Atazavir
UkraineTable of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ATAZAVIR (ATAZAVIR)
Composition:
Active substance: atazanavir;
1 hard capsule contains atazanavir sulfate equivalent to 150 mg, 200 mg, or 300 mg of atazanavir;
Excipients: lactose monohydrate, crospovidone, magnesium stearate.
Pharmaceutical form. Hard capsules.
Main physicochemical characteristics:
Dosage 150 mg: hard gelatin capsules size "1" with an opaque light-green body and an opaque green cap, marked in black with "H" on the cap and "A6" on the body, filled with granular powder ranging from almost white to light yellow;
Dosage 200 mg: hard gelatin capsules size "0" with an opaque light-green body and an opaque green cap, marked in black with "H" on the cap and "A7" on the body, filled with granular powder ranging from almost white to light yellow;
Dosage 300 mg: hard gelatin capsules size "00" with an opaque green body and an opaque orange cap, marked in black with "H" on the cap and "A8" on the body, filled with granular powder ranging from almost white to light yellow.
Pharmacotherapeutic group
Antiviral agents for systemic use. Direct-acting antiviral agents. Protease inhibitors. ATC code J05A E08.
Pharmacological Properties
Pharmacodynamics
Atazanavir is an azapeptide inhibitor of HIV-1 protease (PI). The compound selectively inhibits the virus-specific processing of viral Gag-Pol proteins in cells infected with HIV-1, thereby preventing the formation of mature virions and the infection of other cells.
In vitro data have shown that atazanavir is active against tested strains of HIV-1 (including all studied subtypes) and HIV-2 in various cell cultures.
Pharmacokinetics
The pharmacokinetic properties of atazanavir have been evaluated in healthy adult volunteers and HIV-infected patients, with notable differences observed between these groups. The pharmacokinetics of atazanavir exhibit nonlinear characteristics.
Absorption. Repeated administration of atazanavir 300 mg and ritonavir 100 mg once daily taken with a light meal resulted in peak plasma concentrations of atazanavir being reached approximately 2.5 hours after dosing.
Effect of food. Concomitant administration of atazanavir and ritonavir with food optimizes the bioavailability of atazanavir and reduces pharmacokinetic variability.
Distribution. Atazanavir is 86% bound to plasma proteins, and the extent of protein binding is independent of concentration. Atazanavir binds to both alpha-1-acid glycoprotein and albumin to a similar extent. Atazanavir has been detected in cerebrospinal fluid and seminal fluid.
Metabolism. Atazanavir is primarily metabolized by the CYP3A4 enzyme into oxidized metabolites. The metabolites are excreted in bile in both free and glucuronidated forms. A minor portion of atazanavir undergoes metabolism via N-dealkylation and hydrolysis.
Elimination. After a single 400 mg dose of 14C-atazanavir, 79% and 13% of total radioactivity were recovered in feces and urine, respectively. The proportion of unchanged drug in feces and urine was approximately 20% and 7%, respectively. The mean elimination half-life of atazanavir in HIV-infected adults and volunteers was approximately 12 hours when atazanavir 300 mg was administered with ritonavir 100 mg once daily with a light meal.
Special Populations
Renal impairment. In healthy subjects, renal excretion of unchanged atazanavir accounts for approximately 7% of the administered dose. There are no pharmacokinetic data available for atazanavir with ritonavir in patients with renal impairment. Study results have shown that pharmacokinetic parameters of atazanavir are reduced by 30–50% in patients undergoing hemodialysis compared to those with normal renal function. The mechanism of this reduction is unknown.
Hepatic impairment. Atazanavir is metabolized and eliminated primarily by the liver. Atazanavir (without ritonavir) was studied in adult patients with moderate and severe hepatic impairment after a single 400 mg dose. The mean AUC (0–∞) was 42% higher in patients with hepatic dysfunction compared to healthy individuals. The mean elimination half-life of atazanavir in patients with hepatic impairment was 12.1 hours compared to 6.4 hours in healthy subjects. The effect of hepatic impairment on the pharmacokinetics of atazanavir following a 300 mg dose with ritonavir has not been studied. Increased concentrations of atazanavir, with or without ritonavir, are expected in patients with moderate to severe hepatic impairment.
Age/Sex. No clinically significant pharmacokinetic differences based on age or sex have been observed.
Race. Race has not been shown to influence the pharmacokinetics of atazanavir.
Pediatric population. There is a trend toward higher clearance in younger children when normalized for body weight. As a result, higher peak-to-trough ratios are observed; however, at the recommended doses, geometric mean exposures of atazanavir (Cmin, Cmax, and AUC) in children are expected to be similar to those observed in adult patients.
Clinical Characteristics
Indications
Atazanavir in combination with low-dose ritonavir and other antiretroviral medicinal products is indicated for the treatment of adults and children aged 6 years and older infected with human immunodeficiency virus (HIV-1).
Based on available virological and clinical data in adults, no benefit is expected in patients with viruses resistant to multiple protease inhibitors (≥ 4 PI mutations).
The choice of atazanavir in the treatment of treatment-experienced adults and children should be based on individual viral resistance and patient history.
Contraindications
Hypersensitivity to any component of the medicinal product.
Atazanavir is contraindicated in patients with severe hepatic impairment.
Atazanavir with ritonavir is contraindicated in patients with moderate hepatic impairment.
Concomitant use with simvastatin or lovastatin.
Concomitant use with the PDE5 inhibitor sildenafil is contraindicated only when used for the treatment of pulmonary arterial hypertension. For concomitant use of sildenafil for erectile dysfunction, see sections "Interaction with other medicinal products and other forms of interaction" and "Special precautions".
The combination is contraindicated with medicinal products metabolized in the liver by the CYP3A4 isoenzyme of cytochrome P450 and having a narrow therapeutic range (quetiapine, lurasidone, alfuzosin, astemizole, terfenadine, cisapride, pimozide, quinidine, bepridil, triazolam, oral midazolam (for caution with parenteral midazolam, see "Interaction with other medicinal products and other forms of interaction"), lomitapide, and ergot alkaloids, including ergotamine, dihydroergotamine, ergonovine, and methylergonovine).
Concomitant use with medicinal products that are strong inducers of CYP3A4 due to the potential for loss of therapeutic effect and development of possible resistance (e.g., rifampicin, St John’s wort (Hypericum perforatum), apalutamide, encorafenib, ivosidenib, carbamazepine, phenobarbital, and phenytoin).
Concomitant use with medicinal products containing grazoprevir, including the fixed-dose combination of elbasvir/grazoprevir (used for the treatment of chronic hepatitis C) (see section "Interaction with other medicinal products and other forms of interaction").
Concomitant use with the fixed-dose combination of glecaprevir/pibrentasvir.
Interaction with other medicinal products and other forms of interaction
When atazanavir and ritonavir are used concomitantly, the metabolic interaction profile of ritonavir predominates, as ritonavir is a more potent inhibitor of the CYP3A4 isoenzyme than atazanavir. Prior to initiating therapy with atazanavir and ritonavir, refer to the prescribing information for ritonavir.
Atazanavir is metabolized in the liver via CYP3A4. It inhibits CYP3A4. Therefore, atazanavir is contraindicated with medicinal products that are CYP3A4 substrates and have a narrow therapeutic index: quetiapine, lurasidone, alfuzosin, astemizole, terfenadine, cisapride, pimozide, quinidine, bepridil, triazolam, orally administered midazolam, lomitapide, and ergot alkaloids, including ergotamine and dihydroergotamine (see section "Contraindications").
Concomitant use with medicinal products containing grazoprevir, including the fixed-dose combination of elbasvir/grazoprevir (used for the treatment of chronic hepatitis C), is contraindicated due to increased plasma concentrations of grazoprevir and elbasvir and the potential for increased risk of ALT elevation associated with elevated grazoprevir concentrations (see section "Contraindications").
Concomitant use of atazanavir with the fixed-dose combination of glecaprevir/pibrentasvir is contraindicated due to the potential increased risk of ALT elevation resulting from significantly increased plasma concentrations of both glecaprevir and pibrentasvir (see section "Contraindications").
Other interactions
Interactions between atazanavir and other medicinal products are listed in the table below (increases are indicated as "↑", decreases as "↓", no change as "↔"). Where available, 90% confidence intervals (CI) are shown in parentheses. Studies listed in the table were conducted in healthy volunteers unless otherwise stated. Importantly, many studies were conducted using unboosted atazanavir, which differs from the approved regimen (see section "Special precautions").
If discontinuation of ritonavir is medically justified under limited circumstances (see section "Special precautions"), particular attention should be paid to atazanavir interactions, which may differ in the absence of ritonavir (see information following the table below).
