Metabolism and nutrition disorders:

uncommon: diabetesa, hyperglycaemiaa,b, weight decreased, weight gain, anorexia, appetite increased

Medicinal products by therapeutic area

Interaction

Recommendations concerning co-administration

ANTI-RETROVIRALS

Protease inhibitors: The co-administration of REYATAZ/ritonavir and other protease inhibitors has not been studied but would be expected to increase exposure to other protease inhibitors. Therefore, such co-administration is not recommended.

Ritonavir 100 mg once daily

(atazanavir 300 mg once daily)

Studies conducted in HIV-infected patients.

Atazanavir AUC: ↑250% (↑144% ↑403%)*

Atazanavir C_max: ↑120% (↑56% ↑211%)*

Atazanavir C_min: ↑713% (↑359% ↑1339%)*

* In a combined analysis, atazanavir 300 mg and ritonavir 100 mg (n=33) was compared to atazanavir 400 mg without ritonavir (n=28).

The mechanism of interaction between atazanavir and ritonavir is CYP3A4 inhibition.

Ritonavir 100 mg once daily is used as a booster of atazanavir pharmacokinetics.

Indinavir

Indinavir is associated with indirect unconjugated hyperbilirubinaemia due to inhibition of UGT.

Co-administration of REYATAZ and indinavir is not recommended (see section 4.4).

Nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs)

Lamivudine 150 mg twice daily + zidovudine 300 mg twice daily

(atazanavir 400 mg once daily)

No significant effect on lamivudine and zidovudine concentrations was observed.

Based on these data and because ritonavir is not expected to have a significant impact on the pharmacokinetics of NRTIs, the co-administration of these medicinal products and REYATAZ is not expected to significantly alter the exposure of the co-administered drugs.

Abacavir

The co-administration of abacavir and REYATAZ is not expected to significantly alter the exposure of abacavir.

Didanosine (buffered tablets) 200 mg/stavudine 40 mg, both single dose

(atazanavir 400 mg single dose)

Atazanavir, simultaneous administration with ddI+d4T (fasted)

Atazanavir AUC ↓87% (↓92% ↓79%)

Atazanavir C_max ↓89% (↓94% ↓82%)

Atazanavir C_min ↓84% (↓90% ↓73%)

Atazanavir, dosed 1 hr after ddI+d4T (fasted)

Atazanavir AUC ↔3% (↓36% ↑67%)

Atazanavir C_max ↑12% (↓33% ↑18%)

Atazanavir C_min ↔3% (↓39% ↑73%)

Atazanavir concentrations were greatly decreased when co-administered with didanosine (buffered tablets) and stavudine. The mechanism of interaction is a reduced solubility of atazanavir with increasing pH related to the presence of anti-acid agent in didanosine buffered tablets.

No significant effect on didanosine and stavudine concentrations was observed.

Didanosine should be taken at the fasted state 2 hours after REYATAZ taken with food. The co-administration of stavudine with REYATAZ is not expected to significantly alter the exposure of stavudine.

Didanosine (enteric coated capsules) 400 mg single dose

(atazanavir 300 mg once daily with ritonavir 100 mg once daily)

Didanosine (with food)

Didanosine AUC ↓34% (↓41% ↓27%)

Didanosine C_max ↓38% (↓48% ↓26%)

Didanosine C_min ↑25% (↓8% ↑69%)

No significant effect on atazanavir concentrations was observed when administered with enteric-coated didanosine, but administration with food decreased didanosine concentrations.

Tenofovir disoproxil fumarate 300 mg once daily

(atazanavir 300 mg once daily with ritonavir 100 mg once daily)

Studies conducted in HIV-infected patients

Atazanavir AUC ↓22% (↓35% ↓6%) *

Atazanavir C_max ↓16% (↓30% ↔0%) *

Atazanavir C_min ↓23% (↓43% ↑2%) *

* In a combined analysis from several clinical studies, atazanavir/ritonavir 300/100 mg co-administered with tenofovir disoproxil fumarate 300 mg (n=39) was compared to atazanavir/ritonavir 300/100 mg (n=33).

