral strain with fewer than two NRTI substitutions. The mean baseline CD4 cell count was 337 cells/mm3 (range: 14 to 1,543 cells/mm3) and the mean baseline plasma HIV‑1 RNA level was 4.4 log10 copies/ml (range: 2.6 to 5.88 log10 copies/ml). The population included in this study was moderately pretreated. The primary endpoint was the time‑averaged difference in change from baseline in HIV RNA through 48 weeks. Through 48 weeks of treatment, the decreases from baseline in HIV RNA levels (primary endpoint) were 1.93 log10 copies/ml for REYATAZ + ritonavir and 1.87 log10 copies/ml for lopinavir + ritonavir. REYATAZ + ritonavir was similar (non‑inferior) to lopinavir + ritonavir on this efficacy measure (time‑averaged difference of 0.13, 97.5% confidenceb ATV/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily). c LPV/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily). d Confidence interval [‑0.12, 0.39]).. e Number of patients evaluable. f Intent-to-treat analysis, with missing values considered as failures. Responders on LPV/RTV who completed treatment before Week 96 are excluded from Week 96 analysis. The proportion of patients with HIV RNA < 400 copies/ml were 53% and 43% for ATV/RTV and 54% and 46% for LPV/RTV at weeks 48 and 96 respectively. g Select substitutions include any change at positions L10, K20, L24, V32, L33, M36, M46, G48, I50, I54, L63, A71, G73, V82, I84, and L90 (0-2, 3, 4 or more) at baseline. NA = not applicable. Through 48 weeks of treatment, the mean changes from baseline in HIV RNA levels for REYATAZ + ritonavir and lopinavir + ritonavir were similar (non‑inferior). Consistent results were obtained with the last observation carried forward method of analysis (time‑averaged difference of 0.11, 97.5% confidence interval [‑0.15, 0.36]). The proportions of patients with HIV RNA < 400 copies/ml in the REYATAZ + ritonavir arm and the lopinavir + ritonavir arm were 53% and 54%, respectively, by intent‑to‑treat analysis, with missing values considered as failures. The proportions of patients with HIV RNA < 50 copies/ml in the REYATAZ + ritonavir arm and the lopinavir + ritonavir arm were 36% and 42%, respectively. By as‑treated analysis, excluding missing values, the proportions of patients with HIV RNA < 400 copies/ml (< 50 copies/ml) in the REYATAZ + ritonavir arm and the lopinavir + ritonavir arm were 55% (40%) and 56% (46%), respectively. The mean increases from baseline in CD4 cell count were 110 cells/mm3 and 121 cells/mm3 in the REYATAZ + ritonavir and lopinavir + ritonavir arms, respectively. Analyses of data through 96 Through 96 weeks of treatment demonstrated durability of antiviral activity. Mean, mean HIV RNA changes from baseline at Week 96 (‑2.29 log10 copies/ml for REYATAZ + ritonavir and ‑2.08 log10 copies/ml for lopinavir + ritonavir, time‑averaged difference of 0.14, 97.5% confidence interval [‑0.13, 0.41]) met criteria for non‑inferiority based on observed cases. Consistent results were obtained with the last observation carried forward method of analysis. The proportions of patients with HIV RNA <400 copies/ml (<50 copies/ml) for REYATAZ + ritonavir were 43% (32%) and for lopinavir + ritonavir were 46% (35%). Patients completing treatment while in response after 48 weeks were censored. By as‑treated analysis, excluding missing values, the proportions of patients with HIV RNA <400 copies/ml (<50 copies/ml) for REYATAZ + ritonavir were 84% (72%) and for lopinavir + ritonavir were 82% (72%). It is important to note that at time of the 96‑week analysis, 48 % of patients overall remained on study. Through 48 weeks of treatment, two types of analyses were performed based on baseline genotypic mutations. The first consisted in assessing the HIV RNA change from baseline in the subgroup of patients with < or ≥ of 4 of the following set of mutations: 10, 20, 24, 32, 33, 36, 46, 48, 50, 54, 63, 71, 73, 82, 84 and 90. The second consisted in assessing the HIV RNA change from baseline in the subgroup of patients with < or ≥ of 4 of the following more specific set of mutations: 10, 46, 54, 82, 84, 90. In the analysis performed for patients with ≥ 4 protease gene mutations among the following set of mutations 10, 20, 24, 32, 33, 36, 46, 48, 50, 54, 63, 71, 73, 82, 84 and 90, the results significantly favoured the lopinavir + ritonavir arm. There were too few patients with ≥ 4 of the second more specific set of mutations (i.e. 10, 46, 54, 82, 84, 90) to assess the comparability of the REYATAZ + ritonavir and lopinavir + ritonavir regimens, but reduced virologic activity may be anticipated among patients with this resistance profile. REYATAZ + saquinavir was shown to be inferior to lopinavir + ritonavir. 5.2 Pharmacokinetic properties Special populations Impaired renal function: in healthy subjects, the renal elimination of unchanged atazanavir was approximately 7% of the administered dose. There are no pharmacokinetic data available on for REYATAZ with ritonavir in patients with renal insufficiency (see section 4.2); however, the impact of renal impairment on atazanavir elimination is anticipated to be minimal.. REYATAZ (without ritonavir) has been studied in adult patients with severe renal impairment (n=20), including those on haemodialysis, at multiple doses of 400 mg once daily. Although this study presented some limitations (i.e., unbound drug concentrations not studied), results suggested that the atazanavir pharmacokinetic parameters were decreased by 30% to 50% in patients undergoing haemodialysis compared to patients with normal renal function. The mechanism of this decrease is unknown. (See sections 4.2 and 4.4.) 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 02 March 2004 Date of latest renewal : 09 February: 02 March 2009 10. DATE OF REVISION OF THE TEXT 9th FebruaryJuly 2009 Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/http://www.emea.europa.eu
d Number of patients evaluable. In antiretroviral experienced patients Study 045 is a randomised, multicenter trial comparing REYATAZ (300 mg once daily) with ritonavir (100 mg once daily) to REYATAZ (400 mg once daily) with saquinavir soft gelatine capsules (1,200 mg once daily), and to lopinavir + ritonavir (400/100 mg fixed dose combination twice daily), each in combination with tenofovir (see sections 4.5 and 4.8) and one NRTI, in 347 (of 358 randomised) patients with virologic failure on two or more prior regimens containing at least one PI, NRTI, and NNRTI. For randomised patients, the mean time of prior antiretroviral exposure was 138 weeks for PIs, 281 weeks for NRTIs, and 85 weeks for NNRTIs. At baseline, 34% of patients were receiving a PI and 60% were receiving an NNRTI. Fifteen of 120 (13%) patients in the REYATAZ + ritonavir treatment arm and 17 of 123 (14%) patients in the lopinavir + ritonavir arm had four or more of the PI substitutions L10, M46, I54, V82, I84, and L90. Thirty‑two percent of patients in the study had a viral strain with fewer than two NRTI substitutions. The mean baseline CD4 cell count was 337 cells/mm3 (range: 14 to 