Atazanavir Viatris (previously Atazanavir Mylan) · 4.5 Interaction with other medicinal products and other forms of interaction · 1

HOS-217141 · has-adverse-reaction-information · PDF-Seite 29

Summary of the safety profile Atazanavir has been evaluated for safety in combination therapy with other antiretroviral medicinal products in controlled clinical trials in 1,806 adult patients receiving atazanavir 400 mg once daily (1,151 patients, 52 weeks median duration and 152 weeks maximum duration) or atazanavir 300 mg with ritonavir 100 mg once daily (655 patients, 96 weeks median duration and 108 weeks maximum duration). Adverse reactions were consistent between patients who received atazanavir 400 mg once daily and patients who received atazanavir 300 mg with ritonavir 100 mg once daily, except that jaundice and elevated total bilirubin levels were reported more frequently with atazanavir plus ritonavir. Among patients who received 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 with at least a possible relationship to regimens containing atazanavir and one or more NRTIs were nausea (20%), diarrhoea (10%), and jaundice (13%). Among patients receiving atazanavir 300 mg with ritonavir 100 mg, the frequency of jaundice was 19%. In the majority of cases, jaundice was reported within a few days to a few months after the initiation of treatment (see section 4.4). Chronic kidney disease in HIV-infected patients treated with atazanavir, with or without ritonavir, has been reported during postmarketing surveillance. A large prospective observational study has shown an association between an increased incidence of chronic kidney disease and cumulative exposure to atazanavir/ritonavir-containing regimen in HIV-infected patients with an initially normal eGFR. This association was observed independently of exposure to tenofovir disoproxil. Regular monitoring of the renal function of patients should be maintained throughout the treatment duration (see section 4.4). 29 Tabulated list of adverse reactions Assessment of adverse reactions for atazanavir is based on safety data from clinical studies and post- marketing experience. Frequency is defined using the following convention: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Immune system disorders: uncommon: hypersensitivity Metabol

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HOS-217137 · has-contraindication-information · PDF-Seite 4

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 4 Atazanavir Viatris is contraindicated in patients with severe hepatic insufficiency (see sections 4.2, 4.4 and 5.2). Atazanavir Viatris with ritonavir is contraindicated in patients with moderate hepatic insufficiency (see sections 4.2, 4.4, and 5.2). Co-administration with simvastatin or lovastatin (see section 4.5). Combination of the PDE5 inhibitor sildenafil when used for the treatment of pulmonary arterial hypertension (PAH) only (see section 4.5). For co-administration of sildenafil for the treatment of erectile dysfunction see sections 4.4 and 4.5. Co-administration with medicinal products that are substrates of the CYP3A4 isoform of cytochrome P450 and have narrow therapeutic windows (e.g., quetiapine, lurasidone, alfuzosin, astemizole, terfenadine, cisapride, pimozide, quinidine, bepridil, triazolam, midazolam administered orally (for caution on parenterally administered midazolam, see section 4.5) lomitapide, and ergot alkaloids, particularly, ergotamine, dihydroergotamine, ergonovine, methylergonovine) (see section 4.5). Co-administration 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, apalutamide, encorafenib, ivosidenib, carbamazepine, phenobarbital and phenytoin) (see section 4.5). Co-administration with grazoprevir-containing products, including elbasvir/grazoprevir fixed-dose combination (see section 4.5). Co-administration with glecaprevir/pibrentasvir fixed-dose combination (see section 4.5).

HOS-217136 · has-indication-information · PDF-Seite 3

Atazanavir Viatris, co-administered with low dose ritonavir, is indicated for the treatment of HIV-1-infected adults and paediatric patients 6 years of age and older in combination with other antiretroviral medicinal products (see section 4.2). Based on available virological and clinical data from adult patients, no benefit is expected in patients with strains resistant to multiple protease inhibitors (≥ 4 PI mutations). The choice of Atazanavir Viatris in treatment-experienced adult and paediatric patients should be based on individual viral resistance testing and the patient’s treatment history (see sections 4.4 and 5.1).