The efficacy of REYATAZ/ritonavir in combination with tenofovir disoproxil fumarate in treatment-experienced patients has been demonstrated in clinical study 045 and in treatment naive patients in clinical study 138 (see sections 4.8 and 5.1). The mechanism of interaction between atazanavir and tenofovir disoproxil fumarate is unknown.

When co-administered with tenofovir disoproxil fumarate, it is recommended that REYATAZ 300 mg be given with ritonavir 100 mg and tenofovir disoproxil fumarate 300 mg (all as a single dose with food).

Tenofovir disoproxil fumarate 300 mg once daily

(atazanavir 300 mg once daily with ritonavir 100 mg once daily)

Tenofovir disoproxil fumarate AUC ↑37% (↑30% ↑45%)

Tenofovir disoproxil fumarate C_max ↑34% (↑20% ↑51%)

Tenofovir disoproxil fumarate C_min ↑29% (↑21% ↑36%)

Patients should be closely monitored for tenofovir disoproxil fumarate-associated adverse events, including renal disorders.

Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

Efavirenz 600 mg once daily

(atazanavir 400 mg once daily with ritonavir 100 mg once daily)

Atazanavir (pm): all administered with food

Atazanavir AUC ↔0%(↓9% ↑10%)*

Atazanavir C_max ↑17%(↑8% ↑27%)*

Atazanavir C_min ↓42%(↓51% ↓31%)*

Co-administration of efavirenz and REYATAZ is not recommended (see section 4.4)

Efavirenz 600 mg once daily

(atazanavir 400 mg once daily with ritonavir 200 mg once daily)

Atazanavir (pm): all administered with food

Atazanavir AUC ↔6% (↓10% ↑26%) */**

Atazanavir C_max ↔9% (↓5% ↑26%) */**

Atazanavir C_min ↔12% (↓16% ↑49%) */**

* When compared to REYATAZ 300 mg/ritonavir 100 mg once daily in the evening without efavirenz. This decrease in atazanavir C_min, might negatively impact the efficacy of atazanavir. The mechanism of efavirenz/atazanavir interaction is CYP3A4 induction.

** Based on historical comparison.

Nevirapine 200 mg twice daily

(atazanavir 400 mg once daily with ritonavir 100 mg once daily)

Study conducted in HIV infected patients

Nevirapine AUC ↑26% (↑17% ↑36%)

Nevirapine C_max ↑21% (↑11% ↑32%)

Nevirapine C_min ↑35% (↑25% ↑47%)

Atazanavir AUC ↓19% (↓35% ↑2%) *

Atazanavir C_max ↔2% (↓15% ↑24%) *

Atazanavir C_min ↓59% (↓73% ↓40%) *

* When compared to REYATAZ 300 mg and ritonavir 100 mg without nevirapine. This decrease in atazanavir C_min, might negatively impact the efficacy of atazanavir. The mechanism of nevirapine/atazanavir interaction is CYP3A4 induction.

Co-administration of nevirapine and REYATAZ is not recommended (see section 4.4)

Integrase Inhibitors

Raltegravir 400 mg twice daily

(atazanavir/ritonavir)

Raltegravir AUC ↑41%

Raltegravir C_max ↑24%

Raltegravir C_12hr ↑77%

The mechanism is UGT1A1 inhibition.

No dose adjustment required for raltegravir.

HCV Protease Inhibitors

Boceprevir 800 mg three times daily

(atazanavir 300 mg/ritonavir 100 mg once daily)

boceprevir AUC ↔5%

boceprevir C_max ↔7%

boceprevir C_min ↔18%

atazanavir AUC ↓ 35%

atazanavir C_max ↓ 25%

atazanavir C_min ↓ 49%

ritonavir AUC ↓ 36%

ritonavir C_max ↓ 27%

ritonavir C_min ↓ 45%

Co-administration of atazanavir/ritonavir with boceprevir resulted in lower exposure of atazanavir which may be associated with lower efficacy and loss of HIV control. This co-administration might be considered on a case by case basis if deemed necessary, in patients with suppressed HIV viral loads and with HIV viral strain without any suspected resistance to the HIV regimen. Increased clinical and laboratory monitoring for HIV suppression is warranted.