1,543 cells/mm3) and the mean baseline plasma HIV‑1 RNA level was 4.4 log10 copies/ml (range: 2.6 to 5.88 log10 copies/ml). The population included in this study was moderately pretreated. The primary endpoint was the time‑averaged difference in change from baseline in HIV RNA through 48 weeks. Through 48 weeks of treatment, the decreases from baseline in HIV RNA levels (primary endpoint) were 1.93 log10 copies/ml for REYATAZ + ritonavir and 1.87 log10 copies/ml for lopinavir + ritonavir. REYATAZ + ritonavir was similar (non‑inferior) to lopinavir + ritonavir on this efficacy measure (time‑averaged difference of 0.13, 97.5% confidenceb ATV/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily). c LPV/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily). d Confidence interval [‑0.12, 0.39]).. e Number of patients evaluable. f Intent-to-treat analysis, with missing values considered as failures. Responders on LPV/RTV who completed treatment before Week 96 are excluded from Week 96 analysis. The proportion of patients with HIV RNA < 400 copies/ml were 53% and 43% for ATV/RTV and 54% and 46% for LPV/RTV at weeks 48 and 96 respectively. g Select substitutions include any change at positions L10, K20, L24, V32, L33, M36, M46, G48, I50, I54, L63, A71, G73, V82, I84, and L90 (0-2, 3, 4 or more) at baseline. NA = not applicable. Through 48 weeks of treatment, the mean changes from baseline in HIV RNA levels for REYATAZ + ritonavir and lopinavir + ritonavir were similar (non‑inferior). Consistent results were obtained with the last observation carried forward method of analysis (time‑averaged difference of 0.11, 97.5% confidence interval [‑0.15, 0.36]). The proportions of patients with HIV RNA < 400 copies/ml in the REYATAZ + ritonavir arm and the lopinavir + ritonavir arm were 53% and 54%, respectively, by intent‑to‑treat analysis, with missing values considered as failures. The proportions of patients with HIV RNA < 50 copies/ml in the REYATAZ + ritonavir arm and the lopinavir + ritonavir arm were 36% and 42%, respectively. By as‑treated analysis, excluding missing values, the proportions of patients with HIV RNA < 400 copies/ml (< 50 copies/ml) in the REYATAZ + ritonavir arm and the lopinavir + ritonavir arm were 55% (40%) and 56% (46%), respectively. The mean increases from baseline in CD4 cell count were 110 cells/mm3 and 121 cells/mm3 in the REYATAZ + ritonavir and lopinavir + ritonavir arms, respectively. Analyses of data through 96 Through 96 weeks of treatment demonstrated durability of antiviral activity. Mean, mean HIV RNA changes from baseline at Week 96 (‑2.29 log10 copies/ml for REYATAZ + ritonavir and ‑2.08 log10 copies/ml for lopinavir + ritonavir, time‑averaged difference of 0.14, 97.5% confidence interval [‑0.13, 0.41]) met criteria for non‑inferiority based on observed cases. Consistent results were obtained with the last observation carried forward method of analysis. The proportions of patients with HIV RNA <400 copies/ml (<50 copies/ml) for REYATAZ + ritonavir were 43% (32%) and for lopinavir + ritonavir were 46% (35%). Patients completing treatment while in response after 48 weeks were censored. By as‑treated analysis, excluding missing values, the proportions of patients with HIV RNA <400 copies/ml (<50 copies/ml) for REYATAZ + ritonavir were 84% (72%) and for lopinavir + ritonavir were 82% (72%). It is important to note that at time of the 96‑week analysis, 48 % of patients overall remained on study. Through 48 weeks of treatment, two types of analyses were performed based on baseline genotypic mutations. The first consisted in assessing the HIV RNA change from baseline in the subgroup of patients with < or ≥ of 4 of the following set of mutations: 10, 20, 24, 32, 33, 36, 46, 48, 50, 54, 63, 71, 73, 82, 84 and 90. The second consisted in assessing the HIV RNA change from baseline in the subgroup of patients with < or ≥ of 4 of the following more specific set of mutations: 10, 46, 54, 82, 84, 90. In the analysis performed for patients with ≥ 4 protease gene mutations among the following set of mutations 10, 20, 24, 32, 33, 36, 46, 48, 50, 54, 63, 71, 73, 82, 84 and 90, the results significantly favoured the lopinavir + ritonavir arm. There were too few patients with ≥ 4 of the second more specific set of mutations (i.e. 10, 46, 54, 82, 84, 90) to assess the comparability of the REYATAZ + ritonavir and lopinavir + ritonavir regimens, but reduced virologic activity may be anticipated among patients with this resistance profile. REYATAZ + saquinavir was shown to be inferior to lopinavir + ritonavir. 5.2 Pharmacokinetic properties Special populations Impaired renal function: in healthy subjects, the renal elimination of unchanged atazanavir was approximately 7% of the administered dose. There are no pharmacokinetic data available on for REYATAZ with ritonavir in patients with renal insufficiency (see section 4.2); however, the impact of renal impairment on atazanavir elimination is anticipated to be minimal.. REYATAZ (without ritonavir) has been studied in adult patients with severe renal impairment (n=20), including those on haemodialysis, at multiple doses of 400 mg once daily. Although this study presented some limitations (i.e., unbound drug concentrations not studied), results suggested that the atazanavir pharmacokinetic parameters were decreased by 30% to 50% in patients undergoing haemodialysis compared to patients with normal renal function. The mechanism of this decrease is unknown. (See sections 4.2 and 4.4.) 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 02 March 2004 Date of latest renewal : 09 February: 02 March 2009 10. DATE OF REVISION OF THE TEXT 9th FebruaryJuly 2009 Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/http://www.emea.europa.eu
Study 045 is a randomised, multicenter trial comparing REYATAZ (300 mg once daily) with ritonavir (100 mg once daily) to REYATAZ (400 mg once daily) with saquinavir soft gelatine capsules (1,200 mg once daily), and to lopinavir + ritonavir (400/100 mg fixed dose combination twice daily), each in combination with tenofovir (see sections 4.5 and 4.8) and one NRTI, in 347 (of 358 randomised) patients with virologic failure on two or more prior regimens containing at least one PI, NRTI, and NNRTI. For randomised patients, the mean time of prior antiretroviral exposure was 138 weeks for PIs, 281 weeks for NRTIs, and 85 weeks for NNRTIs. At baseline, 34% of patients were receiving a PI and 60% were receiving an NNRTI. Fifteen of 120 (13%) patients in the REYATAZ + ritonavir treatment arm and 17 of 123 (14%) patients in the lopinavir + ritonavir arm had four or more of the PI substitutions L10, M46, I54, V82, I84, and L90. Thirty‑two percent of patients in the study had a viral strain with fewer than two NRTI substitutions. The mean baseline CD4 cell count was 337 cells/mm3 (range: 14 to 1,543 cells/mm3) and the mean baseline plasma HIV‑1 RNA level was 4.4 log10 copies/ml (range: 2.6 to 5.88 log10 copies/ml). The population included in this study was moderately pretreated.