Interaction of atazanavir with other medicinal products
| Medicinal product, according to therapeutic group |
Interaction |
Recommendations for concomitant use |
| ANTIVIRAL AGENTS FOR HCV TREATMENT |
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| Glecaprevir 200 mg once daily (atazanavir 300 mg / ritonavir 100 mg once daily) |
Atazanavir AUC ↑43 % (↑30 % ↑57 %) Atazanavir Cmax ↑12 % (↑1 % ↑24 %) Atazanavir Cmin ↑23 % (↑13 % ↑134 %) Glecaprevir AUC: ↑958 % (↑678 % ↑1339 %) Glecaprevir Cmax: ↑524 % (↑342 % ↑781 %) Glecaprevir Cmin: ↑1064 % (↑696 % ↑1602 %) Glecaprevir plasma concentrations significantly increased when co-administered with atazanavir / ritonavir. |
Concomitant use of atazanavir and elbasvir / glecaprevir is contraindicated due to a significant increase in glecaprevir plasma concentrations and associated potential risk of elevated ALT levels (see section "Contraindications"). |
| Elbasvir 50 mg once daily (atazanavir 300 mg / ritonavir 100 mg once daily) |
Atazanavir AUC ↑7 % (↓2 % ↑17 %) Atazanavir Cmax ↑2 % (↓4 % ↑8 %) Atazanavir Cmin ↑15 % (↑2 % ↑29 %) Elbasvir AUC: ↑376 % (↑307 % ↑456 %) Elbasvir Cmax: ↑315 % (↑246 % ↑397 %) Elbasvir Cmin: ↑545 % (↑451 % ↑654 %) Elbasvir concentrations increased when co-administered with atazanavir / ritonavir. |
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| Single dose of Sofosbuvir 400 mg / velpatasvir 100 mg / voxilaprevir 100 mg* (atazanavir 300 mg / ritonavir 100 mg once daily) |
Sofosbuvir AUC: ↑40 % (↑25 % ↑57 %) Sofosbuvir Cmax: ↑29 % (↑9 % ↑52 %) Velpatasvir AUC: ↑93 % (↑58 % ↑136 %) Velpatasvir Cmax: ↑29 % (↑7 % ↑56 %) Voxilaprevir AUC: ↑331 % (↑276 % ↑393 %) Voxilaprevir Cmax: ↑342 % (↑265 % ↑435%) *Absence of pharmacokinetic interaction boundaries 70-143 % The effect on atazanavir and ritonavir exposure has not been studied. Expected: ↔ Atazanavir ↔ Ritonavir The mechanism of interaction between atazanavir / ritonavir and sofosbuvir / velpatasvir / voxilaprevir involves inhibition of OATP1B, P-gp, and CYP3A. |
Concomitant use of atazanavir with regimens containing voxilaprevir is expected to increase voxilaprevir concentrations. Concomitant use of atazanavir with regimens containing voxilaprevir is not recommended. |
| Glecaprevir 300 mg / pibrentasvir 120 mg once daily (atazanavir 300 mg / ritonavir 100 mg once daily) |
Glecaprevir AUC: ↑553 % (↑424 % ↑714 %) Glecaprevir Cmax: ↑306 % (↑215 % ↑423 %) Glecaprevir Cmin: ↑1330 % (↑885 % ↑1970 %) Pibrentasvir AUC: ↑64 % (↑48 % ↑82 %) Pibrentasvir Cmax: ↑29 % (↑15 % ↑45 %) Pibrentasvir Cmin: ↑129 % (↑95 % ↑168 %) *Reported effect of atazanavir and ritonavir on the first dose of glecaprevir and pibrentasvir. |
Concomitant use of atazanavir with glecaprevir / pibrentasvir is contraindicated due to the potential risk of elevated ALT levels resulting from a significant increase in plasma concentrations of glecaprevir and pibrentasvir (see section "Contraindications"). |
| ANTIPLATELET AGENTS |
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| Ticagrelor |
The mechanism of interaction involves inhibition of CYP3A4 by atazanavir and/or ritonavir. |
Concomitant use of atazanavir with ticagrelor is not recommended due to the potential for increased antiplatelet activity of ticagrelor. |
| Clopidogrel |
The mechanism of interaction involves inhibition of CYP3A4 by atazanavir and/or ritonavir. |
Concomitant use with clopidogrel is not recommended due to the potential for reduced antiplatelet activity of clopidogrel. |
| Prasugrel |
The mechanism of interaction involves inhibition of CYP3A4 by atazanavir and/or ritonavir. |
No dose adjustment is required when prasugrel is used concomitantly with atazanavir (with or without ritonavir). |
| ANTIRETROVIRAL AGENTS |
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| Protease inhibitors: Concomitant use of atazanavir / ritonavir combination with other protease inhibitors has not been studied, but enhanced protease inhibitor effects are expected. Therefore, such combination is not recommended. |
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| Ritonavir 100 mg once daily (atazanavir 300 mg once daily) The study was conducted in HIV-infected patients. |
Atazanavir AUC: ↑250 % (↑144 % ↑403 %)* Atazanavir Cmax: ↑120 % (↑56 % ↑211 %)* Atazanavir Cmin: ↑713 % (↑359 % ↑1339 %)* *In a combined analysis, atazanavir 300 mg and ritonavir 100 mg (n = 33) were compared with atazanavir 400 mg without ritonavir (n = 28). |
Ritonavir 100 mg once daily should be used to boost the pharmacokinetics of atazanavir. |
| Indinavir |
Indinavir effect is associated with indirect unconjugated hyperbilirubinemia due to inhibition of UGT (uridine-diphosphate glucuronosyltransferase). |
Concomitant use of atazanavir and indinavir is not recommended (see section "Special precautions"). |
| Nucleoside / nucleotide reverse transcriptase inhibitors (NRTIs) |
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| 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 since ritonavir is not expected to have a significant effect on NRTI pharmacokinetics, concomitant administration of these drugs with atazanavir is not expected to significantly alter the effects of the co-administered drugs. |
| Abacavir |
No significant effect of atazanavir / ritonavir combination on abacavir exposure is expected. |
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| Didanosine (buffered tablets) 200 mg / stavudine 40 mg, single dose (atazanavir 400 mg single dose) |
Atazanavir, co-administered with ddI+d4T (fasting) Atazanavir AUC ↓87 % (↓92 % ↓79 %) Atazanavir Cmax ↓89 % (↓94 % ↓82 %) Atazanavir Cmin ↓84 % (↓90 % ↓73 %) Atazanavir, dose administered 1 hour after ddI+d4T (fasting) Atazanavir AUC ↔3 % (↓36 % ↑67 %) Atazanavir Cmax ↑12 % (↓33 % ↑18 %) Atazanavir Cmin ↔3 % (↓39 % ↑73 %) Atazanavir concentrations were significantly reduced when co-administered with didanosine (buffered tablets) and stavudine. The mechanism of interaction is reduced solubility of atazanavir due to increased pH associated with the presence of antacids in buffered didanosine tablets. No significant effect on didanosine and stavudine concentrations was observed. |
Didanosine should be taken on an empty stomach, 2 hours after atazanavir taken with food. Concomitant use of stavudine with atazanavir is not expected to significantly alter the effect 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 Cmax ↓38 % (↓48 % ↓26 %) Didanosine Cmin ↑25 % (↓8 % ↑69 %) No significant effect on atazanavir concentrations was observed when administered with enteric-coated didanosine, but didanosine concentrations were reduced when taken with food. |
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| Tenofovir disoproxil fumarate 300 mg once daily (atazanavir 300 mg once daily with ritonavir 100 mg once daily) The study was conducted in HIV-infected patients. |
Atazanavir AUC ↓22 % (↓35 % ↓6 %)* Atazanavir Cmax ↓16 % (↓30 % ↔0 %)* Atazanavir Cmin ↓23 % (↓43 % ↑2 %)* *In a combined analysis of several clinical studies, atazanavir / ritonavir 300/100 mg given together with tenofovir disoproxil fumarate 300 mg was compared with 300/100 mg atazanavir / ritonavir. The efficacy of atazanavir / ritonavir in combination with tenofovir disoproxil fumarate in treatment-experienced and treatment-naive patients was demonstrated in clinical studies. The mechanism of interaction between atazanavir and tenofovir disoproxil fumarate is unknown. |
When used concomitantly with tenofovir disoproxil fumarate, it is recommended to use atazanavir 300 mg 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 Cmax ↑34 % (↑20 % ↑51 %) Tenofovir disoproxil fumarate Cmin ↑29 % (↑21 % ↑36 %) |
Close monitoring of patients is required due to the potential for tenofovir-related adverse reactions, including renal disorders. |
| Non-nucleoside reverse transcriptase inhibitors (NNRTIs) |
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| Efavirenz 600 mg once daily (atazanavir 400 mg once daily with ritonavir 100 mg once daily) |
Atazanavir (in the evening): all taken with food Atazanavir AUC ↔0 % (↓9 % ↑10 %)* Atazanavir Cmax ↑17 % (↑8 % ↑27 %)* Atazanavir Cmin ↓42 % (↓51 % ↓31 %)* |
Concomitant use of efavirenz and atazanavir is not recommended (see section "Special precautions"). |
| Efavirenz 600 mg once daily (atazanavir 400 mg once daily with ritonavir 200 mg once daily) |
Atazanavir (in the evening): all taken with food Atazanavir AUC ↔6 % (↓10 % ↑26 %)*/** Atazanavir Cmax ↔9 % (↓5 % ↑26 %)*/** Atazanavir Cmin ↔12 % (↓16 % ↑49 %)*/** *Compared with atazanavir 300 mg / ritonavir 100 mg once daily in the evening without efavirenz. This decrease in atazanavir Cmin may negatively affect atazanavir efficacy. The mechanism of efavirenz / atazanavir interaction is CYP3A4 induction. **Based on historical comparison. |
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| Nevaripine 200 mg twice daily (atazanavir 400 mg once daily with ritonavir 100 mg once daily) The study was conducted in HIV-infected patients. |
Nevaripine AUC ↑26 % (↑17 % ↑36 %) Nevaripine Cmax ↑21 % (↑11 % ↑32 %) Nevaripine Cmin ↑35 % (↑25 % ↑47 %) Atazanavir AUC ↓19 % (↓35 % ↑2 %)* Atazanavir Cmax ↔2 % (↓15 % ↑24 %)* Atazanavir Cmin ↓59 % (↓73 % ↓40 %)* *Compared with atazanavir 300 mg / ritonavir 100 mg without nevaripine. This decrease in atazanavir Cmin may negatively affect atazanavir efficacy. The mechanism of nevaripine / atazanavir interaction is CYP3A4 induction. |
Concomitant use of nevaripine and atazanavir is not recommended (see section "Special precautions"). |