ANTIBIOTICS

Clarithromycin 500 mg twice daily

(atazanavir 400 mg once daily)

Clarithromycin AUC ↑94% (↑75% ↑116%)

Clarithromycin C_max ↑50% (↑32% ↑71%)

Clarithromycin C_min ↑160% (↑135% ↑188%)

14-OH clarithromycin

14-OH clarithromycin AUC ↓70% (↓74% ↓66%)

14-OH clarithromycin C_max ↓72% (↓76% ↓67%)

14-OH clarithromycin C_min ↓62% (↓66% ↓58%)

Atazanavir AUC ↑28% (↑16% ↑43%)

Atazanavir C_max ↔6% (↓7% ↑20%)

Atazanavir C_min ↑91% (↑66% ↑121%)

A dose reduction of clarithromycin may result in subtherapeutic concentrations of 14-OH clarithromycin. The mechanism of the clarithromycin/atazanavir interaction is CYP3A4 inhibition.

No recommendation regarding dose reduction can be made; therefore, caution should be exercised if REYATAZ is co-administered with clarithromycin.

ANTIFUNGALS

Ketoconazole 200 mg once daily

(atazanavir 400 mg once daily)

No significant effect on atazanavir concentrations was observed.

Ketoconazole and itraconazole should be used cautiously with REYATAZ/ritonavir, high doses of ketoconazole and itraconazole (>200 mg/day) are not recommended.

Itraconazole

Itraconazole, like ketoconazole, is a potent inhibitor as well as a substrate of CYP3A4.

Based on data obtained with other boosted PIs and ketoconazole, where ketoconazole AUC showed a 3-fold increase, REYATAZ/ritonavir is expected to increase ketoconazole or itraconazole concentrations.

Voriconazole 200 mg twice daily (atazanavir 300 mg/ritonavir 100 mg once daily)

Subjects with at least one functional CYP2C19 allele.

Voriconazole AUC ↓33% (↓42% ↓22%)

Voriconazole C_max ↓10% (↓22% ↓4%)

Voriconazole C_min ↓39% (↓49% ↓28%)

Atazanavir AUC ↓12% (↓18% ↓5%)

Atazanavir C_max ↓13% (↓20% ↓4%)

Atazanavir C_min ↓ 20 % (↓28 % ↓10%)

Ritonavir AUC ↓12% (↓17% ↓7%)

Ritonavir C_max ↓9% (↓17% ↔0%)

Ritonavir C_min ↓25% (↓35% ↓14%)

In the majority of patients with at least one functional CYP2C19 allele, a reduction in both voriconazole and atazanavir exposures are expected.

Co-administration of voriconazole and REYATAZ with ritonavir is not recommended unless an assessment of the benefit/risk to the patient justifies the use of voriconazole (see section 4.4).

At the time voriconazole treatment is required, a patient's CYP2C19 genotype should be performed if feasible.

Therefore if the combination is unavoidable, the following recomendations are made according to the CYP2C19 status:

- in patients with at least one functional CYP2C19 allele, close clinical monitoring for a loss of both voriconazole (clinical signs) and atazanavir (virologic response) efficacy is recommended.

- in patients without a functional CYP2C19 allele, close clinical and laboratory monitoring of voriconazole-associated adverse events is recommended.

If genotyping is not feasible, full monitoring of safety and efficacy should be performed.

Voriconazole 50 mg twice daily (atazanavir 300 mg/ritonavir 100 mg once daily)

Subjects without a functional CYP2C19 allele.

