Atazanavir Viatris (Previously Atazanavir Mylan)

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%. 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 30 association was observed independently of exposure to tenofovir disoproxil. 4). 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 Metabolism and nutrition disorders: uncommon: weight decreased, weight gain, anorexia, appetite increased Psychiatric disorders: uncommon: depression, disorientation, anxiety, insomnia, sleep disorder, abnormal dream Nervous system disorders: common: headache; uncommon: peripheral neuropathy, syncope, amnesia, dizziness, somnolence, dysgeusia Eye disorders: common: ocular icterus Cardiac disorders: uncommon: torsades de pointesa rare: QTc prolongationa, oedema, palpitation Vascular disorders: uncommon: hypertension Respiratory, thoracic and mediastinal disorders: uncommon: dyspnoea Gastrointestinal disorders: common: vomiting, diarrhoea, abdominal pain, nausea, dyspepsia; uncommon: pancreatitis, gastritis, abdominal distension, stomatitis aphthous, 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 and systemic symptoms (DRESS) syndromea,b, angioedemaa, urticaria, alopecia, pruritus; rare: Stevens-Johnson syndromea,b, vesiculobullous rash, eczema, vasodilatation Musculoskeletal and connective tissue disorders: uncommon: muscle atrophy, arthralgia, myalgia; rare: myopathy Renal and urinary disorders: uncommon: nephrolithiasis, haematuria, proteinuria, pollakiuria, interstitial nephritis, chronic kidney diseasea; rare: kidney pain Reproductive system and breast disorders: uncommon: gynaecomastia General disorders and administration site conditions: common: fatigue; uncommon: chest pain, malaise, pyrexia, asthenia; rare: gait disturbance a These adverse reactions were identified through post-marketing surveillance, however, the frequencies were estimated from a statistical calculation based on the total number of patients exposed to atazanavir in randomised controlled and other available clinical trials (n = 2321).

b See description of selected adverse reactions for more details. Description of selected adverse reactions 31 In HIV-infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic infections may arise.

4). Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk factors, advanced HIV disease or long- term exposure to combination antiretroviral therapy (CART). 4). 4). Rash and associated syndromes Rashes are usually mild-to-moderate maculopapular skin eruptions that occur within the first 3 weeks of starting therapy with atazanavir.

4). Laboratory abnormalities The most frequently reported laboratory abnormality in patients receiving regimens containing atazanavir and one or more NRTIs was elevated total bilirubin reported predominantly as elevated indirect [unconjugated] bilirubin (87% Grade 1, 2, 3, or 4).

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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).

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.

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. 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. 1). 3). Haemophiliac patients There have been reports of increased bleeding, including spontaneous skin haematomas and haemarthroses, in type A and B haemophiliac patients treated with protease inhibitors.

In some patients additional factor VIII was given. In more than half of the reported cases, treatment with protease inhibitors was continued or reintroduced if treatment had been discontinued. A causal relationship has been suggested, although the mechanism of action has not been elucidated.

Haemophiliac patients should therefore be made aware of the possibility of increased bleeding. Weight and metabolic parameters An increase in weight and in levels of blood lipids and glucose may occur during antiretroviral therapy. Such changes may in part be linked to the disease control and life style.

For lipids, there is in some cases evidence for a treatment effect, while for weight gain there is no strong evidence relating this to any particular treatment. For monitoring of blood lipids and glucose reference is made to established HIV treatment guidelines.

Lipid disorders should be managed as clinically appropriate. 1). 8). Hepatic transaminase elevations that occur with elevated bilirubin in patients receiving Atazanavir Viatris should be evaluated for alternative aetiologies. Alternative antiretroviral therapy to Atazanavir Viatris may be considered if jaundice or scleral icterus is unacceptable to a patient.

Dose reduction of atazanavir is not recommended because it may result in a loss of therapeutic effect and development of resistance. Indinavir is also associated with indirect (unconjugated) hyperbilirubinaemia due to inhibition of UGT.

5). Withdrawal of ritonavir only under restrictive conditions The recommended standard treatment is atazanavir boosted with ritonavir, ensuring optimal pharmacokinetic parameters and level of virologic suppression. The withdrawal of ritonavir from the boosted regimen of atazanavir is not recommended, but may be considered in adults patients at the dose of 400 mg once daily with food only under the following combined restrictive conditions: • absence of prior virologic failure • undetectable viral load during the last 6 months under current regimen • viral strains not harbouring HIV resistance-associated mutations (RAMs) to current regimen.

Atazanavir given without ritonavir should not be considered in patients treated with a backbone regimen containing tenofovir disoproxil and with other concomitant medications that reduce atazanavir bioavailability (see section

1. 2). 2). 5). 5). 4 and