Bristol-Myers Squibb Pharmaceutical Limited

REYATAZ 150 mg hard capsules

REYATAZ 200 mg hard capsules

REYATAZ 300 mg hard capsules

Each capsule contains 150 mg, 200 mg or 300 mg of atazanavir (as sulphate)

Excipient: 82.18 mg of lactose per 150 mg capsule.

Excipient: 109.57 mg of lactose per 200 mg capsule.

Excipient: 164.36 mg of lactose per 300 mg capsule.

For a full list of excipients, see section 6.1.

Hard capsule

REYATAZ 150 mg capsules are blue and powder blue capsule printed with white and blue inks, with "BMS 150 mg" on one half and with "3624" on the other half.

REYATAZ 200 mg capsules are opaque blue capsule printed with white ink, with "BMS 200 mg" on one half and with "3631" on the other half.

REYATAZ 300 mg capsules are opaque red and blue capsule printed with white ink, with "BMS 300 mg" on one half and with "3622" on the other half.

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 ( 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).

Posology

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 population

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.

Paediatric patients (less than 6 years of age): The safety and efficacy of REYAYAZ in children aged 3 months to 6 years has not been established. Currently available data are described in sections 4.8, 5.1, and 5.2 but no recommendation on a posology can be made. REYATAZ should not be used in children less than 3 months because of safety concerns especially taking into account the potential risk of kernicterus.

Special populations

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).

Pregnancy and Postpartum

During the second and third trimesters of pregnancy:

REYATAZ 300 mg with ritonavir 100 mg may not provide sufficient exposure to atazanavir, especially when the activity of atazanavir or the whole regimen may be compromised due to drug resistance. Since there are limited data available and due to inter-patient variability during pregnancy, Therapeutic Drug Monitoring (TDM) may be considered to ensure adequate exposure.

The risk of a further decrease in atazanavir exposure is expected when atazanavir is given with medicinal products known to reduce its exposure (e.g., tenofovir or H₂-receptor antagonists).

• If tenofovir or an H₂-receptor antagonist is needed, a dose increase to REYATAZ 400 mg with ritonavir 100 mg with TDM may be considered (see sections 4.6 and 5.2).

• It is not recommended to use REYATAZ with ritonavir for pregnant patients who are receiving both tenofovir and an H₂-receptor antagonist.

During postpartum:

Following a possible decrease in atazanavir exposure during the second and third trimester, atazanavir exposures might increase during the first two months after delivery (see section 5.2). Therefore, postpartum patients should be closely monitored for adverse reactions.

• During this time, postpartum patients should follow the same dose recommendation as for non-pregnant patients, including those for co-administration of medicinal products known to affect atazanavir exposure (see section 4.5).

Method of administration: for oral administration. The capsules should be swallowed whole.

Hypersensitivity to the active substance or to any of the excipients (see section 6.1).

Patients with moderate to severe hepatic insufficiency (see sections 4.2 and 4.4).

Combination of rifampicin and REYATAZ with concomitant low-dose ritonavir is contraindicated (see section 4.5).

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.

REYATAZ with ritonavir must not be used in combination with medicinal products that are substrates of the CYP3A4 isoform of cytochrome P450 and have narrow therapeutic windows (e.g., alfuzosin, astemizole, terfenadine, cisapride, pimozide, quinidine, bepridil, triazolam, midazolam administered orally (for caution on parenterally administered midazolam, see section 4.5), and ergot alkaloids, particularly, ergotamine, dihydroergotamine, ergonovine, methylergonovine) (see section 4.5).

REYATAZ must not be used in combination with products containing St. John's wort (Hypericum perforatum) (see section 4.5).

Patients should be advised that current antiretroviral therapy has not been proven to prevent the risk of transmission of HIV to others through blood or sexual contact. Appropriate precautions should continue to be employed.

Co-administration of REYATAZ with ritonavir at doses greater than 100 mg once daily has not been clinically evaluated. The use of higher ritonavir doses may alter the safety profile of atazanavir (cardiac effects, hyperbilirubinaemia) and therefore is not recommended. 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).