Voriconazole AUC ↑561% (↑451% ↑699%)

Voriconazole C_max ↑438% (↑355% ↑539%)

Voriconazole C_min ↑765% (↑571% ↑1,020%)

Atazanavir AUC ↓20% (↓35% ↓3%)

Atazanavir C_max ↓19% (↓34% ↔0.2%)

Atazanavir C_min ↓ 31 % (↓46 % ↓13%)

Ritonavir AUC ↓11% (↓20% ↓1%)

Ritonavir C_max ↓11% (↓24% ↑4%)

Ritonavir C_min ↓19% (↓35% ↑1%)

In a small number of patients without a functional CYP2C19 allele, significantly increased voriconazole exposures are expected.

Fluconazole 200 mg once daily

(atazanavir 300 mg and ritonavir 100 mg once daily)

Atazanavir and fluconazole concentrations were not significantly modified when REYATAZ/ritonavir was co-administered with fluconazole.

No dosage adjustments are needed for fluconazole and REYATAZ.

ANTIMYCOBACTERIAL

Rifabutin 150 mg twice weekly

(atazanavir 300 mg and ritonavir 100 mg once daily)

Rifabutin AUC ↑48% (↑19% ↑84%) **

Rifabutin C_max ↑149% (↑103% ↑206%) **

Rifabutin C_min ↑40% (↑5% ↑87%) **

25-O-desacetyl-rifabutin AUC ↑990% (↑714% ↑1361%) **

25-O-desacetyl-rifabutin C_max ↑677% (↑513% ↑883%) **

25-O-desacetyl-rifabutin C_min ↑1045% (↑715% ↑1510%) **

** When compared to rifabutin 150 mg once daily alone. Total rifabutin and 25-O-desacetyl-rifabutin AUC ↑119% (↑78% ↑169%).

In previous studies, the pharmacokinetics of atazanavir was not altered by rifabutin.

When given with REYATAZ, 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 recommended 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.

Rifampicin

Rifampicin is a strong CYP3A4 inducer and has been shown to cause a 72% decrease in atazanavir AUC which can result in virological failure and resistance development. During attempts to overcome the decreased exposure by increasing the dose of REYATAZ or other protease inhibitors with ritonavir, a high frequency of liver reactions was seen.

The combination of rifampicin and REYATAZ is contraindicated (see section 4.3).

ANTIPSYCOTICS

Quetiapine

Due to CYP3A4 inhibition by REYATAZ, concentrations of quetiapine are expected to increase.

Co-administration of quetiapine with REYATAZ is contraindicated as REYATAZ may increase quetiapine-related toxicity. Increased plasma concentrations of quetiapine may lead to coma (see section 4.3).

ACID REDUCING AGENTS

H₂-Receptor antagonists

Without Tenofovir disoproxil fumarate

In HIV-infected patients with atazanavir/ritonavir at the recommended dose 300/100 mg once daily

For patients not taking tenofovir disoproxil fumarate, if REYATAZ 300 mg/ritonavir 100 mg and H₂-receptor antagonists are co-administered, a dose equivalent to famotidine 20 mg twice daily should not be exceeded. If a higher dose of an H₂-receptor antagonist is required (e.g., famotidine 40 mg twice daily or equivalent) an increase of the REYATAZ/ritonavir dose from 300/100 mg to 400/100 mg can be considered.

Famotidine 20 mg twice daily

Atazanavir AUC ↓18% (↓25% ↑1%)

Atazanavir C_max ↓20% (↓32% ↓7%)

Atazanavir C_min ↔1% (↓16% ↑18%)

Famotidine 40 mg twice daily

Atazanavir AUC ↓23% (↓32% ↓14%)

Atazanavir C_max ↓23% (↓33% ↓12%)

Atazanavir C_min ↓20% (↓31% ↓8%)

In Healthy volunteers with atazanavir/ritonavir at an increased dose of 400/100 mg once daily

Famotidine 40 mg twice daily

Atazanavir AUC ↔3% (↓14% ↑22%)

Atazanavir C_max ↔2% (↓13% ↑8%)

Atazanavir C_min ↓14% (↓32% ↑8%)

With Tenofovir disoproxil fumarate 300 mg once daily

In HIV-infected patients with atazanavir/ritonavir at the recommended dose of 300/100 mg once daily

For patients who are taking tenofovir disoproxil fumarate, if REYATAZ/ritonavir with both tenofovir disoproxil fumarate and an H₂-receptor antagonist are co-administered, a dose increase of REYATAZ to 400 mg with 100 mg of ritonavir is recommended. A dose equivalent to famotidine 40 mg twice daily should not be exceeded.