| Integrase inhibitors |
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| Raltegravir 400 mg twice daily (atazanavir / ritonavir) |
Raltegravir AUC ↑41 % Raltegravir Cmax ↑24 % Raltegravir C12hr ↑77 % Mechanism: inhibition of UGT1A1. |
No dose adjustment of raltegravir is required. |
| ANTIBIOTICS |
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| Clarithromycin 500 mg twice daily (atazanavir 400 mg once daily) |
Clarithromycin AUC ↑94 % (↑75 % ↑116 %) Clarithromycin Cmax ↑50 % (↑32 % ↑71 %) Clarithromycin Cmin ↑160 % (↑135 % ↑188 %) 14-OH clarithromycin 14-OH clarithromycin AUC ↓70 % (↓74 % ↓66 %) 14-OH clarithromycin Cmax ↓72 % (↓76 % ↓67 %) 14-OH clarithromycin Cmin ↓62 % (↓66 % ↓58 %) Atazanavir AUC ↑28 % (↑16 % ↑43 %) Atazanavir Cmax ↔6 % (↓7 % ↑20 %) Atazanavir Cmin ↑91 % (↑66 % ↑121 %) Dose reduction of clarithromycin may lead to subtherapeutic concentrations of 14-OH clarithromycin. The mechanism of clarithromycin / atazanavir interaction is CYP3A4 inhibition. |
No dose reduction recommendations; use atazanavir / ritonavir with clarithromycin with caution. |
| ANTIFUNGAL AGENTS |
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| Ketoconazole 200 mg once daily (atazanavir 400 mg once daily) |
No significant effect on atazanavir concentrations was observed. |
Ketoconazole and itraconazole should be used with caution together with atazanavir / ritonavir; high doses of ketoconazole and itraconazole (>200 mg/day) are not recommended. |
| Itraconazole |
Itraconazole, like ketoconazole, is a potent inhibitor and substrate of CYP3A4. |
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| Based on data from other boosted protease inhibitors and ketoconazole, where ketoconazole AUC showed a threefold increase, it is expected that atazanavir / ritonavir will increase concentrations of ketoconazole or itraconazole. |
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| Voriconazole 200 mg twice daily (atazanavir 300 mg / ritonavir 100 mg once daily) Subjects having at least one functional CYP2C19 allele. |
Voriconazole AUC ↓33 % (↓42 % ↓22 %) Voriconazole Cmax ↓10 % (↓22 % ↓4 %) Voriconazole Cmin ↓39 % (↓49 % ↓28 %) Atazanavir AUC ↓12 % (↓18 % ↓5 %) Atazanavir Cmax ↓13 % (↓20 % ↓4 %) Atazanavir Cmin ↓20 % (↓28 % ↓10%) Ritonavir AUC ↓12 % (↓17 % ↓7 %) Ritonavir Cmax ↓9 % (↓17 % ↔0 %) Ritonavir Cmin ↓25 % (↓35 % ↓14 %) In most patients with at least one functional CYP2C19 allele, reduced concentrations of voriconazole and atazanavir are expected. |
Concomitant use of voriconazole and atazanavir / ritonavir combination is not recommended, except when benefits outweigh risks (see section "Special precautions"). During voriconazole treatment, CYP2C19 genotyping of the patient is recommended. If this combination is necessary, clinical monitoring of efficacy of both drugs is recommended: atazanavir (virological response) and voriconazole (clinical signs) for patients with at least one functional CYP2C19 allele. For patients without a functional CYP2C19 allele, clinical and laboratory monitoring of voriconazole efficacy is recommended to detect adverse reactions. If genotyping is not possible, full safety and efficacy monitoring is required. |
| Voriconazole 50 mg twice daily (atazanavir 300 mg / ritonavir 100 mg once daily) Subjects without functional CYP2C19 allele. |
Voriconazole AUC ↑561 % (↑451 % ↑699 %) Voriconazole Cmax ↑438 % (↑355 % ↑539 %) Voriconazole Cmin ↑765 % (↑571 % ↑1020 %) Atazanavir AUC ↓20 % (↓35 % ↓3 %) Atazanavir Cmax ↓19 % (↓34 % ↔0,2 %) Atazanavir Cmin ↓31 % (↓46 % ↓13 %) Ritonavir AUC ↓11 % (↓20 % ↓1 %) Ritonavir Cmax ↓11 % (↓24 % ↑4 %) Ritonavir Cmin ↓19 % (↓35 % ↑1 %) In a small number of patients without a functional CYP2C19 allele, a significant increase in voriconazole concentration is expected. |
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| Fluconazole 200 mg once daily (atazanavir 300 mg and ritonavir 100 mg once daily) |
Concentrations of atazanavir and fluconazole did not change when atazanavir / ritonavir combination was used concomitantly. |
No dose adjustment is required for fluconazole and atazanavir. |
| ANTITUBERCULOSIS AGENTS |
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| Rifabutin 150 mg twice daily (atazanavir 300 mg and ritonavir 100 mg once daily) |
Rifabutin AUC ↑48 % (↑19 % ↑84 %)** Rifabutin Cmax ↑149 % (↑103 % ↑206 %)** Rifabutin Cmin ↑40 % (↑5 % ↑87 %)** 25-O-desacetyl-rifabutin AUC ↑990 % (↑714 % ↑1361 %)** 25-O-desacetyl-rifabutin Cmax ↑677 % (↑513 % ↑883 %)** 25-O-desacetyl-rifabutin Cmin ↑1045 % (↑715 % ↑1510 %)** ** Compared with rifabutin 150 mg once daily. Total rifabutin and 25-O-desacetyl-rifabutin AUC ↑119 % (↑78 % ↑169 %). In previous studies, atazanavir pharmacokinetics were not altered by rifabutin. |
Rifabutin dose should be 150 mg three times weekly on scheduled days (e.g., Monday, Wednesday, Friday). Close monitoring of the patient is required due to the risk of adverse reactions, including neutropenia and uveitis; dose adjustment of rifabutin may be necessary. Further reduction to 150 mg twice weekly on scheduled days is recommended for patients for whom 150 mg three times weekly is not suitable. A dose of 150 mg twice weekly may not provide optimal rifabutin exposure; there is a risk of resistance development and treatment failure. No dose adjustment of atazanavir / ritonavir is required. |
| Rifampicin |
Rifampicin is a strong CYP3A4 inducer, and it has been shown to cause a 72 % reduction in atazanavir AUC, which may lead to virological failure and resistance development. Attempts to overcome reduced effect by increasing the dose of atazanavir or other protease inhibitors with ritonavir have resulted in a high frequency of hepatic reactions. |
The combination of rifampicin and atazanavir is contraindicated (see section "Contraindications"). |
| NEUROLEPTICS |
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| Quetiapine |
Due to inhibition of CYP3A4 by the drug, quetiapine concentration increases. |
Concomitant use of quetiapine and atazanavir is contraindicated due to increased quetiapine-related toxicity. Increased plasma concentration of quetiapine may lead to coma (see section "Contraindications"). |
| Lurasidone |
Atazanavir is expected to increase lurasidone levels in plasma due to CYP3A4 inhibition. |
Concomitant use of lurasidone with atazanavir is contraindicated, as it may enhance lurasidone-related toxicity (see section "Contraindications"). |
| ACID-REDUCING AGENTS |
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| H2-receptor antagonists |
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| Without tenofovir disoproxil fumarate |
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| In HIV-infected patients with atazanavir / ritonavir at recommended dose 300/100 mg once daily |
For patients not taking tenofovir disoproxil fumarate, when atazanavir 300 mg / ritonavir 100 mg is used concomitantly with H2-receptor antagonists, the dose equivalent to famotidine 20 mg twice daily should not be exceeded. If a higher dose of H2-receptor antagonist is needed (e.g., famotidine 40 mg twice daily or equivalent), dose escalation of atazanavir / ritonavir from 300/100 mg to 400/100 mg may be considered. |
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| Famotidine 20 mg twice daily |
Atazanavir AUC ↓18 % (↓25 % ↑1 %) Atazanavir Cmax ↓20 % (↓32 % ↓7 %) Atazanavir Cmin ↔1 % (↓16 % ↑18 %) |
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| Famotidine 40 mg twice daily |
Atazanavir AUC ↓23 % (↓32 % ↓14 %) Atazanavir Cmax ↓23 % (↓33 % ↓12 %) Atazanavir Cmin ↓20 % (↓31 % ↓8 %) |
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| In healthy volunteers with atazanavir / ritonavir at increased dose 400/100 mg once daily |
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| Famotidine 40 mg twice daily |
Atazanavir AUC ↔3 % (↓14 % ↑22 %) Atazanavir Cmax ↔2 % (↓13 % ↑8 %) Atazanavir Cmin ↓14 % (↓32 % ↑8 %) |
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| With tenofovir disoproxil fumarate 300 mg once daily |
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| In HIV-infected patients with atazanavir / ritonavir at recommended dose 300/100 mg once daily |
For patients taking tenofovir disoproxil fumarate, when atazanavir / ritonavir is used concomitantly with tenofovir disoproxil fumarate and H2-receptor antagonists, dose escalation of atazanavir to 400 mg and ritonavir to 100 mg is recommended. The dose equivalent to famotidine 40 mg twice daily should not be exceeded. |
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| Famotidine 20 mg twice daily |
Atazanavir AUC ↓21 % (↓34 % ↓4 %)* Atazanavir Cmax ↓21 % (↓36 % ↓4 %)* Atazanavir Cmin ↓19 % (↓37 % ↑5 %)* |
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| Famotidine 40 mg twice daily |
Atazanavir AUC ↓24 % (↓36 % ↓11 %)* Atazanavir Cmax ↓23 % (↓36 % ↓8 %)* Atazanavir Cmin ↓25 % (↓47 % ↑7 %)* |
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| In HIV-infected patients with atazanavir / ritonavir at increased dose 400/100 mg once daily |
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| Famotidine 20 mg twice daily |
Atazanavir AUC ↑18 % (↑6.5 % ↑30 %)* Atazanavir Cmax ↑18 % (↑6.7 % ↑31 %)* Atazanavir Cmin ↑24 % (↑10 % ↑39 %)* |
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| Famotidine 40 mg twice daily |
Atazanavir AUC ↔2.3 % (↓13 % ↑10 %)* Atazanavir Cmax ↔5 % (↓17 % ↑8.4 %)* Atazanavir Cmin ↔1.3 % (↓10 % ↑15 %)* |