Patients with coexisting conditions

Atazanavir is primarily hepatically metabolised and increased plasma concentrations were observed in patients with hepatic impairment (see sections 4.2 and 4.3). The safety and efficacy of REYATAZ has not been established in patients with significant underlying liver disorders. Patients with chronic hepatitis B or C and treated with combination antiretroviral therapy are at an increased risk for severe and potentially fatal hepatic adverse reactions. In case of concomitant antiviral therapy for hepatitis B or C, please refer also to the relevant Summary of Product Characteristics for these medicinal products (see section 4.8).

Patients with pre-existing liver dysfunction, including chronic active hepatitis, have an increased frequency of liver function abnormalities during combination antiretroviral therapy and should be monitored according to standard practice. If there is evidence of worsening liver disease in such patients, interruption or discontinuation of treatment must be considered.

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).

Dose related asymptomatic prolongations in PR interval with REYATAZ have been observed in clinical studies. Caution should be used with medicinal products known to induce PR prolongations. In 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 (see section 5.1). Particular caution should be used when prescribing REYATAZ in association with medicinal products which have the potential to increase the QT interval and/or in patients with pre-existing risk factors (bradycardia, long congenital QT, electrolyte imbalances (see sections 4.8 and 5.3).

There have been reports of increased bleeding, including spontaneous skin haematomas and haemarthroses, in type A and B haemophiliac patients treated with protease inhibitors. In some patients additional factor VIII was given. In more than half of the reported cases, treatment with protease inhibitors was continued or reintroduced if treatment had been discontinued. A causal relationship has been suggested, although the mechanism of action has not been elucidated. Haemophiliac patients should therefore be made aware of the possibility of increased bleeding.

Fat redistribution and metabolic disorders

Combination antiretroviral therapy has been associated with the redistribution of body fat (lipodystrophy) in HIV patients. The long-term consequences of these events are currently unknown. Knowledge about the mechanism is incomplete. A connection between visceral lipomatosis and protease inhibitors and lipoatrophy and nucleoside reverse transcriptase inhibitors has been hypothesised. A higher risk of lipodystrophy has been associated with individual factors such as older age, and with drug related factors such as longer duration of antiretroviral treatment and associated metabolic disturbances. Clinical examination should include evaluation for physical signs of fat redistribution.

Combination antiretroviral therapy (CART), including REYATAZ (with or without ritonavir)-based CART, is associated with dyslipidaemia. Consideration should be given to the measurement of fasting serum lipids and blood glucose. Lipid disorders should be managed as clinically appropriate (see section 4.8).

In clinical studies, REYATAZ (with or without ritonavir) has been shown to induce dyslipidaemia to a lesser extent than comparators. The clinical impact of such findings has not been demonstrated in the absence of specific studies on cardiovascular risk. The selection of antiretroviral therapy must be guided principally by antiviral efficacy. Consultation with standard guidelines for management of dyslipidaemia is recommended.

Hyperglycaemia

New onset diabetes mellitus, hyperglycaemia, and exacerbation of existing diabetes mellitus have been reported in patients receiving protease inhibitors. In some of these, the hyperglycaemia was severe and in some cases also associated with ketoacidosis. Many patients had confounding medical conditions, some of which required therapy with medicinal products that have been associated with development of diabetes or hyperglycaemia.

Hyperbilirubinaemia

Reversible elevations in indirect (unconjugated) bilirubin related to inhibition of UDP-glucuronosyl transferase (UGT) have occurred in patients receiving REYATAZ (see section 4.8). Hepatic transaminase elevations that occur with elevated bilirubin in patients receiving REYATAZ should be evaluated for alternative etiologies. Alternative antiretroviral therapy to REYATAZ may be considered if jaundice or scleral icterus is unacceptable to a patient. Dose reduction of atazanavir is not recommended because it may result in a loss of therapeutic effect and development of resistance.