HOS-217139 · has-interaction-information · PDF-Seite 9

When atazanavir and ritonavir are co-administered, the metabolic drug interaction profile for ritonavir may predominate because ritonavir is a more potent CYP3A4 inhibitor than atazanavir. The Summary of Product Characteristics for ritonavir must be consulted before initiation of therapy with atazanavir and ritonavir. Atazanavir is metabolised in the liver through CYP3A4. It inhibits CYP3A4. Therefore, atazanavir is contraindicated with medicinal products that are substrates of CYP3A4 and have a narrow therapeutic index: quetiapine, lurasidone, alfuzosin, astemizole, terfenadine, cisapride, pimozide, quinidine, bepridil, triazolam, orally administered midazolam, lomitapide, and ergot alkaloids, particularly ergotamine and dihydroergotamine (see section 4.3). Co-administration of atazanavir with grazoprevir-containing products, including elbasvir/grazoprevir fixed- dose combination is contraindicated because of the increase in grazoprevir and elbasvir plasma concentrations and potential for the increase in risk of ALT elevations associated with increased grazoprevir concentrations (see section 4.3). Co-administration of atazanavir with glecaprevir/pibrentasvir fixed-dose combination is contraindicated because of the potential increase in the risk of ALT elevations due to a significant increase in glecaprevir and pibrentasvir plasma concentrations (see section 4.3). Other interactions Interactions between atazanavir and other medicinal products are listed in the table below (increase is indicated as “↑”, decrease as “↓”, no change as “↔”). If available, 90% confidence intervals (CI) are shown in parentheses. The studies presented in Table 2 were conducted in healthy subjects unless otherwise noted. Of importance, many studies were conducted with unboosted atazanavir, which is not the recommended regimen of atazanavir (see section 4.4). If withdrawal of ritonavir is medically warranted under restrictive conditions (see section 4.4), special attention should be given to atazanavir interactions that may differ in the absence of ritonavir (see information below Table 2). Interactions between atazanavir and other medicinal products, including those for which coadministration is contraindicated, are listed in the table below: Table 2: Interactions between atazanavir and other medicinal products Medicinal products by Interaction Recommendations therapeutic area

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HOS-217140 · has-pregnancy-information · PDF-Seite 28

Pregnancy A large amount of data on pregnant women (more than 2 000 pregnancy outcomes) indicate no increase in malformative toxicity of atazanavir. Animal studies also do not indicate reproductive toxicity (see section 5.3). The use of Atazanavir Viatris may be considered during pregnancy, if necessary. In clinical trial AI424-182 atazanavir/ritonavir (300/100 mg or 400/100 mg) in combination with zidovudine/lamivudine was administered to 41 pregnant women during the second or third trimester. Six of 20 (30%) women on atazanavir/ritonavir 300/100 mg and 13 of 21 (62%) women on atazanavir /ritonavir 400/100 mg experienced grades 3 to 4 hyperbilirubinaemia. There were no cases of lactic acidosis observed in the clinical trial AI424-182. 28 The study assessed 40 infants who received antiretroviral prophylactic treatment (which did not include atazanavir) and were negative for HIV-1 DNA at the time of delivery and/or during the first 6 months postpartum. Three of 20 infants (15%) born to women treated with atazanavir/ritonavir 300/100 mg and four of 20 infants (20%) born to women treated with atazanavir/ritonavir 400/100 mg experienced grade 3-4 bilirubin. There was no evidence of pathologic jaundice and six of 40 infants in this study received phototherapy for a maximum of 4 days. There were no reported cases of kernicterus in neonates. For dosing recommendations see section 4.2 and for pharmacokinetic data see section 5.2. It is not known whether Atazanavir Viatris with ritonavir administered to the mother during pregnancy will exacerbate physiological hyperbilirubinaemia and lead to kernicterus in neonates and infants. In the prepartum period, additional monitoring should be considered. Breast-feeding Atazanavir has been detected in human milk. In order to avoid transmission of HIV to the infant it is recommended that women living with HIV do not breast-feed their infants. Fertility In a nonclinical fertility and early embryonic development study in rats, atazanavir altered oestrus cycling with no effects on mating or fertility (see section 5.3).

HOS-217138 · has-warning-information · PDF-Seite 5

Co-administration of atazanavir with ritonavir at doses greater than 100 mg once daily has not been clinically evaluated. The use of higher ritonavir doses may alter the safety profile of atazanavir (cardiac effects, hyperbilirubinaemia) and therefore is not recommended. Only when atazanavir with ritonavir is co-administered with efavirenz, a dose increase of ritonavir to 200 mg once daily could be considered. In this instance, close clinical monitoring is warranted (see Interaction with other Medicinal Products below). Patients with coexisting conditions Hepatic impairment Atazanavir is primarily hepatically metabolised and increased plasma concentrations were observed in patients with hepatic impairment (see sections 4.2 and 4.3). The safety and efficacy of atazanavir has not been established in patients with significant underlying liver disorders. Patients with chronic hepatitis B or C and treated with combination antiretroviral therapy are at an increased risk for severe and potentially fatal hepatic adverse reactions. In case of concomitant antiviral therapy for hepatitis B or C, please refer also to the relevant Summary of Product Characteristics for these medicinal products (see section 4.8). Patients with pre-existing liver dysfunction, including chronic active hepatitis, have an increased frequency of liver function abnormalities during combination antiretroviral therapy and should be monitored according to standard practice. If there is evidence of worsening liver disease in such patients, interruption or discontinuation of treatment must be considered. Renal impairment No dosage adjustment is needed in patients with renal impairment. However, Atazanavir Viatris is not recommended in patients undergoing haemodialysis (see sections 4.2 and 5.2). QT prolongation Dose-related asymptomatic prolongations in PR interval with atazanavir have been observed in clinical studies. Caution should be used with medicinal products known to induce PR prolongations. In patients with pre-existing conduction problems (second degree or higher atrioventricular or complex bundle-branch 5 block), Atazanavir Viatris should be used with caution and only if the benefits exceed the risk (see section 5.1). Particular caution should be used when prescribing Atazanavir Viatris in association with medicinal products which have the potential to increase the QT interval and/or in patients with pre-existing risk factors

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