The primary endpoint was the time‑averaged difference in change from baseline in HIV RNA through 48 weeks.
Through 48 weeks of treatment, the decreases from baseline in HIV RNA levels (primary endpoint) were 1.93 log10 copies/ml for REYATAZ + ritonavir and 1.87 log10 copies/ml for lopinavir + ritonavir. REYATAZ + ritonavir was similar (non‑inferior) to lopinavir + ritonavir on this efficacy measure (time‑averaged difference of 0.13, 97.5% confidenceb ATV/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily). c LPV/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily). d Confidence interval [‑0.12, 0.39]).. e Number of patients evaluable. f Intent-to-treat analysis, with missing values considered as failures. Responders on LPV/RTV who completed treatment before Week 96 are excluded from Week 96 analysis. The proportion of patients with HIV RNA < 400 copies/ml were 53% and 43% for ATV/RTV and 54% and 46% for LPV/RTV at weeks 48 and 96 respectively. g Select substitutions include any change at positions L10, K20, L24, V32, L33, M36, M46, G48, I50, I54, L63, A71, G73, V82, I84, and L90 (0-2, 3, 4 or more) at baseline. NA = not applicable. Through 48 weeks of treatment, the mean changes from baseline in HIV RNA levels for REYATAZ + ritonavir and lopinavir + ritonavir were similar (non‑inferior). Consistent results were obtained with the last observation carried forward method of analysis (time‑averaged difference of 0.11, 97.5% confidence interval [‑0.15, 0.36]). The proportions of patients with HIV RNA < 400 copies/ml in the REYATAZ + ritonavir arm and the lopinavir + ritonavir arm were 53% and 54%, respectively, by intent‑to‑treat analysis, with missing values considered as failures. The proportions of patients with HIV RNA < 50 copies/ml in the REYATAZ + ritonavir arm and the lopinavir + ritonavir arm were 36% and 42%, respectively. By as‑treated analysis, excluding missing values, the proportions of patients with HIV RNA < 400 copies/ml (< 50 copies/ml) in the REYATAZ + ritonavir arm and the lopinavir + ritonavir arm were 55% (40%) and 56% (46%), respectively. The mean increases from baseline in CD4 cell count were 110 cells/mm3 and 121 cells/mm3 in the REYATAZ + ritonavir and lopinavir + ritonavir arms, respectively. Analyses of data through 96 Through 96 weeks of treatment demonstrated durability of antiviral activity. Mean, mean HIV RNA changes from baseline at Week 96 (‑2.29 log10 copies/ml for REYATAZ + ritonavir and ‑2.08 log10 copies/ml for lopinavir + ritonavir, time‑averaged difference of 0.14, 97.5% confidence interval [‑0.13, 0.41]) met criteria for non‑inferiority based on observed cases. Consistent results were obtained with the last observation carried forward method of analysis. The proportions of patients with HIV RNA <400 copies/ml (<50 copies/ml) for REYATAZ + ritonavir were 43% (32%) and for lopinavir + ritonavir were 46% (35%). Patients completing treatment while in response after 48 weeks were censored. By as‑treated analysis, excluding missing values, the proportions of patients with HIV RNA <400 copies/ml (<50 copies/ml) for REYATAZ + ritonavir were 84% (72%) and for lopinavir + ritonavir were 82% (72%). It is important to note that at time of the 96‑week analysis, 48 % of patients overall remained on study. Through 48 weeks of treatment, two types of analyses were performed based on baseline genotypic mutations. The first consisted in assessing the HIV RNA change from baseline in the subgroup of patients with < or ≥ of 4 of the following set of mutations: 10, 20, 24, 32, 33, 36, 46, 48, 50, 54, 63, 71, 73, 82, 84 and 90. The second consisted in assessing the HIV RNA change from baseline in the subgroup of patients with < or ≥ of 4 of the following more specific set of mutations: 10, 46, 54, 82, 84, 90. In the analysis performed for patients with ≥ 4 protease gene mutations among the following set of mutations 10, 20, 24, 32, 33, 36, 46, 48, 50, 54, 63, 71, 73, 82, 84 and 90, the results significantly favoured the lopinavir + ritonavir arm. There were too few patients with ≥ 4 of the second more specific set of mutations (i.e. 10, 46, 54, 82, 84, 90) to assess the comparability of the REYATAZ + ritonavir and lopinavir + ritonavir regimens, but reduced virologic activity may be anticipated among patients with this resistance profile. REYATAZ + saquinavir was shown to be inferior to lopinavir + ritonavir. 5.2 Pharmacokinetic properties Special populations Impaired renal function: in healthy subjects, the renal elimination of unchanged atazanavir was approximately 7% of the administered dose. There are no pharmacokinetic data available on for REYATAZ with ritonavir in patients with renal insufficiency (see section 4.2); however, the impact of renal impairment on atazanavir elimination is anticipated to be minimal.. REYATAZ (without ritonavir) has been studied in adult patients with severe renal impairment (n=20), including those on haemodialysis, at multiple doses of 400 mg once daily. Although this study presented some limitations (i.e., unbound drug concentrations not studied), results suggested that the atazanavir pharmacokinetic parameters were decreased by 30% to 50% in patients undergoing haemodialysis compared to patients with normal renal function. The mechanism of this decrease is unknown. (See sections 4.2 and 4.4.) 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 02 March 2004 Date of latest renewal : 09 February: 02 March 2009 10. DATE OF REVISION OF THE TEXT 9th FebruaryJuly 2009 Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/http://www.emea.europa.eu
c LPV/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily). d Confidence interval [‑0.12, 0.39]).. e Number of patients evaluable. f Intent-to-treat analysis, with missing values considered as failures. Responders on LPV/RTV who completed treatment before Week 96 are excluded from Week 96 analysis. The proportion of patients with HIV RNA < 400 copies/ml were 53% and 43% for ATV/RTV and 54% and 46% for LPV/RTV at weeks 48 and 96 respectively. g Select substitutions include any change at positions L10, K20, L24, V32, L33, M36, M46, G48, I50, I54, L63, A71, G73, V82, I84, and L90 (0-2, 3, 4 or more) at baseline. NA = not applicable. Through 48 weeks of treatment, the mean changes from baseline in HIV RNA levels for REYATAZ + ritonavir and lopinavir + ritonavir were similar (non‑inferior). Consistent results were obtained with the last observation carried forward method of analysis (time‑averaged difference of 0.11, 97.5% confidence interval [‑0.15, 0.36]). The proportions of patients with HIV RNA < 400 copies/ml in the REYATAZ + ritonavir arm and the lopinavir + ritonavir arm were 53% and 54%, respectively, by intent‑to‑treat analysis, with missing values considered as failures. The proportions of patients with HIV RNA < 50 copies/ml in the REYATAZ + ritonavir arm and the lopinavir + ritonavir arm were 36% and 42%, respectively. By as‑treated analysis, excluding missing values, the proportions of patients with HIV RNA < 400 copies/ml (< 50 copies/ml) in the REYATAZ + ritonavir arm and the lopinavir + ritonavir arm were 55% (40%) and 