Famotidine 20 mg twice daily

Atazanavir AUC ↓21% (↓34% ↓4%) *

Atazanavir C_max ↓21% (↓36% ↓4%) *

Atazanavir C_min ↓19% (↓37% ↑5%) *

Famotidine 40 mg twice daily

Atazanavir AUC ↓24% (↓36% ↓11%)*

Atazanavir C_max ↓23% (↓36% ↓8%) *

Atazanavir C_min ↓25% (↓47% ↑7%) *

In HIV-infected patients with atazanavir/ritonavir at an increased dose of 400/100 mg once daily

Famotidine 20 mg twice daily

Atazanavir AUC ↑18% (↑6.5% ↑30%)*

Atazanavir C_max ↑18% (↑6.7% ↑31%)*

Atazanavir C_min ↑24 % (↑10% ↑39%)*

Famotidine 40 mg twice daily

Atazanavir AUC «2.3% (↓13% ↑10%)*

Atazanavir C_max «5% (↓17% ↑8.4%)*

Atazanavir C_min «1.3% (↓10% ↑15)*

* When compared to atazanavir 300 mg once daily with ritonavir 100 mg once daily 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 disoproxil fumarate, 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 once daily

(atazanavir 400 mg once daily with ritonavir 100 mg once daily)

Atazanavir (am): 2 hr after omeprazole

Atazanavir AUC ↓61% (↓65% ↓55%)

Atazanavir C_max ↓66% (↓62% ↓49%)

Atazanavir C_min ↓65% (↓71% ↓59%)

Co-administration of REYATAZ with ritonavir and proton pump inhibitors is not recommended. If the combination 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 once daily

(atazanavir 400 mg once daily with ritonavir 100 mg once daily)

Atazanavir (am): 1 hr after omeprazole

Atazanavir AUC ↓30% (↓43% ↓14%) *

Atazanavir C_max ↓31% (↓42% ↓17%) *

Atazanavir C_min ↓31% (↓46% ↓12%) *

* When compared to atazanavir 300 mg once daily with ritonavir 100 mg once daily.

The decrease in AUC, C_max, and C_min 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.

Antacids

Antacids and medicinal products containing buffers

Reduced plasma concentrations of atazanavir may be the consequence of increased gastric pH if antacids, including buffered medicinal products, are administered with REYATAZ.

REYATAZ should be administered 2 hours before or 1 hour after antacids or buffered medicinal products.

ALPHA 1-ADRENORECEPTOR ANTAGONIST

Alfuzosin

Potential for increased alfuzosin concentrations which can result in hypotension. The mechanism of interaction is CYP3A4 inhibition by REYATAZ and/or ritonavir.

Co-administration of alfuzosin with REYATAZ is contraindicated (see section 4.3)

ANTICOAGULANTS

Warfarin

Co-administration with REYATAZ has the potential to increase or decrease warfarin concentrations.

It is recommended that the International Normalised Ratio (INR) be monitored carefully during treatment with REYATAZ, especially when commencing therapy.

ANTIEPILEPTICS

Carbamazepine

REYATAZ may increase plasma levels of carbamazepine due to CYP3A4 inhibition.

Due to carbamazepine inducing effect, a reduction in REYATAZ exposure cannot be ruled out.

Carbamazepine should be used with caution in combination with REYATAZ. If necessary, monitor carbamazepine serum concentrations and adjust the dose accordingly. Close monitoring of the patient's virologic response should be excercised.

Phenytoin, phenobarbital

Ritonavir may decrease plasma levels of phenytoin and/or phenobarbital due to CYP2C9 and CYP2C19 induction.