Indinavir is also associated with indirect (unconjugated) hyperbilirubinaemia due to inhibition of UGT. Combinations of REYATAZ and indinavir have not been studied and co-administration of these medicinal products is not recommended (see section 4.5).

Nephrolithiasis

Nephrolithiasis has been reported in patients receiving REYATAZ (see section 4.8). If signs or symptoms of nephrolithiasis occur, temporary interruption or discontinuation of treatment may be considered.

Immune reactivation syndrome

In HIV-infected patients with severe immune deficiency at the time of institution of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first few weeks or months of initiation of CART. Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections, and Pneumocystis carinii pneumonia. Any inflammatory symptoms should be evaluated and treatment instituted when necessary.

Osteonecrosis

Although the etiology is considered to be multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported particularly in patients with advanced HIV-disease and/or long-term exposure to combination antiretroviral therapy (CART). Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.

Rash and associated syndromes

Rashes are usually mild -to-moderate maculopapular skin eruptions that occur within the first 3 weeks of starting therapy with REYATAZ.

Stevens-Johnson syndrome (SJS), erythema multiforme, toxic skin eruptions and drug rash with eosinophilia and systemic symptoms (DRESS) syndrome have been reported in patients receiving REYATAZ. Patients should be advised of the signs and symptoms and monitored closely for skin reactions. REYATAZ should be discontinued if severe rash develops.

The best results in managing these events come from early diagnosis and immediate interruption of any suspect medicines. If the patient has developed SJS or DRESS associated with the use of REYATAZ, REYATAZ may not be restarted.

Interactions with other medicinal products

Co-administration of REYATAZ with simvastatin or lovastatin is not recommended (see section 4.5).

Co-administration of REYATAZ with nevirapine or efavirenz is not recommended (see section 4.5).

If the co-administration of REYATAZ with an NNRTI is required, an increase in the dose of both REYATAZ and ritonavir to 400 mg and 200 mg, respectively, in combination with efavirenz could be considered with close clinical monitoring.

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.

Co-administration of REYATAZ with proton pump inhibitors is not recommended (see section 4.5). If the combination of REYATAZ 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.

Co-administration of REYATAZ/ritonavir in combination with tenofovir and an H₂-receptor antagonist should be avoided (see section 4.5).

Lactose

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

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 4 PI mutations, in treatment experienced children even lower numbers of PI mutations may be predictive of a lack of benefit (see section 5.1).

When REYATAZ and ritonavir are co-administered, the metabolic drug interaction profile for ritonavir may predominate because ritonavir is a more potent CYP3A4 inhibitor than atazanavir. The Summary of Product Characteristics for ritonavir must be consulted before initiation of therapy with REYATAZ and ritonavir.

Atazanavir is metabolised in the liver through CYP3A4. It inhibits CYP3A4. Therefore, REYATAZ with ritonavir is contraindicated with medicinal products that are substrates of CYP3A4 and have a narrow therapeutic index: astemizole, terfenadine, cisapride, pimozide, quinidine, bepridil, triazolam, orally administered midazolam, and ergot alkaloids, particularly ergotamine and dihydroergotamine (see section 4.3).

Other interactions

Interactions between atazanavir/ritonavir and protease inhibitors, antiretroviral agents other than protease inhibitors, and other non-antiretroviral medicinal products are listed in the tables below (increase is indicated as “↑”, decrease as “”, no change as “↔”). If available, 90% confidence intervals (CI) are shown in parentheses. The studies presented in Table 2 were conducted in healthy subjects unless otherwise noted. Of importance, many studies were conducted with unboosted atazanavir, which is not the approved regimen of atazanavir.

Table 2: Interactions between REYATAZ and other medicinal products

Paediatric population

Interaction studies have only been performed in adults.

Pregnancy

A moderate amount of data in pregnant women (between 300-1000) pregnancy outcomes) indicate no malformative toxicity of atazanavir. Animal studies do not indicate reproductive toxicity (see section 5.3). The use of REYATAZ may be considered during pregnancy only if the potential benefit justifies the potential risk.