56% (46%), respectively. The mean increases from baseline in CD4 cell count were 110 cells/mm3 and 121 cells/mm3 in the REYATAZ + ritonavir and lopinavir + ritonavir arms, respectively. Analyses of data through 96 Through 96 weeks of treatment demonstrated durability of antiviral activity. Mean, mean HIV RNA changes from baseline at Week 96 (‑2.29 log10 copies/ml for REYATAZ + ritonavir and ‑2.08 log10 copies/ml for lopinavir + ritonavir, time‑averaged difference of 0.14, 97.5% confidence interval [‑0.13, 0.41]) met criteria for non‑inferiority based on observed cases. Consistent results were obtained with the last observation carried forward method of analysis. The proportions of patients with HIV RNA <400 copies/ml (<50 copies/ml) for REYATAZ + ritonavir were 43% (32%) and for lopinavir + ritonavir were 46% (35%). Patients completing treatment while in response after 48 weeks were censored. By as‑treated analysis, excluding missing values, the proportions of patients with HIV RNA <400 copies/ml (<50 copies/ml) for REYATAZ + ritonavir were 84% (72%) and for lopinavir + ritonavir were 82% (72%). It is important to note that at time of the 96‑week analysis, 48 % of patients overall remained on study. Through 48 weeks of treatment, two types of analyses were performed based on baseline genotypic mutations. The first consisted in assessing the HIV RNA change from baseline in the subgroup of patients with < or ≥ of 4 of the following set of mutations: 10, 20, 24, 32, 33, 36, 46, 48, 50, 54, 63, 71, 73, 82, 84 and 90. The second consisted in assessing the HIV RNA change from baseline in the subgroup of patients with < or ≥ of 4 of the following more specific set of mutations: 10, 46, 54, 82, 84, 90. In the analysis performed for patients with ≥ 4 protease gene mutations among the following set of mutations 10, 20, 24, 32, 33, 36, 46, 48, 50, 54, 63, 71, 73, 82, 84 and 90, the results significantly favoured the lopinavir + ritonavir arm. There were too few patients with ≥ 4 of the second more specific set of mutations (i.e. 10, 46, 54, 82, 84, 90) to assess the comparability of the REYATAZ + ritonavir and lopinavir + ritonavir regimens, but reduced virologic activity may be anticipated among patients with this resistance profile. REYATAZ + saquinavir was shown to be inferior to lopinavir + ritonavir. 5.2 Pharmacokinetic properties Special populations Impaired renal function: in healthy subjects, the renal elimination of unchanged atazanavir was approximately 7% of the administered dose. There are no pharmacokinetic data available on for REYATAZ with ritonavir in patients with renal insufficiency (see section 4.2); however, the impact of renal impairment on atazanavir elimination is anticipated to be minimal.. REYATAZ (without ritonavir) has been studied in adult patients with severe renal impairment (n=20), including those on haemodialysis, at multiple doses of 400 mg once daily. Although this study presented some limitations (i.e., unbound drug concentrations not studied), results suggested that the atazanavir pharmacokinetic parameters were decreased by 30% to 50% in patients undergoing haemodialysis compared to patients with normal renal function. The mechanism of this decrease is unknown. (See sections 4.2 and 4.4.) 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 02 March 2004 Date of latest renewal : 09 February: 02 March 2009 10. DATE OF REVISION OF THE TEXT 9th FebruaryJuly 2009 Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/http://www.emea.europa.eu
d Confidence interval [‑0.12, 0.39]).. e Number of patients evaluable. f Intent-to-treat analysis, with missing values considered as failures. Responders on LPV/RTV who completed treatment before Week 96 are excluded from Week 96 analysis. The proportion of patients with HIV RNA < 400 copies/ml were 53% and 43% for ATV/RTV and 54% and 46% for LPV/RTV at weeks 48 and 96 respectively. g Select substitutions include any change at positions L10, K20, L24, V32, L33, M36, M46, G48, I50, I54, L63, A71, G73, V82, I84, and L90 (0-2, 3, 4 or more) at baseline. NA = not applicable. Through 48 weeks of treatment, the mean changes from baseline in HIV RNA levels for REYATAZ + ritonavir and lopinavir + ritonavir were similar (non‑inferior). Consistent results were obtained with the last observation carried forward method of analysis (time‑averaged difference of 0.11, 97.5% confidence interval [‑0.15, 0.36]). The proportions of patients with HIV RNA < 400 copies/ml in the REYATAZ + ritonavir arm and the lopinavir + ritonavir arm were 53% and 54%, respectively, by intent‑to‑treat analysis, with missing values considered as failures. The proportions of patients with HIV RNA < 50 copies/ml in the REYATAZ + ritonavir arm and the lopinavir + ritonavir arm were 36% and 42%, respectively. By as‑treated analysis, excluding missing values, the proportions of patients with HIV RNA < 400 copies/ml (< 50 copies/ml) in the REYATAZ + ritonavir arm and the lopinavir + ritonavir arm were 55% (40%) and 56% (46%), respectively. The mean increases from baseline in CD4 cell count were 110 cells/mm3 and 121 cells/mm3 in the REYATAZ + ritonavir and lopinavir + ritonavir arms, respectively. Analyses of data through 96 Through 96 weeks of treatment demonstrated durability of antiviral activity. Mean, mean HIV RNA changes from baseline at Week 96 (‑2.29 log10 copies/ml for REYATAZ + ritonavir and ‑2.08 log10 copies/ml for lopinavir + ritonavir, time‑averaged difference of 0.14, 97.5% confidence interval [‑0.13, 0.41]) met criteria for non‑inferiority based on observed cases. Consistent results were obtained with the last observation carried forward method of analysis. The proportions of patients with HIV RNA <400 copies/ml (<50 copies/ml) for REYATAZ + ritonavir were 43% (32%) and for lopinavir + ritonavir were 46% (35%). Patients completing treatment while in response after 48 weeks were censored. By as‑treated analysis, excluding missing values, the proportions of patients with HIV RNA <400 copies/ml (<50 copies/ml) for REYATAZ + ritonavir were 84% (72%) and for lopinavir + ritonavir were 82% (72%). It is important to note that at time of the 96‑week analysis, 48 % of patients overall remained on study. Through 48 weeks of treatment, two types of analyses were performed based on baseline genotypic mutations. The first consisted in assessing the HIV RNA change from baseline in the subgroup of patients with < or ≥ of 4 of the following set of mutations: 10, 20, 24, 32, 33, 36, 46, 48, 50, 54, 63, 71, 73, 82, 84 and 90. The second consisted in assessing the HIV RNA change from baseline in the subgroup of patients with < or ≥ of 4 of the following more specific set of mutations: 10, 46, 54, 82, 84, 90. In the analysis performed for patients with ≥ 4 protease gene mutations among the following set of mutations 10, 20, 24, 32, 33, 36, 46, 48, 50, 54, 63, 71, 73, 82, 84 and 90, the results significantly favoured the lopinavir + ritonavir arm. There were too few patients with ≥ 4 of the second more specific set of mutations (i.e. 10, 46, 54, 82, 84, 90) to assess the comparability of the REYATAZ + ritonavir and lopinavir + ritonavir regimens, but reduced virologic activity may be anticipated among patients with this resistance profile. REYATAZ + saquinavir was shown to be inferior to lopinavir + ritonavir. 