Due to phenytoin/phenobarbital inducing effect, a reduction in REYATAZ exposure cannot be ruled out.

Phenobarbital and phenytoin should be used with caution in combination with REYATAZ/ritonavir.

When REYATAZ/ritonavir is co-administered with either phenytoin or phenobarbital, a dose adjustment of phenytoin or phenobarbital may be required.

Close monitoring of patient's virologic response should be exercised.

Lamotrigine

Co-administration of lamotrigine and REYATAZ/ritonavir may decrease lamotrigine plasma concentrations due to UGT1A4 induction.

Lamotrigine should be used with caution in combination with REYATAZ/ritonavir.

If necessary, monitor lamotrigine concentrations and adjust the dose accordingly.

ANTINEOPLASTICS AND IMMUNOSUPRESSANTS

Antineoplastics

Irinotecan

Atazanavir inhibits UGT and may interfere with the metabolism of irinotecan, resulting in increased irinotecan toxicities.

If REYATAZ is co-administered with irinotecan, patients should be closely monitored for adverse events related to irinotecan.

Immunosuppressants

Cyclosporin

Tacrolimus

Sirolimus

Concentrations of these immunosuppressants may be increased when co-administered with REYATAZ due to CYP3A4 inhibition.

More frequent therapeutic concentration monitoring of these medicinal products is recommended until plasma levels have been stabilised.

CARDIOVASCULAR AGENTS

Antiarrhythmics

Amiodarone,

Systemic lidocaine,

Quinidine

Concentrations of these antiarrhythmics may be increased when co-administered with REYATAZ The mechanism of amiodarone or systemic lidocaine/atazanavir interaction is CYP3A inhibition. Quinidine has a narrow therapeutic window and is contraindicated due to potential inhibition of CYP3A by REYATAZ.

Caution is warranted and therapeutic concentration monitoring is recommended when available. The concomitant use of quinidine is contraindicated (see section 4.3).

Calcium channel blockers

Bepridil

REYATAZ should not be used in combination with medicinal products that are substrates of CYP3A4 and have a narrow therapeutic index.

Co-administration with bepridil is contraindicated (see section 4.3)

Diltiazem 180 mg once daily

(atazanavir 400 mg once daily)

Diltiazem AUC ↑125% (↑109% ↑141%)

Diltiazem C_max ↑98% (↑78% ↑119%)

Diltiazem C_min ↑142% (↑114% ↑173%)

Desacetyl-diltiazem AUC ↑165% (↑145% ↑187%)

Desacetyl-diltiazem C_max ↑172% (↑144% ↑203%)

Desacetyl-diltiazem C_min ↑121% (↑102% ↑142%)

No significant effect on atazanavir concentrations was observed. There was an increase in the maximum PR interval compared to atazanavir alone. Co-administration of diltiazem and REYATAZ/ritonavir has not been studied. The mechanism of diltiazem/atazanavir interaction is CYP3A4 inhibition.

An initial dose reduction of diltiazem by 50% is recommended, with subsequent titration as needed and ECG monitoring.

Verapamil

Serum concentrations of verapamil may be increased by REYATAZ due to CYP3A4 inhibition.

Caution should be exercised when verapamil is co-administered with REYATAZ.

CORTICOSTEROIDS

Fluticasone propionate intranasal 50 µg 4 times daily for 7 days

(ritonavir 100 mg capsules twice daily)

The fluticasone propionate plasma levels increased significantly, whereas the intrinsic cortisol levels decreased by approximately 86% (90% confidence interval 82%-89%). Greater effects may be expected when fluticasone propionate is inhaled. Systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression have been reported in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate; this could also occur with other corticosteroids metabolized via the P450 3A pathway, e.g., budesonide. The effects of high fluticasone systemic exposure on ritonavir plasma levels are yet unknown. The mechanism of interaction is CYP3A4 inhibition.