In clinical trial AI424-182 REYATAZ/ritonavir (300/100 mg or 400/100 mg) in combination with zidovudine/lamivudine was administered to 41 pregnant women during the second or third trimester. Six of 20 (30%) women on REYATAZ/ritonavir 300/100 mg and 13 of 21 (62%) women on REYATAZ/ritonavir 400/100 mg experienced grades 3 to 4 hyperbilirubinaemia. There were no cases of lactic acidosis observed in the clinical trial AI424-182.

The study assessed 40 infants who received antiretroviral prophylactic treatment (which did not include REYATAZ) and were negative for HIV-1 DNA at the time of delivery and/or during the first 6 months postpartum. Three of 20 infants (15%) born to women treated with REYATAZ/ritonavir 300/100 mg and four of 20 infants (20%) born to women treated with REYATAZ/ritonavir 400/100 mg experienced grade 3-4 bilirubin. There was no evidence of pathologic jaundice and six of 40 infants in this study received phototherapy for a maximum of 4 days. There were no reported cases of kernicterus in neonates.

For dosing recommendations see section 4.2 and for pharmacokinetic data see section 5.2.

It is not known whether REYATAZ administered to the mother during pregnancy will exacerbate physiological hyperbilirubinaemia and lead to kernicterus in neonates and infants. In the prepartum period, additional monitoring should be considered.

Breast-feeding

It is unknown whether atazanavir or atazanavir metabolites are excreted in human milk. Studies in rats have demonstrated that atazanavir is excreted in the milk. As a general rule, it is recommended that HIV infected women not breast-feed their infants in order to avoid transmission of HIV.

Fertility

In a nonclinical fertility and early embryonic development study in rats, atazanavir altered oestrus cycling with no effects on mating or fertility (see section 5.3).

Patients should be informed that dizziness has been reported during treatment with regimens containing REYATAZ (see section 4.8).

a. Summary of the safety profile

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, 96°weeks median duration and 108 weeks maximum duration).

Adverse reactions were consistent between patients who received REYATAZ 400 mg once daily and patients who received REYATAZ 300 mg with ritonavir 100 mg once daily, except that jaundice and elevated total bilirubin levels were reported more frequently with REYATAZ plus ritonavir.

Among patients who received REYATAZ 400 mg once daily or REYATAZ 300 mg with ritonavir 100 mg once daily, the only adverse reactions of any severity reported very commonly with at least a possible relationship to regimens containing REYATAZ and one or more NRTIs were nausea (20%), diarrhoea (10%), and jaundice (13%). Among patients receiving REYATAZ 300 mg with ritonavir 100 mg, the frequency of jaundice was 19%. In the majority of cases, jaundice was reported within a few days to a few months after the initiation of treatment (see section 4.4).

b. Tabulated list of adverse reactions

Assessment of adverse reactions for REYATAZ is based on safety data from clinical studies and post-marketing experience. Frequency is defined using the following convention: very common ( 1/10), common ( 1/100 to < 1/10), uncommon ( 1/1,000 to < 1/100), rare ( 1/10,000 to < 1/1,000), very rare (< 1/10,000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

^a These adverse reactions were identified through post-marketing surveillance but not observed in clinical trials with REYATAZ. The frequency category was estimated from a statistical calculation based on the total number of patients exposed to REYATAZ in randomised controlled and other available clinical trials (n = 2321).

^b See section c. Description of selected adverse reactions for more details.

c. Description of selected adverse reactions

In HIV-infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic infections may arise (see section 4.4).

Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk factors, advanced HIV disease or long-term exposure to combination antiretroviral therapy (CART). The frequency of this is unknown (see section 4.4).

Combination antiretroviral therapy has been associated with redistribution of body fat (lipodystrophy) in HIV patients, including loss of peripheral and facial subcutaneous fat, increased intra-abdominal and visceral fat, breast hypertrophy, and dorsocervical fat accumulation (buffalo hump).