5.2 Pharmacokinetic properties Special populations Impaired renal function: in healthy subjects, the renal elimination of unchanged atazanavir was approximately 7% of the administered dose. There are no pharmacokinetic data available on for REYATAZ with ritonavir in patients with renal insufficiency (see section 4.2); however, the impact of renal impairment on atazanavir elimination is anticipated to be minimal.. REYATAZ (without ritonavir) has been studied in adult patients with severe renal impairment (n=20), including those on haemodialysis, at multiple doses of 400 mg once daily. Although this study presented some limitations (i.e., unbound drug concentrations not studied), results suggested that the atazanavir pharmacokinetic parameters were decreased by 30% to 50% in patients undergoing haemodialysis compared to patients with normal renal function. The mechanism of this decrease is unknown. (See sections 4.2 and 4.4.) 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 02 March 2004 Date of latest renewal : 09 February: 02 March 2009 10. DATE OF REVISION OF THE TEXT 9th FebruaryJuly 2009 Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/http://www.emea.europa.eu
e Number of patients evaluable. f Intent-to-treat analysis, with missing values considered as failures. Responders on LPV/RTV who completed treatment before Week 96 are excluded from Week 96 analysis. The proportion of patients with HIV RNA < 400 copies/ml were 53% and 43% for ATV/RTV and 54% and 46% for LPV/RTV at weeks 48 and 96 respectively. g Select substitutions include any change at positions L10, K20, L24, V32, L33, M36, M46, G48, I50, I54, L63, A71, G73, V82, I84, and L90 (0-2, 3, 4 or more) at baseline. NA = not applicable. Through 48 weeks of treatment, the mean changes from baseline in HIV RNA levels for REYATAZ + ritonavir and lopinavir + ritonavir were similar (non‑inferior). Consistent results were obtained with the last observation carried forward method of analysis (time‑averaged difference of 0.11, 97.5% confidence interval [‑0.15, 0.36]). The proportions of patients with HIV RNA < 400 copies/ml in the REYATAZ + ritonavir arm and the lopinavir + ritonavir arm were 53% and 54%, respectively, by intent‑to‑treat analysis, with missing values considered as failures. The proportions of patients with HIV RNA < 50 copies/ml in the REYATAZ + ritonavir arm and the lopinavir + ritonavir arm were 36% and 42%, respectively. By as‑treated analysis, excluding missing values, the proportions of patients with HIV RNA < 400 copies/ml (< 50 copies/ml) in the REYATAZ + ritonavir arm and the lopinavir + ritonavir arm were 55% (40%) and 56% (46%), respectively. The mean increases from baseline in CD4 cell count were 110 cells/mm3 and 121 cells/mm3 in the REYATAZ + ritonavir and lopinavir + ritonavir arms, respectively. Analyses of data through 96 Through 96 weeks of treatment demonstrated durability of antiviral activity. Mean, mean HIV RNA changes from baseline at Week 96 (‑2.29 log10 copies/ml for REYATAZ + ritonavir and ‑2.08 log10 copies/ml for lopinavir + ritonavir, time‑averaged difference of 0.14, 97.5% confidence interval [‑0.13, 0.41]) met criteria for non‑inferiority based on observed cases. Consistent results were obtained with the last observation carried forward method of analysis. The proportions of patients with HIV RNA <400 copies/ml (<50 copies/ml) for REYATAZ + ritonavir were 43% (32%) and for lopinavir + ritonavir were 46% (35%). Patients completing treatment while in response after 48 weeks were censored. By as‑treated analysis, excluding missing values, the proportions of patients with HIV RNA <400 copies/ml (<50 copies/ml) for REYATAZ + ritonavir were 84% (72%) and for lopinavir + ritonavir were 82% (72%). It is important to note that at time of the 96‑week analysis, 48 % of patients overall remained on study. Through 48 weeks of treatment, two types of analyses were performed based on baseline genotypic mutations. The first consisted in assessing the HIV RNA change from baseline in the subgroup of patients with < or ≥ of 4 of the following set of mutations: 10, 20, 24, 32, 33, 36, 46, 48, 50, 54, 63, 71, 73, 82, 84 and 90. The second consisted in assessing the HIV RNA change from baseline in the subgroup of patients with < or ≥ of 4 of the following more specific set of mutations: 10, 46, 54, 82, 84, 90. In the analysis performed for patients with ≥ 4 protease gene mutations among the following set of mutations 10, 20, 24, 32, 33, 36, 46, 48, 50, 54, 63, 71, 73, 82, 84 and 90, the results significantly favoured the lopinavir + ritonavir arm. There were too few patients with ≥ 4 of the second more specific set of mutations (i.e. 10, 46, 54, 82, 84, 90) to assess the comparability of the REYATAZ + ritonavir and lopinavir + ritonavir regimens, but reduced virologic activity may be anticipated among patients with this resistance profile. REYATAZ + saquinavir was shown to be inferior to lopinavir + ritonavir. 5.2 Pharmacokinetic properties Special populations Impaired renal function: in healthy subjects, the renal elimination of unchanged atazanavir was approximately 7% of the administered dose. There are no pharmacokinetic data available on for REYATAZ with ritonavir in patients with renal insufficiency (see section 4.2); however, the impact of renal impairment on atazanavir elimination is anticipated to be minimal.. REYATAZ (without ritonavir) has been studied in adult patients with severe renal impairment (n=20), including those on haemodialysis, at multiple doses of 400 mg once daily. Although this study presented some limitations (i.e., unbound drug concentrations not studied), results suggested that the atazanavir pharmacokinetic parameters were decreased by 30% to 50% in patients undergoing haemodialysis compared to patients with normal renal function. The mechanism of this decrease is unknown. (See sections 4.2 and 4.4.) 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 02 March 2004 Date of latest renewal : 09 February: 02 March 2009 10. DATE OF REVISION OF THE TEXT 9th FebruaryJuly 2009 Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/http://www.emea.europa.eu