Co-administration of REYATAZ/ritonavir and these glucocorticoids is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects (see section 4.4). A dose reduction of the glucocorticoid should be considered with close monitoring of local and systemic effects or a switch to a glucocorticoid, which is not a substrate for CYP3A4 (e.g., beclomethasone). Moreover, in case of withdrawal of glucocorticoids, progressive dose reduction may have to be performed over a longer period.

ERECTILE DYSFUNCTION

PDE5 Inhibitors

Sildenafil, tadalafil, vardenafil

Sildenafil, tadalafil and vardenafil are metabolised by CYP3A4. Co-administration with REYATAZ may result in increased concentrations of the PDE5 inhibitor and an increase in PDE5-associated adverse events, including hypotension, visual changes, and priapism. The mechanism of this interaction is CYP3A4 inhibition.

Patients should be warned about these possible side effects when using PDE5 inhibitors for erectile dysfunction with REYATAZ (see section 4.4).

Also see PULMONARY ARTERIAL HYPERTENSION in this table for futher information regarding co-administration of REYATAZ with sildenafil.

HERBAL PRODUCTS

St. John’s wort (Hypericum perforatum)

Concomitant use of St. John's wort with REYATAZ may be expected to result in significant reduction in plasma levels of atazanavir. This effect may be due to an induction of CYP3A4. There is a risk of loss of therapeutic effect and development of resistance (see section 4.3).

Co-administration of REYATAZ with products containing St. John's wort is contraindicated.

HORMONAL CONTRACEPTIVES

Ethinyloestradiol 25 μg + norgestimate

(atazanavir 300 mg once daily with ritonavir 100 mg once daily)

Ethinyloestradiol AUC ↓19% (↓25% ↓13%)

Ethinyloestradiol C_max ↓16% (↓26% ↓5%)

Ethinyloestradiol C_min ↓37% (↓45% ↓29%)

Norgestimate AUC ↑85% (↑67% ↑105%)

Norgestimate C_max ↑68% (↑51% ↑88%)

Norgestimate C_min ↑102% (↑77% ↑131%)

While the concentration of ethinyloestradiol was increased with atazanavir given alone, due to both UGT and CYP3A4 inhibition by atazanavir, the net effect of atazanavir/ritonavir is a decrease in ethinyloestradiol levels because of the inducing effect of ritonavir.

The increase in progestin exposure may lead to related side-effects (e.g. insulin resistance, dyslipidemia, acne and spotting), thus possibly affecting the compliance.

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 strict compliance with this contraceptive dosing regimen. Co-administration of REYATAZ/ritonavir with other hormonal contraceptives or oral contraceptives containing progestogens other than norgestimate has not been studied, and therefore should be avoided. An alternate reliable method of contraception is recommended.

Ethinyloestradiol 35 µg + norethindrone
(atazanavir 400 mg once daily)

Ethinyloestradiol AUC ↑48% (↑31% ↑68%)

Ethinyloestradiol C_max ↑15% (↓1% ↑32%)

Ethinyloestradiol C_min ↑91% (↑57% ↑133%)

Norethindrone AUC ↑110% (↑68% ↑162%)

Norethindrone C_max ↑67% (↑42% ↑196%)

Norethindrone C_min ↑262% (↑157% ↑409%)

The increase in progestin exposure may lead to related side-effects (e.g. insulin resistance, dyslipidemia, acne and spotting), thus possibly affecting the compliance.

LIPID LOWERING AGENTS

HMG-CoA reductase inhibitors

Simvastatin

Lovastatin

Simvastatin and lovastatin are highly dependent on CYP3A4 for their metabolism and co-administration with REYATAZ may result in increased concentrations.

Co-administration of simvastatin or lovastatin with REYATAZ is contraindicated due to an increased risk of myopathy including rhabdomyolysis. (see section 4.3).

Atorvastatin

The risk of myopathy including rhabdomyolysis may also be increased with atorvastatin, which is also metabolised by CYP3A4.

Co-administration of atorvastatin with REYATAZ is not recommended. If the use of atorvastatin is considered strictly necessary, the lowest possible dose of atorvastatin should be administered with careful safety monitoring (see section 4.4).