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| * Compared with atazanavir 300 mg once daily with ritonavir 100 mg once daily and tenofovir disoproxil fumarate 300 mg, all as a single dose with food. Compared with 300 mg atazanavir and 100 mg ritonavir without tenofovir disoproxil fumarate, atazanavir concentrations are expected to decrease further by approximately 20 %. The mechanism of interaction involves reduced solubility of atazanavir due to increased pH in the gastrointestinal tract when H2-receptor antagonists are used. |
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| Proton pump inhibitors |
||
| Omeprazole 40 mg once daily (atazanavir 400 mg with ritonavir 100 mg once daily) |
Atazanavir (in the morning): 2 hours after omeprazole Atazanavir AUC ↓61 % (↓65 % ↓55 %) Atazanavir Cmax ↓66 % (↓62 % ↓49 %) Atazanavir Cmin ↓65 % (↓71 % ↓59 %) |
Concomitant use of atazanavir with ritonavir and proton pump inhibitors is not recommended. If such combination is considered necessary, patient monitoring is recommended with dose escalation of atazanavir to 400 mg with ritonavir 100 mg; doses of proton pump inhibitors equivalent to omeprazole 20 mg should not be exceeded (see section "Special precautions"). |
| Omeprazole 20 mg once daily (atazanavir 400 mg once daily with ritonavir 100 mg once daily) |
Atazanavir (in the morning): 1 hour after omeprazole Atazanavir AUC ↓30 % (↓43 % ↓14 %)* Atazanavir Cmax ↓31 % (↓42 % ↓17 %)* Atazanavir Cmin ↓31 % (↓46 % ↓12 %)* * Compared with atazanavir 300 mg once daily with ritonavir 100 mg once daily. Reduction in AUC, Cmax, and Cmin was not mitigated by increasing the dose of atazanavir / ritonavir (400 mg/100 mg once daily), which were administered separately from omeprazole by 12 hours. Similar results are expected with other proton pump inhibitors. Reduced atazanavir exposure may negatively affect drug efficacy. The mechanism of interaction involves reduced solubility of atazanavir due to increased pH in the gastrointestinal tract when proton pump inhibitors are used. |
|
| Antacids |
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| Antacids and medicinal products containing buffers |
Reduced atazanavir plasma concentrations may result from increased gastric pH if antacids or other buffered agents are administered concomitantly with the drug. |
Atazanavir should be administered 2 hours before or 1 hour after antacids or buffered medicinal products. |
| α1-ADRENERGIC ANTAGONISTS |
||
| Alfuzosin |
Increased plasma concentration of alfuzosin may lead to arterial hypotension. The mechanism of interaction is inhibition of CYP3A4 by atazanavir and/or ritonavir. |
Concomitant use of alfuzosin and atazanavir is contraindicated (see section "Contraindications"). |
| ANTICOAGULANTS |
||
| Direct oral anticoagulants (DOACs) |
||
| Apixaban Rivaroxaban |
Potential increase in apixaban and rivaroxaban concentrations, which may lead to increased risk of bleeding. Mechanism of interaction involves inhibition of CYP3A4 and P-gp by atazanavir / ritonavir. Ritonavir is a potent inhibitor of both CYP3A4 and P-gp. Atazanavir is a CYP3A4 inhibitor. Potential inhibition of P-gp by atazanavir is unknown and cannot be excluded. |
Concomitant use of apixaban or rivaroxaban with atazanavir and ritonavir is not recommended. |
| Dabigatran |
Potential increase in dabigatran concentration, which may lead to increased risk of bleeding. Mechanism of interaction involves P-gp inhibition. Ritonavir is a strong P-gp inhibitor. Potential P-gp inhibition by atazanavir is unknown and cannot be excluded. |
Concomitant use of dabigatran with atazanavir and ritonavir is not recommended. |
| Edoxaban |
Potential increase in edoxaban concentration, which may lead to increased risk of bleeding. Mechanism of interaction involves P-gp inhibition by atazanavir / ritonavir. Ritonavir is a strong P-gp inhibitor. Potential P-gp inhibition by atazanavir is unknown and cannot be excluded. |
Use edoxaban with caution when used with atazanavir. Refer to the edoxaban product information for appropriate dosing recommendations when used concomitantly with P-gp inhibitors. |
| Vitamin K antagonists |
||
| Warfarin |
Concomitant use with atazanavir has the potential to increase or decrease warfarin concentrations. |
Regular monitoring of international normalized ratio (INR) is recommended during atazanavir treatment, especially at the beginning of therapy. |
| ANTIEPILEPTIC AGENTS |
||
| Carbamazepine |
Atazanavir may increase carbamazepine plasma levels through CYP3A4 inhibition. |
Carbamazepine should be used with caution in combination with atazanavir. If necessary, serum carbamazepine concentrations should be monitored and dose adjusted accordingly. Close monitoring of the patient's virological response is required. |
| Phenytoin, phenobarbital |
Ritonavir may reduce phenytoin and/or phenobarbital plasma levels through induction of CYP2C9 and CYP2C19. |
Phenobarbital and phenytoin should be used with caution in combination with atazanavir / ritonavir. If atazanavir / ritonavir is used concomitantly with phenytoin or phenobarbital, dose adjustment of phenytoin or phenobarbital may be required. Close monitoring of the patient's virological response is required. |
| Lamotrigine |
Concomitant use of lamotrigine with atazanavir / ritonavir may lead to reduced lamotrigine plasma concentrations due to induction of UGT1A4. |
Lamotrigine should be used with caution in combination with atazanavir / ritonavir. If necessary, lamotrigine concentrations should be monitored and dose adjusted accordingly. |
| ANTINEOPLASTIC AGENTS AND IMMUNOSUPPRESSANTS |
||
| Antineoplastic agents |
||
| Apalutamide |
Mechanism of interaction involves induction of CYP3A4 by apalutamide and inhibition of CYP3A4 by atazanavir / ritonavir. |
Concomitant use with atazanavir (with or without ritonavir) is contraindicated due to the potential for reduced atazanavir and ritonavir plasma concentrations, leading to loss of virological response and possible resistance to protease inhibitors (see section "Contraindications"). Additionally, serum concentrations of apalutamide may increase when used concomitantly with atazanavir / ritonavir, which may lead to serious adverse effects, including seizures. |
| Encorafenib |
Mechanism of interaction involves inhibition of CYP3A4 by atazanavir and/or ritonavir. |
Concomitant use of encorafenib with atazanavir (with or without ritonavir) is contraindicated due to the potential for loss of virological response, resistance development, increased encorafenib plasma concentrations, and further risk of serious adverse effects such as QT interval prolongation (see section "Contraindications"). |
| Ivosidenib |
Mechanism of interaction involves inhibition of CYP3A4 by atazanavir and/or ritonavir. |
Concomitant use of ivosidenib with atazanavir (with or without ritonavir) is contraindicated due to the potential for loss of virological response, resistance development, increased ivosidenib plasma concentrations, and further risk of serious adverse effects such as QT interval prolongation (see section "Contraindications"). |
| Irinotecan |
Atazanavir inhibits UGT and may interfere with irinotecan metabolism, resulting in increased irinotecan toxicity. |
Patients require close monitoring for potential adverse reactions related to irinotecan. |
| Immunosuppressants |
||
| Cyclosporine Tacrolimus Sirolimus |
Concentrations of these drugs may increase when used concomitantly with atazanavir due to CYP3A4 inhibition |
Regular monitoring of therapeutic concentrations of these drugs is recommended until plasma levels stabilize. |
| CARDIOVASCULAR AGENTS |
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| Antiarrhythmic agents |
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| Amiodarone, systemic lidocaine, quinidine |
Concentrations of these drugs may increase when used concomitantly with the drug. Mechanism of interaction of amiodarone or systemic lidocaine with atazanavir is CYP3A inhibition. Quinidine has a narrow therapeutic range and is contraindicated due to potential CYP3A inhibition by the drug. |
Caution and therapeutic monitoring of concentrations of these drugs are required. Concomitant use of quinidine is contraindicated (see section "Contraindications"). |
| Calcium channel blockers |
||
| Bepridil |
Atazanavir should not be used in combination with drugs that are CYP3A4 substrates and have a narrow therapeutic index. |
Concomitant use with bepridil is contraindicated (see section "Contraindications"). |
| Diltiazem 180 mg once daily (atazanavir 400 mg once daily) |
Diltiazem AUC ↑125 % (↑109 % ↑141 %) Diltiazem Cmax ↑98 % (↑78 % ↑119 %) Diltiazem Cmin ↑142 % (↑114 % ↑173 %) Desacetyl-diltiazem AUC ↑165 % (↑145 % ↑187 %) Desacetyl-diltiazem Cmax ↑172 % (↑144 % ↑203 %) Desacetyl-diltiazem Cmin ↑121 % (↑102 % ↑142 %) No significant effect on atazanavir concentrations was observed. Increased maximum PR interval compared to atazanavir alone. Concomitant administration of diltiazem with atazanavir / ritonavir has not been studied. Mechanism of interaction between diltiazem and atazanavir is CYP3A4 inhibition. |
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 atazanavir through CYP3A4 inhibition. |
Use of verapamil and atazanavir combination should be with caution. |
| CORICOSTEROIDS |
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| Dexamethasone and other corticosteroids (all routes of administration) |