f Intent-to-treat analysis, with missing values considered as failures. Responders on LPV/RTV who completed treatment before Week 96 are excluded from Week 96 analysis. The proportion of patients with HIV RNA < 400 copies/ml were 53% and 43% for ATV/RTV and 54% and 46% for LPV/RTV at weeks 48 and 96 respectively. g Select substitutions include any change at positions L10, K20, L24, V32, L33, M36, M46, G48, I50, I54, L63, A71, G73, V82, I84, and L90 (0-2, 3, 4 or more) at baseline. NA = not applicable. Through 48 weeks of treatment, the mean changes from baseline in HIV RNA levels for REYATAZ + ritonavir and lopinavir + ritonavir were similar (non‑inferior). Consistent results were obtained with the last observation carried forward method of analysis (time‑averaged difference of 0.11, 97.5% confidence interval [‑0.15, 0.36]). The proportions of patients with HIV RNA < 400 copies/ml in the REYATAZ + ritonavir arm and the lopinavir + ritonavir arm were 53% and 54%, respectively, by intent‑to‑treat analysis, with missing values considered as failures. The proportions of patients with HIV RNA < 50 copies/ml in the REYATAZ + ritonavir arm and the lopinavir + ritonavir arm were 36% and 42%, respectively. By as‑treated analysis, excluding missing values, the proportions of patients with HIV RNA < 400 copies/ml (< 50 copies/ml) in the REYATAZ + ritonavir arm and the lopinavir + ritonavir arm were 55% (40%) and 56% (46%), respectively. The mean increases from baseline in CD4 cell count were 110 cells/mm3 and 121 cells/mm3 in the REYATAZ + ritonavir and lopinavir + ritonavir arms, respectively. Analyses of data through 96 Through 96 weeks of treatment demonstrated durability of antiviral activity. Mean, mean HIV RNA changes from baseline at Week 96 (‑2.29 log10 copies/ml for REYATAZ + ritonavir and ‑2.08 log10 copies/ml for lopinavir + ritonavir, time‑averaged difference of 0.14, 97.5% confidence interval [‑0.13, 0.41]) met criteria for non‑inferiority based on observed cases. Consistent results were obtained with the last observation carried forward method of analysis. The proportions of patients with HIV RNA <400 copies/ml (<50 copies/ml) for REYATAZ + ritonavir were 43% (32%) and for lopinavir + ritonavir were 46% (35%). Patients completing treatment while in response after 48 weeks were censored. By as‑treated analysis, excluding missing values, the proportions of patients with HIV RNA <400 copies/ml (<50 copies/ml) for REYATAZ + ritonavir were 84% (72%) and for lopinavir + ritonavir were 82% (72%). It is important to note that at time of the 96‑week analysis, 48 % of patients overall remained on study. Through 48 weeks of treatment, two types of analyses were performed based on baseline genotypic mutations. The first consisted in assessing the HIV RNA change from baseline in the subgroup of patients with < or ≥ of 4 of the following set of mutations: 10, 20, 24, 32, 33, 36, 46, 48, 50, 54, 63, 71, 73, 82, 84 and 90. The second consisted in assessing the HIV RNA change from baseline in the subgroup of patients with < or ≥ of 4 of the following more specific set of mutations: 10, 46, 54, 82, 84, 90. In the analysis performed for patients with ≥ 4 protease gene mutations among the following set of mutations 10, 20, 24, 32, 33, 36, 46, 48, 50, 54, 63, 71, 73, 82, 84 and 90, the results significantly favoured the lopinavir + ritonavir arm. There were too few patients with ≥ 4 of the second more specific set of mutations (i.e. 10, 46, 54, 82, 84, 90) to assess the comparability of the REYATAZ + ritonavir and lopinavir + ritonavir regimens, but reduced virologic activity may be anticipated among patients with this resistance profile. REYATAZ + saquinavir was shown to be inferior to lopinavir + ritonavir. 5.2 Pharmacokinetic properties Special populations Impaired renal function: in healthy subjects, the renal elimination of unchanged atazanavir was approximately 7% of the administered dose. There are no pharmacokinetic data available on for REYATAZ with ritonavir in patients with renal insufficiency (see section 4.2); however, the impact of renal impairment on atazanavir elimination is anticipated to be minimal.. REYATAZ (without ritonavir) has been studied in adult patients with severe renal impairment (n=20), including those on haemodialysis, at multiple doses of 400 mg once daily. Although this study presented some limitations (i.e., unbound drug concentrations not studied), results suggested that the atazanavir pharmacokinetic parameters were decreased by 30% to 50% in patients undergoing haemodialysis compared to patients with normal renal function. The mechanism of this decrease is unknown. (See sections 4.2 and 4.4.) 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 02 March 2004 Date of latest renewal : 09 February: 02 March 2009 10. DATE OF REVISION OF THE TEXT 9th FebruaryJuly 2009 Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/http://www.emea.europa.eu
g Select substitutions include any change at positions L10, K20, L24, V32, L33, M36, M46, G48, I50, I54, L63, A71, G73, V82, I84, and L90 (0-2, 3, 4 or more) at baseline. NA = not applicable. Through 48 weeks of treatment, the mean changes from baseline in HIV RNA levels for REYATAZ + ritonavir and lopinavir + ritonavir were similar (non‑inferior). Consistent results were obtained with the last observation carried forward method of analysis (time‑averaged difference of 0.11, 97.5% confidence interval [‑0.15, 0.36]). The proportions of patients with HIV RNA < 400 copies/ml in the REYATAZ + ritonavir arm and the lopinavir + ritonavir arm were 53% and 54%, respectively, by intent‑to‑treat analysis, with missing values considered as failures. The proportions of patients with HIV RNA < 50 copies/ml in the REYATAZ + ritonavir arm and the lopinavir + ritonavir arm were 36% and 42%, respectively. By as‑treated analysis, excluding missing values, the proportions of patients with HIV RNA < 400 copies/ml (< 50 copies/ml) in the REYATAZ + ritonavir arm and the lopinavir + ritonavir arm were 55% (40%) and 56% (46%), respectively. The mean increases from baseline in CD4 cell count were 110 cells/mm3 and 121 cells/mm3 in the REYATAZ + ritonavir and lopinavir + ritonavir arms, respectively. Analyses of data through 96 Through 96 weeks of treatment demonstrated durability of antiviral activity. Mean, mean HIV RNA changes from baseline at Week 96 (‑2.29 log10 copies/ml for REYATAZ + ritonavir and ‑2.08 log10 copies/ml for lopinavir + ritonavir, time‑averaged difference of 0.14, 97.5% confidence interval [‑0.13, 0.41]) met criteria for non‑inferiority based on observed cases. Consistent results were obtained with the last observation carried forward method of analysis. The proportions of patients with HIV RNA <400 copies/ml (<50 copies/ml) for REYATAZ + ritonavir were 43% (32%) and for lopinavir + ritonavir were 46% (35%). Patients completing treatment while in response after 48 weeks were censored. By as‑treated analysis, excluding missing values, the proportions of patients with HIV RNA <400 copies/ml (<50 copies/ml) for REYATAZ + ritonavir were 84% (72%) and for lopinavir + ritonavir were 82% (72%). It is important to note that at time of the 96‑week analysis, 48 % of patients overall remained on study. Through 48 weeks of treatment, two types of analyses were performed based on baseline genotypic mutations. The first consisted in assessing the HIV RNA change from baseline in the subgroup of patients with < or ≥ of 4 of the following set of mutations: 10, 20, 24, 32, 33, 36, 46, 48, 50, 54, 63, 71, 73, 82, 84 and 90. The second consisted in assessing the HIV RNA change from baseline in the subgroup of patients with < or ≥ of 4 of the following more specific set of mutations: 10, 46, 54, 82, 84, 90. In the analysis performed for patients with ≥ 4 protease gene mutations among the following set of mutations 10, 20, 24, 32, 33, 36, 46, 48, 50, 54, 63, 71, 73, 82, 84 and 90, the results significantly favoured the lopinavir + ritonavir arm. There were too few patients with ≥ 4 of the second more specific set of mutations (i.e. 10, 46, 54, 82, 84, 90) to assess the comparability of the REYATAZ + ritonavir and lopinavir + ritonavir regimens, but reduced virologic activity may be anticipated among patients with this resistance profile. REYATAZ + saquinavir was shown to be inferior to lopinavir + ritonavir. 