Pravastatin

Fluvastatin

Although not studied, there is a potential for an increase in pravastatin or fluvastatin exposure when co-administered with protease inhibitors. Pravastatin is not metabolised by CYP3A4. Fluvastatin is partially metabolised by CYP2C9.

Caution should be exercised.

INHALED BETA AGONISTS

Salmeterol

Co-administration with REYATAZ may result in increased concentrations of salmeterol and an increase in salmeterol-associated adverse events.

The mechanism of interaction is CYP3A4 inhibition by atazanavir and/or ritonavir.

Co-administration of salmeterol with REYATAZ is not recommended (see section 4.4).

OPIOIDS

Buprenorphine, once daily, stable maintenance dose

(atazanavir 300 mg once daily with ritonavir 100 mg once daily)

Buprenorphine AUC ↑67%

Buprenorphine C_max ↑37%

Buprenorphine C_min ↑69%

Norbuprenorphine AUC ↑105%

Norbuprenorphine C_max ↑61%

Norbuprenorphine C_min ↑101%

The mechanism of interaction is CYP3A4 and UGT1A1 inhibition.

Concentrations of atazanavir (when given with ritonavir) were not significantly affected.

Co-administration with REYATAZ with ritonavir warrants clinical monitoring for sedation and cognitive effects. A dose reduction of buprenorphine may be considered.

Methadone, stable maintenance dose

(atazanavir 400 mg once daily)

No significant effect on methadone concentrations was observed. Given that low dose ritonavir (100 mg twice daily) has been shown to have no significant effect on methadone concentrations, no interaction is expected if methadone is co-administered with REYATAZ, based on these data.

No dosage adjustment is necessary if methadone is co-administered with REYATAZ.

PULMONARY ARTERIAL HYPERTENSION

PDE5 Inhibitors

Sildenafil

Co-administration with REYATAZ may result in increased concentrations of the PDE5 inhibitor and an increase in PDE5-inhibitor-associated adverse events.

The mechanism of interaction is CYP3A4 inhibition by atazanavir and/or ritonavir.

A safe and effective dose in combination with REYATAZ has not been 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).

SEDATIVES

Benzodiazepines

Midazolam

Triazolam

Midazolam and triazolam are extensively metabolized by CYP3A4. Co-administration with REYATAZ may cause a large increase in the concentration of these benzodiazepines. No drug interaction study has been performed for the co-administration of REYATAZ with benzodiazepines. Based on data for other CYP3A4 inhibitors, plasma concentrations of midazolam are expected to be significantly higher when midazolam is given orally. Data from concomitant use of parenteral midazolam with other protease inhibitors suggest a possible 3-4 fold increase in midazolam plasma levels.

Co-administration of REYATAZ with triazolam or orally administered midazolam is contraindicated (see section 4.3), whereas caution should be used with co-administration of REYATAZ and parenteral midazolam. If REYATAZ is co-administered with parenteral midazolam, it should be done in an intensive care unit (ICU) or similar setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage adjustment for midazolam should be considered, especially if more than a single dose of midazolam is administered.

renal and urinary disorders:

uncommon: nephrolithiasisa, hematuria, proteinuria, pollakiuria, interstitial nephritis;

rare: kidney pain

Integrase Inhibitors

Raltegravir 400 mg BID

(atazanavir/ritonavir)

raltegravir

↑ 41%

↑ 24%

C_12hr↑ 77%

No dose adjustment required for Isentress.

The mechanism is UGT1A1 inhibition.

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.

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.

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, C_max, and C_min 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.

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).}

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)}

Parameter

REYATAZ/ritonaviraritonavir^b (300 mg/100 mg
once daily)

n=440

lopinavir/ritonavirbLopinavir/ritonavir^c (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 patients^d

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 analysis^e

86

(n=392^f)

91

(n=352)

89

(n=372)

89

(n=331)

Difference estimate^e

     [95% CI]

Week 48: -3% [-7.6%, 1.5%]