Concomitant use with dexamethasone or other corticosteroids that induce CYP3A may lead to loss of atazanavir therapeutic effect and development of resistance to atazanavir and/or ritonavir. Alternative corticosteroids should be considered. Mechanism of interaction involves induction of CYP3A4 by dexamethasone and inhibition of CYP3A4 by atazanavir and/or ritonavir. |
Concomitant use with corticosteroids (all routes of administration) metabolized by CYP3A, especially with prolonged use, may increase the risk of systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression. The potential benefit of treatment should be weighed against the risk of systemic corticosteroid effects. For co-administration of corticosteroids administered subcutaneously, sensitive to CYP3A inhibition, refer to the corticosteroid product characteristics for conditions or methods of administration that enhance systemic absorption. |
| Intranasal fluticasone propionate 50 mcg 4 times daily for 7 days (ritonavir, 100 mg capsules twice daily) and Inhaled / nasal corticosteroids |
Plasma levels of fluticasone propionate significantly increased, while cortisol levels decreased by approximately 86 % (90 % confidence interval 82–89 %). A greater effect is expected with inhaled fluticasone propionate. Concomitant use of ritonavir with inhaled (or intranasal) fluticasone propionate formulations has been associated with systemic adverse reactions of systemic corticosteroids (Cushing's syndrome, adrenal suppression); similar effects are possible with concomitant use with other systemic corticosteroids metabolized by CYP3A4 isoenzyme, e.g., budesonide. The systemic effect of fluticasone propionate on ritonavir plasma levels is unknown. The mechanism of interaction is related to CYP3A4 induction. Concomitant use of atazanavir (with or without ritonavir) with other inhaled / nasal corticosteroids is expected to lead to similar effects. |
Concomitant use of fluticasone propionate with atazanavir / ritonavir is not recommended, except when potential benefit outweighs the risk of systemic adverse reactions of systemic corticosteroids (see section "Special precautions"). Consideration should be given to reducing the dose of glucocorticoids, taking into account local and systemic adverse effects, or use glucocorticoids that are not CYP3A4 substrates (e.g., beclomethasone). Additionally, when discontinuing glucocorticoid therapy, the dose should be tapered gradually over a prolonged period. Concomitant use of inhaled / nasal corticosteroids with atazanavir (with or without ritonavir) may increase plasma concentrations of inhaled / nasal corticosteroids. Use with caution. Consider alternatives to inhaled / nasal corticosteroids, especially for prolonged use. |
| AGENTS USED IN ERECTILE DYSFUNCTION |
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| PDE-5 inhibitors |
||
| Sildenafil, tadalafil, vardenafil |
Sildenafil, tadalafil, and vardenafil are metabolized via CYP3A4. Concomitant use of atazanavir with PDE-5 inhibitors may lead to significant increases in PDE-5 inhibitor concentrations and enhanced adverse reactions, such as arterial hypotension, visual disturbances, priapism. The mechanism of this interaction is CYP3A4 inhibition. |
Patients should be warned about adverse effects when using PDE-5 inhibitors for erectile dysfunction treatment together with atazanavir (see section "Special precautions"). Cases of pulmonary arterial hypertension have been reported with concomitant use of sildenafil and atazanavir. |
| GONADOTROPIN-RELEASING HORMONE (GnRH) RECEPTOR ANTAGONISTS |
||
| Elagolix |
Mechanism of interaction involves increased elagolix exposure due to inhibition of CYP3A4 by atazanavir and/or ritonavir. |
Concomitant use of elagolix 200 mg twice daily with atazanavir (with or without ritonavir) for more than 1 month is not recommended due to potential risk of adverse effects such as bone mass loss and elevated liver transaminases. Limit concomitant use of elagolix 150 mg once daily with atazanavir (with or without ritonavir) to 6 months. |
| KINASE INHIBITORS |
||
| Fostamatinib |
Mechanism of interaction involves inhibition of CYP3A4 by atazanavir and/or ritonavir. |
Concomitant use of fostamatinib with atazanavir (with or without ritonavir) may increase plasma concentration of R406, the active metabolite of fostamatinib. Monitor for R406 toxicity leading to dose-dependent adverse effects such as hepatotoxicity and neutropenia. Dose reduction of fostamatinib may be required. |
| HERBAL MEDICINAL PRODUCTS |
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| St. John's wort (Hypericum perforatum) |
Concomitant use of St. John's wort with atazanavir is expected to lead to a significant decrease in atazanavir plasma levels. This effect may be associated with CYP3A4 induction. There is a risk of loss of therapeutic effect and development of resistance. |
Combination of St. John's wort products and atazanavir is contraindicated. |
| HORMONAL CONTRACEPTIVES |
||
| Ethinylestradiol 25 mcg + norgestimate (atazanavir 300 mg once daily and ritonavir 100 mg once daily) |
Ethinylestradiol AUC ↓19 % (↓25 % ↓13 %) Ethinylestradiol Cmax ↓16 % (↓26 % ↓5 %) Ethinylestradiol Cmin ↓37 % (↓45 % ↓29 %) Norgestimate AUC ↑85 % (↑67 % ↑105 %) Norgestimate Cmax ↑68 % (↑51 % ↑88 %) Norgestimate Cmin ↑102 % (↑77 % ↑131 %) Despite increased ethinylestradiol concentrations when atazanavir is used alone due to inhibition of UGT and CYP3A4 by atazanavir, the net effect of atazanavir / ritonavir is reduced ethinylestradiol levels due to the inducing effect of ritonavir. Increased progestin exposure may cause adverse effects (e.g., insulin resistance, dyslipidemia, acne, and spotting), which may affect compliance. |
It is recommended to use contraceptives containing at least 30 mcg of ethinylestradiol. Strict adherence to the prescribed contraceptive dose is required. Concomitant use of atazanavir / ritonavir with other hormonal contraceptives or oral contraceptives containing norgestimate or progesterone has not been studied, so such combination is not recommended. An alternative reliable method of contraception is recommended. |
| Ethinylestradiol 35 mcg + norethindrone (atazanavir 400 mg once daily) |
Ethinylestradiol AUC ↑48 % (↑31 % ↑68 %) Ethinylestradiol Cmax ↑15 % (↓1 % ↑32 %) Ethinylestradiol Cmin ↑91 % (↑57% ↑133 %) Norethindrone AUC ↑110 % (↑68 % ↑162 %) Norethindrone Cmax ↑67 % (↑42 % ↑196 %) Norethindrone Cmin ↑262 % (↑157 % ↑409 %) Increased progestin exposure may cause adverse effects (e.g., insulin resistance, dyslipidemia, acne, and spotting), which may affect compliance. |
|
| HYPOlipidEMIC AGENTS |
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| HMG-CoA reductase inhibitors |
||
| Simvastatin Lovastatin |
Simvastatin and lovastatin are extensively metabolized by CYP3A4, and their blood concentrations may increase when used concomitantly with atazanavir. |
Concomitant use of simvastatin and lovastatin with atazanavir is contraindicated due to increased risk of myopathy, including rhabdomyolysis (see section "Contraindications"). |
| Atorvastatin |
Risk of myopathy, including rhabdomyolysis, increases with atorvastatin use, which is also metabolized by CYP3A4. |
Concomitant use of atazanavir with atorvastatin is not recommended. If atorvastatin use is necessary, the lowest dose of atorvastatin should be prescribed and the patient monitored (see section "Special precautions"). |
| Pravastatin Fluvastatin |
Not studied. Data suggest that concomitant use with protease inhibitors may increase exposure to pravastatin and fluvastatin. Pravastatin is not metabolized by CYP3A4, while fluvastatin is partially metabolized by CYP2C9. |
Caution is required. |
| Other lipid-modifying agents |
||
| Lomitapide |
Lomitapide metabolism is highly dependent on CYP3A4, and concomitant use of atazanavir with ritonavir may lead to increased concentrations. |
Concomitant use of lomitapide and atazanavir with ritonavir is contraindicated due to potential risk of significant increases in transaminase levels and hepatotoxicity (see section "Contraindications"). |
| INHALED ß-AGONISTS |
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| Salmeterol |
Concomitant use with atazanavir may lead to increased salmeterol concentrations and increased salmeterol-related adverse effects. Mechanism of interaction is CYP3A4 inhibition by atazanavir and/or ritonavir. |
Concomitant use of salmeterol with atazanavir is not recommended (see section "Special precautions"). |
| OPIOIDS |
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| Buprenorphine, once daily, stable maintenance dose (atazanavir 300 mg once daily with ritonavir 100 mg once daily) |
Buprenorphine AUC ↑67 % Buprenorphine Cmax ↑37 % Buprenorphine Cmin ↑69 % Norbuprenorphine AUC ↑105 % Norbuprenorphine Cmax ↑61 % Norbuprenorphine Cmin ↑101 % Mechanism of interaction – CYP3A4 and UGT1A1 inhibition. Atazanavir concentration (when used with ritonavir) did not change significantly. |
Concomitant use with atazanavir and ritonavir requires clinical monitoring of sedation and cognitive effects. Dose reduction of buprenorphine may be considered. |
| Methadone, stable maintenance dose (atazanavir 400 mg once daily) |
No significant effect on methadone concentration was observed. Administration of low-dose ritonavir (100 mg twice daily) did not significantly affect methadone concentration. Based on these data, no interaction was expected with concomitant use of methadone and atazanavir. |
No dose adjustment is required when methadone is used concomitantly with atazanavir. |
| PULMONARY ARTERIAL HYPERTENSION |
||
| PDE-5 inhibitors |