5.2 Pharmacokinetic properties Special populations Impaired renal function: in healthy subjects, the renal elimination of unchanged atazanavir was approximately 7% of the administered dose. There are no pharmacokinetic data available on for REYATAZ with ritonavir in patients with renal insufficiency (see section 4.2); however, the impact of renal impairment on atazanavir elimination is anticipated to be minimal.. REYATAZ (without ritonavir) has been studied in adult patients with severe renal impairment (n=20), including those on haemodialysis, at multiple doses of 400 mg once daily. Although this study presented some limitations (i.e., unbound drug concentrations not studied), results suggested that the atazanavir pharmacokinetic parameters were decreased by 30% to 50% in patients undergoing haemodialysis compared to patients with normal renal function. The mechanism of this decrease is unknown. (See sections 4.2 and 4.4.) 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 02 March 2004 Date of latest renewal : 09 February: 02 March 2009 10. DATE OF REVISION OF THE TEXT 9th FebruaryJuly 2009 Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/http://www.emea.europa.eu
NA = not applicable. Through 48 weeks of treatment, the mean changes from baseline in HIV RNA levels for REYATAZ + ritonavir and lopinavir + ritonavir were similar (non‑inferior). Consistent results were obtained with the last observation carried forward method of analysis (time‑averaged difference of 0.11, 97.5% confidence interval [‑0.15, 0.36]). The proportions of patients with HIV RNA < 400 copies/ml in the REYATAZ + ritonavir arm and the lopinavir + ritonavir arm were 53% and 54%, respectively, by intent‑to‑treat analysis, with missing values considered as failures. The proportions of patients with HIV RNA < 50 copies/ml in the REYATAZ + ritonavir arm and the lopinavir + ritonavir arm were 36% and 42%, respectively. By as‑treated analysis, excluding missing values, the proportions of patients with HIV RNA < 400 copies/ml (< 50 copies/ml) in the REYATAZ + ritonavir arm and the lopinavir + ritonavir arm were 55% (40%) and 56% (46%), respectively. The mean increases from baseline in CD4 cell count were 110 cells/mm3 and 121 cells/mm3 in the REYATAZ + ritonavir and lopinavir + ritonavir arms, respectively. Analyses of data through 96 Through 96 weeks of treatment demonstrated durability of antiviral activity. Mean, mean HIV RNA changes from baseline at Week 96 (‑2.29 log10 copies/ml for REYATAZ + ritonavir and ‑2.08 log10 copies/ml for lopinavir + ritonavir, time‑averaged difference of 0.14, 97.5% confidence interval [‑0.13, 0.41]) met criteria for non‑inferiority based on observed cases. Consistent results were obtained with the last observation carried forward method of analysis. The proportions of patients with HIV RNA <400 copies/ml (<50 copies/ml) for REYATAZ + ritonavir were 43% (32%) and for lopinavir + ritonavir were 46% (35%). Patients completing treatment while in response after 48 weeks were censored. By as‑treated analysis, excluding missing values, the proportions of patients with HIV RNA <400 copies/ml (<50 copies/ml) for REYATAZ + ritonavir were 84% (72%) and for lopinavir + ritonavir were 82% (72%). It is important to note that at time of the 96‑week analysis, 48 % of patients overall remained on study. Through 48 weeks of treatment, two types of analyses were performed based on baseline genotypic mutations. The first consisted in assessing the HIV RNA change from baseline in the subgroup of patients with < or ≥ of 4 of the following set of mutations: 10, 20, 24, 32, 33, 36, 46, 48, 50, 54, 63, 71, 73, 82, 84 and 90. The second consisted in assessing the HIV RNA change from baseline in the subgroup of patients with < or ≥ of 4 of the following more specific set of mutations: 10, 46, 54, 82, 84, 90. In the analysis performed for patients with ≥ 4 protease gene mutations among the following set of mutations 10, 20, 24, 32, 33, 36, 46, 48, 50, 54, 63, 71, 73, 82, 84 and 90, the results significantly favoured the lopinavir + ritonavir arm. There were too few patients with ≥ 4 of the second more specific set of mutations (i.e. 10, 46, 54, 82, 84, 90) to assess the comparability of the REYATAZ + ritonavir and lopinavir + ritonavir regimens, but reduced virologic activity may be anticipated among patients with this resistance profile. REYATAZ + saquinavir was shown to be inferior to lopinavir + ritonavir. 5.2 Pharmacokinetic properties Special populations Impaired renal function: in healthy subjects, the renal elimination of unchanged atazanavir was approximately 7% of the administered dose. There are no pharmacokinetic data available on for REYATAZ with ritonavir in patients with renal insufficiency (see section 4.2); however, the impact of renal impairment on atazanavir elimination is anticipated to be minimal.. REYATAZ (without ritonavir) has been studied in adult patients with severe renal impairment (n=20), including those on haemodialysis, at multiple doses of 400 mg once daily. Although this study presented some limitations (i.e., unbound drug concentrations not studied), results suggested that the atazanavir pharmacokinetic parameters were decreased by 30% to 50% in patients undergoing haemodialysis compared to patients with normal renal function. The mechanism of this decrease is unknown. (See sections 4.2 and 4.4.) 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 02 March 2004 Date of latest renewal : 09 February: 02 March 2009 10. DATE OF REVISION OF THE TEXT 9th FebruaryJuly 2009 Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/http://www.emea.europa.eu
Through 48 weeks of treatment, the mean changes from baseline in HIV RNA levels for REYATAZ + ritonavir and lopinavir + ritonavir were similar (non‑inferior). Consistent results were obtained with the last observation carried forward method of analysis (time‑averaged difference of 0.11, 97.5% confidence interval [‑0.15, 0.36]). The proportions of patients with HIV RNA < 400 copies/ml in the REYATAZ + ritonavir arm and the lopinavir + ritonavir arm were 53% and 54%, respectively, by intent‑to‑treat analysis, with missing values considered as failures. The proportions of patients with HIV RNA < 50 copies/ml in the REYATAZ + ritonavir arm and the lopinavir + ritonavir arm were 36% and 42%, respectively. By as‑treated analysis, excluding missing values, the proportions of patients with HIV RNA < 400 copies/ml (< 50 copies/ml) in the REYATAZ + ritonavir arm and the lopinavir + ritonavir arm were 55% (40%) and 56% (46%), respectively. The mean increases from baseline in CD4 cell count were 110 cells/mm3 and 121 cells/mm3 in the REYATAZ + ritonavir and lopinavir + ritonavir arms, respectively.