Combination antiretroviral therapy has been associated with metabolic abnormalities such as hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, hyperglycaemia, and hyperlactataemia (see sections 4.4 and 5.1).

Rash and associated syndromes

Rashes are usually mild-to-moderate maculopapular skin eruptions that occur within the first 3 weeks of starting therapy with REYATAZ.

Stevens-Johnson syndrome (SJS), erythema multiforme, toxic skin eruptions and drug rash with eosinophilia and systemic symptoms (DRESS) syndrome have been reported with the use of REYATAZ (see section 4.4).

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 (87% Grade 1, 2, 3, or 4). Grade 3 or 4 elevation of total bilirubin was noted in 37% (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 96 weeks, 48% 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) (5%), low neutrophils (5%), elevated aspartate aminotransferase/serum glutamic-oxaloacetic transaminase (AST/SGOT) (3%), and elevated lipase (3%).

Two percent of patients treated with REYATAZ experienced concurrent Grade 3-4 ALT/AST and Grade 3-4 total bilirubin elevations.

d. Paediatric population

In clinical studies, paediatric patients 3 months to less than 18 years of age had a mean duration of treatment with REYATAZ of 115 weeks. The safety profile in these studies was overall comparable to that seen in adults. Both asymptomatic first-degree (23%) and second-degree (1%) atrioventricular block were reported in paediatric patients. The most frequently reported laboratory abnormality in paediatric patients receiving REYATAZ was elevation of total bilirubin ( 2.6 times ULN, Grade 3-4) which occurred in 45% of patients.

e. Other special populations

Patients co-infected with hepatitis B and/or hepatitis C virus

Among 1,151 patients receiving atazanavir 400 mg once daily, 177 patients were co-infected with chronic hepatitis B or C, and among 655 patients receiving atazanavir 300 mg once daily with ritonavir 100 mg once daily, 97 patients were co-infected with chronic hepatitis B or C. Co-infected patients were more likely to have baseline hepatic transaminase elevations than those without chronic viral hepatitis. No differences in frequency of bilirubin elevations were observed between these patients and those without viral hepatitis. The frequency of treatment emergent hepatitis or transaminase elevations in co-infected patients was comparable between REYATAZ and comparator regimens (see section 4.4).

Human experience of acute overdose with REYATAZ is limited. Single doses up to 1,200 mg have been taken by healthy volunteers without symptomatic untoward effects. At high doses that lead to high drug exposures, jaundice due to indirect (unconjugated) hyperbilirubinaemia (without associated liver function test changes) or PR interval prolongations may be observed (see sections 4.4 and 4.8).

Treatment of overdose with REYATAZ should consist of general supportive measures, including monitoring of vital signs and electrocardiogram (ECG), and observations of the patient's clinical status. If indicated, elimination of unabsorbed atazanavir should be achieved by emesis or gastric lavage. Administration of activated charcoal may also be used to aid removal of unabsorbed drug. There is no specific antidote for overdose with REYATAZ. Since atazanavir is extensively metabolised by the liver and is highly protein bound, dialysis is unlikely to be beneficial in significant removal of this medicinal product.

Pharmacotherapeutic group: protease inhibitor, ATC code: J05AE08

Mechanism of action: atazanavir is an azapeptide HIV-1 protease inhibitor (PI). The compound selectively inhibits the virus-specific processing of viral Gag-Pol proteins in HIV-1 infected cells, thus preventing formation of mature virions and infection of other cells.

Antiviral activity in vitro: atazanavir exhibits anti-HIV-1 (including all clades tested) and anti-HIV-2 activity in cell culture.

Resistance

Antiretroviral treatment naive adult 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. Resistance levels to atazanavir ranged from 3.5- to 29-fold without evidence of phenotypic cross resistance to other PIs. In clinical trials of antiretroviral treatment naive patients treated with boosted atazanavir, the I50L substitution did not emerge in any patient without baseline PI substitutions. The N88S substitution has been rarely observed in patients with virologic failure on atazanavir (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.