||
| Sildenafil |
Concomitant use of atazanavir / ritonavir may lead to increased concentrations of PDE-5 inhibitors and enhanced PDE-5 inhibitor-related adverse effects. Mechanism of interaction is CYP3A4 inhibition by atazanavir and/or ritonavir. |
A safe and effective dose in combination with atazanavir has not been established for sildenafil in the treatment of pulmonary arterial hypertension. Sildenafil used for the treatment of pulmonary arterial hypertension is contraindicated (see section "Contraindications"). |
| SEDATIVES |
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| Benzodiazepines |
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| Midazolam Triazolam |
Midazolam and triazolam are metabolized by CYP3A4. Concomitant use of atazanavir may cause a significant increase in benzodiazepine plasma concentrations. No interaction study between atazanavir and benzodiazepines has been conducted. Based on data from other CYP3A4 inhibitors, midazolam plasma concentrations are expected to be significantly higher when midazolam is administered orally. Data on concomitant use of parenteral midazolam with other protease inhibitors suggest a possible 3-4 fold increase in midazolam plasma levels. |
Concomitant use of atazanavir with triazolam or oral midazolam is contraindicated (see section "Contraindications"), while caution is required when using atazanavir with parenteral midazolam. Concomitant use of atazanavir with parenteral midazolam should be performed in an intensive care unit or similar setting where emergency assistance is available in case of respiratory depression or prolonged sedation. Midazolam doses should be considered, especially if multiple doses are administered. |
In case of discontinuation of ritonavir from the recommended treatment regimen with boosted atazanavir, see section "Special precautions".
The same recommendations regarding drug interactions will apply, except:
- concomitant use is not recommended with tenofovir, proton pump inhibitors, and buprenorphine; contraindicated with carbamazepine, phenytoin, and phenobarbital;
- concomitant use with famotidine is not recommended, but if necessary, atazanavir without ritonavir should be administered 2 hours after or 12 hours before famotidine; no single dose of famotidine should exceed 20 mg, and the total daily dose of famotidine should not exceed 40 mg;
- it should be noted that:
- concomitant use of apixaban, dabigatran, or rivaroxaban with atazanavir without ritonavir may affect the concentrations of apixaban, dabigatran, or rivaroxaban;
- concomitant use of voriconazole and atazanavir without ritonavir may affect atazanavir concentrations;
- concomitant use of fluticasone and atazanavir without ritonavir may increase fluticasone concentrations compared to fluticasone administered alone;
- if an oral contraceptive is used concomitantly with atazanavir without ritonavir, it is recommended that the oral contraceptive contain no more than 30 mcg of ethinylestradiol;
- lamotrigine does not require dose adjustment.
Children
Drug interaction studies have been conducted only in adult patients.
Special precautions for use
Before prescribing the medication, individual viral resistance and patient history should be evaluated.
Although effective viral suppression with antiretroviral therapy has been shown to substantially reduce the risk of sexual transmission, residual risk cannot be excluded. Patients must be advised that antiretroviral therapy does not eliminate the risk of HIV transmission via blood or sexual contact, and therefore preventive measures should be taken.
Concomitant use of atazanavir with ritonavir at doses exceeding 100 mg once daily has not been clinically evaluated. Higher doses of ritonavir may alter the safety profile of atazanavir (cardiac effects, hyperbilirubinemia) and are therefore not recommended. Only when atazanavir with ritonavir is used concomitantly with efavirenz, may the dose of ritonavir be increased to 200 mg once daily. In such cases, appropriate clinical monitoring is warranted (see "Interaction with other medicinal products" below).
Patients with concomitant diseases
Hepatic impairment. Atazanavir is primarily metabolized in the liver, and increased plasma concentrations have been observed in patients with impaired liver function. There are no data on the safety and efficacy of atazanavir in patients with severe liver disease. Patients with chronic hepatitis B or C receiving combination antiretroviral therapy are at an increased risk of serious and potentially fatal hepatic adverse reactions. If concomitant antiviral therapy for hepatitis B or C is administered, refer also to the respective product information for these medications.
Patients with pre-existing liver dysfunction, including chronic active hepatitis, are at increased risk of hepatic abnormalities during combination antiretroviral therapy and should be monitored according to standard practice. If liver function deteriorates, temporary discontinuation or permanent withdrawal of antiviral agents should be considered.
Renal impairment. Dose adjustment is not required. However, atazanavir is not recommended for patients undergoing hemodialysis.
QT interval prolongation. Dose-dependent asymptomatic PR interval prolongation has been observed with atazanavir. Caution should be exercised when using medicinal products known to induce PR interval prolongation. Atazanavir should be used with caution in patients with pre-existing conduction abnormalities (second-degree atrioventricular block or bundle branch block), and only if the potential benefit outweighs the risk. Particular caution is advised when prescribing atazanavir concomitantly with medicinal products that have the potential to prolong the QT interval and/or in patients with predisposing risk factors (bradycardia, congenital long QT syndrome, electrolyte imbalances).
Patients with hemophilia. Bleeding events, including spontaneous skin bruising and hemarthrosis, have been observed in patients with hemophilia A and B treated with protease inhibitors. Some of these patients required administration of factor VIII. More than half of these patients continued or resumed treatment with protease inhibitors after interruption. A causal relationship between bleeding and treatment is suspected, although the mechanism of action of protease inhibitors in this regard is not fully understood. Patients with hemophilia should be informed about the potential for such complications.
Body weight and metabolic disturbances
During antiretroviral therapy, increases in body weight and blood lipid and glucose levels may occur. These changes may be partially related to disease control and lifestyle. For lipids, there is evidence of a treatment effect in some cases, whereas for weight gain, there is no substantial evidence linking it to any specific treatment. Monitoring of blood lipid and glucose levels should be performed according to established HIV treatment guidelines. Specialist consultation is required for management of lipid disorders. In clinical trials, atazanavir with ritonavir was associated with less dyslipidemia compared to lopinavir with ritonavir in both treatment-naïve and treatment-experienced patients.
Hyperbilirubinemia
Reversible increases in indirect (unconjugated) bilirubin levels have been observed in patients receiving atazanavir, related to inhibition of uridine diphosphate glucuronosyltransferase (UGT). Elevated liver transaminases occurring with elevated bilirubin in patients on atazanavir should be evaluated for alternative etiologies. If jaundice or scleral icterus is undesirable for the patient, alternative antiretroviral therapy may be considered. Dose reduction is not recommended, as this may lead to loss of therapeutic effect or development of resistance.
Indinavir is also associated with indirect (unconjugated) hyperbilirubinemia due to UGT inhibition. The combination of atazanavir and indinavir has not been studied and is therefore not recommended.
Discontinuation of ritonavir only under restrictive conditions
The recommended standard treatment is atazanavir boosted with ritonavir, which ensures optimal pharmacokinetic parameters and virological suppression.
Discontinuation of ritonavir from a boosted atazanavir regimen is not recommended but may be considered in adult patients receiving 400 mg once daily with food only under the following combined restrictive conditions:
- no prior virological treatment failure;
- undetectable viral load for the last 6 months on the current regimen;
- viral strains without HIV-associated resistance mutations (RAMs) relevant to the current regimen.
Atazanavir without ritonavir should not be considered for patients receiving regimens containing tenofovir disoproxil fumarate and other concomitant drugs that reduce atazanavir bioavailability (see section "Interaction with other medicinal products and other forms of interaction" regarding withdrawal of ritonavir from the recommended boosted atazanavir regimen) or in cases of suspected stimulant responsiveness.
Atazanavir without ritonavir should not be used during pregnancy, as this may result in suboptimal efficacy, raising particular concerns regarding maternal infection and vertical transmission.
Cholelithiasis. Cholelithiasis has been reported with atazanavir use. Some patients required hospitalization for appropriate treatment, and complications occurred in some cases. If signs of cholelithiasis persist, atazanavir therapy should be temporarily or permanently discontinued.