Analyses of data through 96 Through 96 weeks of treatment demonstrated durability of antiviral activity. Mean, mean HIV RNA changes from baseline at Week 96 (‑2.29 log10 copies/ml for REYATAZ + ritonavir and ‑2.08 log10 copies/ml for lopinavir + ritonavir, time‑averaged difference of 0.14, 97.5% confidence interval [‑0.13, 0.41]) met criteria for non‑inferiority based on observed cases. Consistent results were obtained with the last observation carried forward method of analysis. The proportions of patients with HIV RNA <400 copies/ml (<50 copies/ml) for REYATAZ + ritonavir were 43% (32%) and for lopinavir + ritonavir were 46% (35%). Patients completing treatment while in response after 48 weeks were censored. By as‑treated analysis, excluding missing values, the proportions of patients with HIV RNA <400 copies/ml (<50 copies/ml) for REYATAZ + ritonavir were 84% (72%) and for lopinavir + ritonavir were 82% (72%). It is important to note that at time of the 96‑week analysis, 48 % of patients overall remained on study.
Through 48 weeks of treatment, two types of analyses were performed based on baseline genotypic mutations. The first consisted in assessing the HIV RNA change from baseline in the subgroup of patients with < or ≥ of 4 of the following set of mutations: 10, 20, 24, 32, 33, 36, 46, 48, 50, 54, 63, 71, 73, 82, 84 and 90.
The second consisted in assessing the HIV RNA change from baseline in the subgroup of patients with < or ≥ of 4 of the following more specific set of mutations: 10, 46, 54, 82, 84, 90. In the analysis performed for patients with ≥ 4 protease gene mutations among the following set of mutations 10, 20, 24, 32, 33, 36, 46, 48, 50, 54, 63, 71, 73, 82, 84 and 90, the results significantly favoured the lopinavir + ritonavir arm. There were too few patients with ≥ 4 of the second more specific set of mutations (i.e. 10, 46, 54, 82, 84, 90) to assess the comparability of the REYATAZ + ritonavir and lopinavir + ritonavir regimens, but reduced virologic activity may be anticipated among patients with this resistance profile.
REYATAZ + saquinavir was shown to be inferior to lopinavir + ritonavir.
5.2 Pharmacokinetic properties
Special populations
Impaired renal function: in healthy subjects, the renal elimination of unchanged atazanavir was approximately 7% of the administered dose. There are no pharmacokinetic data available on for REYATAZ with ritonavir in patients with renal insufficiency (see section 4.2); however, the impact of renal impairment on atazanavir elimination is anticipated to be minimal.. REYATAZ (without ritonavir) has been studied in adult patients with severe renal impairment (n=20), including those on haemodialysis, at multiple doses of 400 mg once daily. Although this study presented some limitations (i.e., unbound drug concentrations not studied), results suggested that the atazanavir pharmacokinetic parameters were decreased by 30% to 50% in patients undergoing haemodialysis compared to patients with normal renal function. The mechanism of this decrease is unknown. (See sections 4.2 and 4.4.) 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 02 March 2004 Date of latest renewal : 09 February: 02 March 2009 10. DATE OF REVISION OF THE TEXT 9th FebruaryJuly 2009 Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/http://www.emea.europa.eu
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation: 02 March 2004 Date of latest renewal : 09 February: 02 March 2009 10. DATE OF REVISION OF THE TEXT 9th FebruaryJuly 2009 Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/http://www.emea.europa.eu
Date of latest renewal : 09 February: 02 March 2009
10. DATE OF REVISION OF THE TEXT 9th FebruaryJuly 2009 Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/http://www.emea.europa.eu
10. DATE OF REVISION OF THE TEXT
9th FebruaryJuly 2009
Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/http://www.emea.europa.eu
Red iron oxideBlack iron oxideYellow iron oxide
Section 4.4 and 4.8: Information concerning class labelling osteonecrosis included.
Section 2. - Lactose content added.
Section 4.2 - updated to include 'experience in children is limited'.
Section 4.5 - Updated to include information regarding interaction between atazanavir and tenofovir.
Section 4.6 - Updated to include 'There are no adequare data from use of atazanavir in pregnant women'
Section 4.7 - Updated to include 'No studies on the effect on ability to drive and use machines have been performed.'
Section 4.8 - Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Postmarketing experience: diabetes mellitus and hyperglycaemia included as postmarketing adverse events.
Section 5.1 - Following paragraph added:
This medicinal product has been authorised under “Exceptional Circumstances”. This means that for scientific reasons, it has not been possible to obtain complete information on this medicinal product. The European Medicines Agency (EMEA) will review any new information which may become available every year and this SPC will be updated as necessary.
Section 6.1: Isopropyl alcohol added
Section 6.4 - 'Store in the original packaged' included.
Section 6.6 - 'Any unused product or waste material should be disposed of in accordance with local requirements' added.