The M184I/V substitution emerged in 5/26 REYATAZ/ritonavir and 7/26 lopinavir/ritonavir virologic failure patients, respectively.

Antiretroviral treatment experienced adult 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.

None of the de novo substitutions (see Table 4) 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 major and minor resistance substitutions described previously to be involved in protease inhibitor resistance.

Clinical results

In antiretroviral naive adult patients

Study 138 is an international randomised, open-label, multicenter, prospective trial of 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 REYATAZ/ritonavir arm showed 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 (Table 5).

Analyses of data through 96 weeks of treatment demonstrated durability of antiviral activity (Table 5).

Table 5: Efficacy Outcomes in Study 138 ^a

^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 adult 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 6).

Table 6: Efficacy Outcomes at Week 48^a and at Week 96 (Study 045)

^a 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).

^b 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.

^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]). 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.

Through 96 weeks of treatment, mean HIV RNA changes from baseline for REYATAZ + ritonavir and lopinavir + ritonavir met criteria for non-inferiority based on observed cases. Consistent results were obtained with the last observation carried forward method of analysis. 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.

REYATAZ + saquinavir was shown to be inferior to lopinavir + ritonavir.

Paediatric population

Assessment of the pharmacokinetics, safety, tolerability, and efficacy of REYATAZ is based on data from the open-label, multicenter clinical trial PACTG 1020A conducted in patients from 3 months to 21 years of age. Overall in this study, 182 paediatric patients (81 antiretroviral-naive and 101 antiretroviral-experienced) received once daily REYATAZ (capsule or powder formulation), with or without ritonavir, in combination with two NRTIs.

The clinical data derived from this study are inadequate to support the use of atazanavir (with or without ritonavir) in children below 6 years of age.

Efficacy data observed in the 41 paediatric patients aged 6 years to less than 18 years that received REYATAZ capsules with ritonavir are presented in Table 7. For treatment-naive paediatric patients, the mean baseline CD4 cell count was 344 cells/mm³ (range: 2 to 800 cells/ mm³) and mean baseline plasma HIV 1 RNA was 4.67 log₁₀ copies/ml (range: 3.70 to 5.00 log₁₀ copies/ml). For treatment-experienced paediatric patients, the mean baseline CD4 cell count was 522 cells/mm³ (range: 100 to 1157 cells/ mm³) and mean baseline plasma HIV 1 RNA was 4.09 log₁₀ copies/ml (range: 3.28 to 5.00 log₁₀ copies/ml).

Table 7: Efficacy Outcomes (paediatric patients 6 years to less than 18 years of age) at Week 48 (Study PACTG 1020A)

^a Intent-to-treat analysis, with missing values considered as failures.

^b Number of patients evaluable.

^c PI major L24I, D30N, V32I, L33F, M46IL, I47AV, G48V, I50LV, F53LY,I54ALMSTV, L76V, V82AFLST, I84V, N88DS, L90M; PI minor: L10CFIRV, V11I, E35G, K43T, Q58E, A71ILTV, G73ACST, T74P, N83D, L89V.

^d Includes patients with baseline resistance data.

NA = not applicable.

Data in the paediatric population are very limited. Available data do suggest that atazanavir in combination with ritonavir may not be effective in treatment experienced children even with very few (<3) PI mutations.

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).

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.

Absorption: in HIV-infected patients (n=33, combined studies), multiple dosing of REYATAZ 300 mg once daily with ritonavir 100 mg once daily with food produced a geometric mean (CV%) for atazanavir, C_max of 4466 (42%) ng/ml, with time to C_max of approximately 2.5 hours. The geometric mean (CV%) for atazanavir C_min and AUC was 654 (76%) ng/ml and 44185 (51%) ng•h/ml, respectively.