Chronic kidney disease. Cases of chronic kidney disease in HIV-infected patients receiving atazanavir with or without ritonavir have been reported during post-marketing surveillance. A large observational study showed an association between increased incidence of chronic kidney disease and cumulative exposure to regimens containing atazanavir/ritonavir in HIV-infected patients with normal baseline estimated glomerular filtration rate. This association was observed independently of tenofovir disoproxil exposure. Regular monitoring of renal function should be maintained throughout treatment duration (see section "Adverse reactions").
Nephrolithiasis. Nephrolithiasis has been reported with atazanavir use. Some patients required hospitalization for treatment, and complications occurred in some cases. In some instances, nephrolithiasis was associated with acute or chronic renal failure. If signs or symptoms of nephrolithiasis occur, temporary interruption or discontinuation of therapy may be considered.
Immune reconstitution syndrome. In HIV-infected patients commencing combination antiretroviral therapy, inflammatory responses to indolent or opportunistic infections may occur, potentially causing severe clinical conditions or symptom exacerbation. These events are typically observed within the first weeks or months of antiretroviral treatment. Examples include cytomegalovirus retinitis, generalized and/or localized mycobacterial infections, and Pneumocystis jirovecii pneumonia. The severity of any inflammatory symptoms should be assessed, and appropriate treatment initiated. Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have also been reported during immune reconstitution; however, the time to onset is more variable, and these events may occur several months after initiation of treatment.
Osteonecrosis. Although the etiology is considered multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, body mass index), cases of osteonecrosis have been reported, particularly in patients with advanced HIV infection and/or long-term exposure to combination antiretroviral therapy (cART). Patients should be advised to seek medical attention if they experience joint pain, joint stiffness, or difficulty walking.
Rashes and associated syndromes. Maculopapular rashes, usually mild or moderate in severity, may occur within the first 3 weeks of atazanavir therapy. Stevens-Johnson syndrome, erythema multiforme, drug rash with eosinophilia and systemic symptoms (DRESS), and other severe cutaneous reactions have been reported with atazanavir use. At the first signs of any skin reaction, the medication should be discontinued. Atazanavir must not be re-administered if a patient develops Stevens-Johnson syndrome or DRESS.
Interaction with other medicinal products
Combination of atazanavir with atorvastatin is not recommended.
Concomitant use of atazanavir with nevirapine or efavirenz is not recommended.
If combination of atazanavir with non-nucleoside reverse transcriptase inhibitors is required, the doses of atazanavir and ritonavir should be increased to 400 mg and 200 mg, respectively, when used with efavirenz; therapy should be administered with careful clinical monitoring.
Atazanavir is primarily metabolized by CYP3A4. Concomitant use of atazanavir with medicinal products that inhibit CYP3A4 is not recommended.
Phosphodiesterase-5 (PDE-5) inhibitors (sildenafil, tadalafil, vardenafil) for erectile dysfunction should be prescribed with particular caution; patients receiving atazanavir and ritonavir should receive lower doses of these agents. Concomitant use may lead to significant increases in PDE-5 inhibitor concentrations and enhanced adverse reactions, such as hypotension, visual disturbances, and priapism.
Concomitant use of voriconazole and atazanavir with ritonavir is not recommended unless the benefit outweighs the risk.
Decreased exposure of both voriconazole and atazanavir is expected in most patients. In a small number of patients lacking functional CYP2C19 alleles, significantly increased voriconazole exposure is expected.
Concomitant use of atazanavir/ritonavir with fluticasone or other glucocorticoids metabolized by CYP3A4 is not recommended unless the potential benefit of systemic corticosteroid therapy outweighs the risk of adverse effects, including Cushing's syndrome and adrenal suppression.
Concomitant use of salmeterol with atazanavir/ritonavir increases the risk of cardiovascular adverse reactions associated with salmeterol. The combination of salmeterol and atazanavir is not recommended.
Atazanavir absorption may be reduced when gastric pH is increased for any reason.
Combination of atazanavir with proton pump inhibitors is not recommended.
If combination with proton pump inhibitors is necessary, medical supervision is recommended, and the dose of atazanavir should be increased to 400 mg and ritonavir to 100 mg; proton pump inhibitor doses should not exceed the equivalent of omeprazole 20 mg.
Concomitant use of atazanavir with oral hormonal contraceptives containing progestins (except norgestimate) has not been studied. Therefore, such combination is not recommended.
Children
Safety
Asymptomatic PR interval prolongation has been observed more frequently in pediatric patients than in adults. Asymptomatic first- and second-degree atrioventricular block has been reported in pediatric patients (see section "Adverse reactions"). Caution should be exercised when using medicinal products known to prolong the PR interval. Atazanavir should be used with caution in pediatric patients with pre-existing conduction abnormalities (second-degree atrioventricular block or bundle branch block), and only if benefits outweigh risks. Cardiological monitoring is recommended based on clinical findings (e.g., bradycardia).
Efficacy
Atazanavir/ritonavir is ineffective against viral strains containing multiple resistance mutations.
Excipients
Lactose. The medication should not be administered to patients with rare hereditary problems of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption.
Use during pregnancy or breastfeeding
Pregnancy
Moderate data from pregnant women (from 300 to 1000 pregnancy outcomes) indicate no teratogenic effect of atazanavir. Animal studies do not indicate reproductive toxicity. Use of atazanavir with ritonavir during pregnancy may be considered only if the potential benefit justifies the potential risk.
In a clinical trial, atazanavir/ritonavir (300/100 mg or 400/100 mg) in combination with zidovudine/lamivudine was administered to pregnant women during the second or third trimester. Grade 3–4 hyperbilirubinemia occurred in 30% of women receiving atazanavir/ritonavir 300/100 mg and in 62% of women receiving 400/100 mg. In another clinical trial, no cases of lactic acidosis were observed.
In a study evaluating 40 infants who received prophylactic antiretroviral treatment (not including atazanavir) and were HIV-1 DNA negative at delivery and/or within the first 6 months postpartum, grade 3–4 bilirubin levels were observed in 15% of infants born to mothers receiving atazanavir/ritonavir 300/100 mg and in 20% of infants born to mothers receiving 400/100 mg. No pathological jaundice was observed, and six of the 40 infants in this study received phototherapy for up to 4 days. No cases of kernicterus were reported in newborns.
It is unknown whether atazanavir with ritonavir administered to pregnant women may exacerbate physiological hyperbilirubinemia and lead to bilirubin encephalopathy in newborns and infants. Additional monitoring is required in the prenatal period.
Breastfeeding
Atazanavir has been detected in human milk. To prevent HIV transmission to infants, breastfeeding is not recommended for women living with HIV.
Patients should be closely monitored in the postpartum period due to increased risk of adverse reactions.
Ability to influence reaction speed when driving or operating machinery
Patients should be informed about the possibility of dizziness during atazanavir treatment.
Dosage and Administration
The decision to initiate therapy should be made by a physician experienced in the management of HIV infections.
The medication is for oral use. Swallow capsules whole.
Adults
The recommended dose of atazanavir is 300 mg once daily co-administered with ritonavir 100 mg once daily with food. Ritonavir is used as a pharmacokinetic enhancer of atazanavir (see section "Special Warnings and Precautions": Discontinuation of ritonavir – only under restrictive conditions).
Children (aged 6 to 18 years and body weight at least 15 kg)
The dose of atazanavir capsules for children should be based on body weight as shown in the table below, and should not exceed the recommended adult dose. Atazanavir must be taken together with ritonavir and with food.
Dosage for children (aged 6 to 18 years and body weight at least 15 kg) for atazanavir with ritonavir
| Body weight (kg) |
Atazanavir, once daily |
Ritonavir, once daily |
| From 15 to 35 |
200 mg |
100 mg |
| At least 35 |
300 mg |
100 mg |
Special Populations
Renal Impairment
Dose adjustment is not required. Atazanavir with ritonavir is not recommended for patients undergoing hemodialysis (see section "Special Warnings and Precautions for Use").
Hepatic Impairment
The use of atazanavir with ritonavir has not been studied in patients with hepatic dysfunction. Atazanavir with ritonavir should be used with caution in patients with mild hepatic impairment. Atazanavir with ritonavir should not be used in patients with moderate and severe hepatic impairment (see sections "Contraindications" and "Special Warnings and Precautions for Use").
In case of discontinuation of ritonavir from an initial recommended ritonavir-boosted regimen, unboosted atazanavir may be maintained in patients with mild hepatic impairment at a dose of 400 mg and in patients with moderate hepatic impairment at a reduced dose of 300 mg once daily with food. Unboosted atazanavir should not be used in patients with severe hepatic impairment.
Pregnancy and Postpartum Period
Second and Third Trimesters of Pregnancy
Atazanavir 300 mg with ritonavir 100 mg may not provide adequate atazanavir exposure, particularly if atazanavir activity or the entire regimen may be compromised due to drug resistance. Given the limited available data and inter-patient variability during pregnancy, therapeutic drug monitoring (TDM) may be considered to ensure adequate exposure.
A further reduction in atazanavir exposure is expected when atazanavir is co-administered with medicinal products known to decrease its exposure (e.g., tenofovir disoproxil fumarate or H2-receptor antagonists).
- If tenofovir disoproxil fumarate or H2-receptor antagonists are required, dose escalation of atazanavir 400 mg with ritonavir 100 mg should be considered, with TDM.