Food effect: co-administration of REYATAZ and ritonavir with food optimises the bioavailability of atazanavir. Co-administration of a single 300-mg dose of REYATAZ and 100-mg dose of ritonavir with a light meal resulted in a 33% increase in the AUC and a 40% increase in both the C_max and the 24-hour concentration of atazanavir relative to the fasting state. Co-administration with a high-fat meal did not affect the AUC of atazanavir relative to fasting conditions and the C_max was within 11% of fasting values. The 24-hour concentration following a high fat meal was increased by approximately 33% due to delayed absorption; the median T_max increased from 2.0 to 5.0 hours. Administration of REYATAZ with ritonavir with either a light or a high-fat meal decreased the coefficient of variation of AUC and C_max by approximately 25% compared to the fasting state. To enhance bioavailability and minimise variability, REYATAZ is to be taken with food.

Distribution: atazanavir was approximately 86% bound to human serum proteins over a concentration range of 100 to 10,000 ng/ml. Atazanavir binds to both alpha-1-acid glycoprotein (AAG) and albumin to a similar extent (89% and 86%, respectively, at 1,000 ng/ml). In a multiple-dose study in HIV-infected patients dosed with 400 mg of atazanavir once daily with a light meal for 12 weeks, atazanavir was detected in the cerebrospinal fluid and semen.

Metabolism: studies in humans and in vitro studies using human liver microsomes have demonstrated that atazanavir is principally metabolised by CYP3A4 isozyme to oxygenated metabolites. Metabolites are then excreted in the bile as either free or glucuronidated metabolites. Additional minor metabolic pathways consist of N-dealkylation and hydrolysis. Two minor metabolites of atazanavir in plasma have been characterised. Neither metabolite demonstrated in vitro antiviral activity.

Elimination: following a single 400-mg dose of ¹⁴C-atazanavir, 79% and 13% of the total radioactivity was recovered in the faeces and urine, respectively. Unchanged drug accounted for approximately 20% and 7% of the administered dose in the faeces and urine, respectively. Mean urinary excretion of unchanged drug was 7% following 2 weeks of dosing at 800 mg once daily. In HIV-infected adult patients (n=33, combined studies) the mean half-life within a dosing interval for atazanavir was 12 hours at steady state following a dose of 300 mg daily with ritonavir 100 mg once daily with a light meal.

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 for REYATAZ with ritonavir in patients with renal insufficiency. 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.)

Impaired hepatic function: atazanavir is metabolised and eliminated primarily by the liver. The effects of hepatic impairment on the pharmacokinetics of atazanavir after a 300 mg dose with ritonavir have not been studied. Concentrations of atazanavir with or without ritonavir are expected to be increased in patients with moderately or severely impaired hepatic function (see sections 4.2, 4.3, and 4.4).

Age/Gender: a study of the pharmacokinetics of atazanavir was performed in 59 healthy male and female subjects (29 young, 30 elderly). There were no clinically important pharmacokinetic differences based on age or gender.

Race: a population pharmacokinetic analysis of samples from Phase II clinical trials indicated no effect of race on the pharmacokinetics of atazanavir.

Pregnancy:

The pharmacokinetic data from HIV-infected pregnant women receiving REYATAZ capsules with ritonavir are presented in Table 8.

Table 8: Steady-State Pharmacokinetics of Atazanavir with ritonavir in HIV-Infected Pregnant Women in the Fed State

Paediatric population

The pharmacokinetics of atazanavir in paediatric patients exhibit an increased absorption rate compared to adults. There is a slight trend toward a higher clearance in younger children when normalised for body weight. As a result, greater peak to trough ratios are observed. The geometric mean AUC values in paediatric patients at recommended doses are expected to be similar to those observed in adults, with higher geometric mean C_max (13-17%) and lower geometric mean C_min (up to 30%) values compared to those in adults. The variability of pharmacokinetic parameters in younger children is higher.