- The use of atazanavir with ritonavir is not recommended for pregnant women receiving both tenofovir disoproxil fumarate and H2-receptor antagonists.
(See section "Special Warnings and Precautions for Use" Discontinuation of Ritonavir Only Under Limited Circumstances).
Postpartum Period
Following the potential decrease in atazanavir exposure during the second and third trimesters, atazanavir exposure may increase during the first 2 months postpartum. Therefore, postpartum patients should be closely monitored for adverse reactions.
- During this period, postpartum patients should follow the same dosing recommendations as non-pregnant patients, including those related to concomitant administration of medicinal products known to affect atazanavir exposure.
Children
To be used in children aged 6 years and older.
Overdose
Experience with acute atazanavir overdose in patients is limited. Single doses up to 1200 mg have been administered to healthy volunteers without symptomatic adverse effects. At high doses leading to high drug exposure, jaundice due to indirect (unconjugated) hyperbilirubinemia (without corresponding changes in liver function tests) or prolongation of the PR interval may occur (see sections "Special Warnings and Precautions for Use" and "Adverse Reactions").
Management of atazanavir overdose should consist of general supportive measures, including monitoring of vital signs and electrocardiogram (ECG), as well as observation of the patient's clinical status. If indicated, elimination of unabsorbed atazanavir should be achieved by inducing emesis or gastric lavage. Activated charcoal may also be used to remove unabsorbed drug. There is no specific antidote for atazanavir overdose. Because atazanavir is extensively metabolized in the liver and highly protein-bound, dialysis is unlikely to be effective in drug elimination.
Adverse Reactions
The safety of atazanavir was evaluated in combination therapy with other antiretroviral agents in patients receiving either atazanavir 400 mg once daily or atazanavir 300 mg with ritonavir 100 mg once daily. Adverse reactions were similar between these groups, except for the occurrence of jaundice and elevated bilirubin levels in patients receiving atazanavir with ritonavir.
Among patients receiving atazanavir 400 mg once daily or atazanavir 300 mg with ritonavir 100 mg once daily, the only adverse reactions of any severity reported very commonly, at least possibly related to regimens containing atazanavir and one or more NRTIs, were nausea (20%), diarrhea (10%), and jaundice (13%). Among patients receiving atazanavir 300 mg with ritonavir 100 mg, the incidence of jaundice was 19%. In most cases, jaundice was observed within a few days to several months after initiation of treatment.
Chronic kidney disease has been reported in HIV-infected patients receiving atazanavir with or without ritonavir during post-marketing surveillance. A large prospective observational study showed an association between increased incidence of chronic kidney disease and cumulative exposure to regimens containing atazanavir/ritonavir in HIV-infected patients with normal baseline eGFR. This association was observed independently of the effect of tenofovir disoproxil. Regular monitoring of renal function in patients should be maintained throughout the duration of treatment.
The adverse reactions listed below are based on clinical trial and post-marketing data. Frequency is defined as follows: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10,000, < 1/1000), and very rare (< 1/10,000). Within each frequency grouping, adverse reactions are presented in order of decreasing prominence.
| Immune system disorders |
Uncommon: hypersensitivity |
| Metabolism and nutrition disorders |
Uncommon: decreased or increased body weight, anorexia, increased appetite |
| Psychiatric disorders |
Uncommon: depression, confusion, restlessness, insomnia, sleep disorders, abnormal dreams |
| Nervous system disorders |
Common: headache; Uncommon: peripheral neuropathy, loss of consciousness, amnesia, dizziness, somnolence, taste disturbance |
| Eye disorders |
Common: icteric sclera |
| Cardiac disorders |
Uncommon: torsades de pointes ventricular tachycardiaa Rare: QT interval prolongationa, edema, palpitations Uncommon: arterial hypertension |
| Respiratory system disorders |
Uncommon: dyspnea |
| Gastrointestinal disorders |
Common: vomiting, diarrhea, abdominal pain, nausea, dyspepsia; Uncommon: pancreatitis, gastritis, abdominal distension, aphthous stomatitis, flatulence, dry mouth |
| Hepatobiliary disorders |
Common: jaundice; Uncommon: hepatitis, cholelithiasisa, cholestasisa; Rare: hepatosplenomegaly, cholecystitisa |
| Skin and subcutaneous tissue disorders |
Common: rash; Uncommon: erythema multiformea,b, toxic skin eruptionsa,b, drug rash with eosinophilia, drug reaction with eosinophilia and systemic symptoms (DRESS)a,b, angioneurotic edemaa, urticaria, alopecia, pruritus; Rare: Stevens-Johnson syndromea,b, vesiculobullous rash, eczema, vasodilation |
| Musculoskeletal and connective tissue disorders |
Uncommon: muscle atrophy, arthralgia, myalgia; Rare: myopathy |
| Renal and urinary disorders |
Uncommon: nephrolithiasisa, hematuria, proteinuria, polyuria, interstitial nephritis, chronic kidney diseasea; Rare: renal pain |
| Reproductive system disorders |
Uncommon: gynecomastia |
| General disorders |
Common: fatigue; Uncommon: chest pain, malaise, fever, asthenia; Rare: gait disturbance |
a These adverse reactions were identified during post-marketing surveillance; however, frequencies were estimated by statistical calculation based on the total number of patients who received atazanavir in randomized controlled and other available clinical trials (n = 2321).
b See description of selected adverse reactions for more detailed information.
Description of selected adverse reactions
In HIV-infected patients with severe immune deficiency, an inflammatory reaction to asymptomatic or residual opportunistic infections may occur at initiation of combination antiretroviral therapy (cART). Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have also been reported; however, reports on the time to onset are more variable, and these events may occur many months after initiation of treatment (see section "Special warnings and precautions for use").
Cases of osteonecrosis have been reported, particularly in patients with generally recognized risk factors, advanced HIV infection, or long-term exposure to combination antiretroviral therapy (cART). The frequency of this is unknown (see section "Special warnings and precautions for use").
Metabolic parameters
Body weight and levels of lipids and blood glucose may increase during antiretroviral therapy (see section "Special warnings and precautions for use").
Rash and related syndromes
Rashes are typically mild or moderate maculopapular skin rashes occurring within the first 3 weeks of starting atazanavir treatment.
Stevens-Johnson syndrome (SJS), toxic skin eruptionsb, drug rash with eosinophilia, and systemic symptoms (DRESS) have been reported with atazanavir use (see section "Special warnings and precautions for use").
Laboratory abnormalities
The most commonly reported laboratory abnormality in patients receiving regimens containing atazanavir and one or more NRTIs was elevated total bilirubin, reported predominantly as increased indirect (unconjugated) bilirubin (87%, grade 1, 2, 3, or 4). Grade 3 or 4 increases in total bilirubin were observed in 37% (6% grade 4). Among treatment-experienced patients receiving atazanavir 300 mg once daily and ritonavir 100 mg once daily with a median duration of 95 weeks, 53% of patients experienced grade 3-4 increases in total bilirubin. Among treatment-naïve patients receiving atazanavir 300 mg once daily and ritonavir 100 mg once daily with a median duration of 96 weeks, 48% of patients experienced grade 3-4 increases in total bilirubin (see section "Special warnings and precautions for use").
Other notable laboratory abnormalities (grade 3 or 4) reported in ≥ 2% of patients receiving regimens containing atazanavir 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 receiving atazanavir had concurrent grade 3-4 increases in both ALT/AST and total bilirubin.
Pediatric population
In pediatric patients aged 3 months to 18 years receiving atazanavir oral powder or capsules, the safety profile was generally comparable to that observed in adults. Asymptomatic first-degree (23%) and second-degree (1%) atrioventricular blocks were observed in pediatric patients. The most commonly reported laboratory abnormality in children receiving atazanavir was elevated total bilirubin (≥ 2.6 times above normal, grade 3-4), observed in 45% of patients.
In two clinical studies, pediatric patients aged 3 months to 11 years had a median treatment duration of 80 weeks with atazanavir oral powder. No deaths occurred. The safety profile in these studies was generally comparable to that observed in previous pediatric studies and adult trials. The most frequent laboratory abnormalities reported in pediatric patients receiving atazanavir oral powder were elevated total bilirubin (≥ 2.6 times above ULN, grade 3-4; 16%) and elevated amylase (grade 3-4; 33%), generally of non-pancreatic origin. Elevations in ALT were reported more frequently in children than in adults.
Other special populations
Patients co-infected with hepatitis B virus and/or hepatitis C virus
Co-infected patients are more prone to baseline elevations in liver transaminases than those without chronic viral hepatitis. There were no differences in the frequency of bilirubin elevations between these patients and those without viral hepatitis. The incidence of hepatitis or transaminase elevations in co-infected patients was comparable between atazanavir and comparator regimens (see section "Special warnings and precautions for use").
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after medicinal product authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the automated pharmacovigilance information system at: https://aisf.dec.gov.ua.
Shelf life. 2 years.
Storage conditions
Store in the original packaging at a temperature not exceeding 25 °C, in a place inaccessible to children.
Packaging
Capsules 150 mg, 200 mg: 60 capsules in a container, 1 container in a cardboard box.
Capsules 300 mg: 30 capsules in a container, 1 container in a cardboard box.
Prescription status. Prescription only.
Manufacturer. Hetero Labs Limited.
Manufacturer's address and location of its operations
Unit III, Formulation Plot No 22 - 110 IDA, Jeedimetla, Hyderabad, 500 055 Telangana, India.