In repeat-dose toxicity studies, conducted in mice, rats, and dogs, atazanavir-related findings were generally confined to the liver and included generally minimal to mild increases in serum bilirubin and liver enzymes, hepatocellular vacuolation and hypertrophy, and, in female mice only, hepatic single-cell necrosis. Systemic exposures of atazanavir in mice (males), rats, and dogs at doses associated with hepatic changes were at least equal to that observed in humans given 400 mg once daily. In female mice, atazanavir exposure at a dose that produced single-cell necrosis was 12 times the exposure in humans given 400 mg once daily. Serum cholesterol and glucose were minimally to mildly increased in rats but not in mice or dogs.

During in vitro studies, cloned human cardiac potassium channel (hERG), was inhibited by 15% at a concentration (30 μM) of atazanavir corresponding to 30-fold the free drug concentration at C_max in humans. Similar concentrations of atazanavir increased by 13% the action potential duration (APD₉₀) in rabbit Purkinje fibres study. Electrocardiographic changes (sinus bradycardia, prolongation of PR interval, prolongation of QT interval, and prolongation of QRS complex) were observed only in an initial 2-week oral toxicity study performed in dogs. Subsequent 9-month oral toxicity studies in dogs showed no drug-related electrocardiographic changes. The clinical relevance of these non-clinical data is unknown. Potential cardiac effects of this product in humans cannot be ruled out (see sections 4.4 and 4.8). The potential for PR prolongation should be considered in cases of overdose (see section4.9).

In a fertility and early embryonic development study in rats, atazanavir altered oestrus cycling with no effects on mating or fertility. No teratogenic effects were observed in rats or rabbits at maternally toxic doses. In pregnant rabbits, gross lesions of the stomach and intestines were observed in dead or moribund does at maternal doses 2 and 4 times the highest dose administered in the definitive embryo-development study. In the pre- and postnatal development assessment in rats, atazanavir produced a transient reduction in body weight in the offspring at a maternally toxic dose. Systemic exposure to atazanavir at doses that resulted in maternal toxicity was at least equal to or slightly greater than that observed in humans given 400 mg once daily.

Atazanavir was negative in an Ames reverse-mutation assay but did induce chromosomal aberrations in vitro in both the absence and presence of metabolic activation. In in vivo studies in rats, atazanavir did not induce micronuclei in bone marrow, DNA damage in duodenum (comet assay), or unscheduled DNA repair in liver at plasma and tissue concentrations exceeding those that were clastogenic in vitro.

In long-term carcinogenicity studies of atazanavir in mice and rats, an increased incidence of benign hepatic adenomas was seen in female mice only. The increased incidence of benign hepatic adenomas in female mice was likely secondary to cytotoxic liver changes manifested by single-cell necrosis and is considered to have no relevance for humans at intended therapeutic exposures. There were no tumorigenic findings in male mice or in rats.

Atazanavir increased opacity of bovine corneas in an in vitro ocular irritation study, indicating it may be an ocular irritant upon direct contact with the eye.

Capsule content:

Crospovidone

Lactose monohydrate

Magnesium stearate

Capsule shells:

Gelatine

Indigocarmin (E132)

Titanium dioxide (E171)

300 mg capsule shells also contain:

Red iron oxide

Black iron oxide

Yellow iron oxide

White ink containing:

Shellac

Titanium dioxide (E171)

Ammonium hydroxide

Propylene glycol

Simethicone

150 mg capsule shells also contain blue ink containing:

Shellac

Propylene glycol

Ammonium hydroxide

Indigocarmin (E132)

Not applicable.

2 years

Do not store above 25°C.

Each carton contains one high-density polyethylene (HDPE) bottle closed with child-resistant polypropylene closure. Each bottle contains 30 or 60 hard capsules.

Not all pack sizes may be marketed.

Any unused product or waste material should be disposed of in accordance with local requirements.

BRISTOL-MYERS SQUIBB PHARMA EEIG

Uxbridge Business Park

Sanderson Road

Uxbridge UB8 1DH

United Kingdom

Date of first authorisation: 02 March 2004

Date of latest renewal: 02 March 2009

22 November 2011

Detailed information on this product is available on the website of the European Medicines Agency http://www.ema.europa.eu

POM