Evotaz · 4.5 Interaction with other medicinal products and other forms of interaction · 1

HOS-216863 · has-adverse-reaction-information · PDF-Seite 33

Summary of the safety profile The overall safety profile of EVOTAZ is based on available data from clinical trials conducted with atazanavir, atazanavir boosted with either cobicistat or ritonavir, and post-marketing data. As EVOTAZ contains atazanavir and cobicistat, the adverse reactions associated with each of the individual components may be expected. In a Phase III study (GS-US-216-0114), the most frequently reported adverse reactions in the atazanavir boosted with cobicistat group were associated with elevated bilirubin levels (see Table 2). In two controlled clinical trials, where subjects received atazanavir alone (400 mg once daily) or atazanavir (300 mg daily) boosted with ritonavir (100 mg daily), the most frequently reported adverse reactions were nausea, diarrhoea and jaundice. 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 (see section 4.4). Tabulated list of adverse reactions Adverse reactions are listed by system organ class and frequency: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100) and rare (≥ 1/10,000 to 1/1,000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. 33 Table 2: Tabulated summary of adverse reactions System Organ Class Adverse Reactions Frequency Immune system disorders uncommon hypersensitivity Metabolism and nutrition disorders common increased appetite uncommon weight decreased, weight gain, anorexia Psychiatric disorders common insomnia, abnormal dreams uncommon depression, sleep disorder, disorientation, anxiety Nervous system disorders common headache, dizziness, somnolence, dysgeusia uncommon peripheral neuropathy, syncope, amnesia Eye disorders very common ocular icterus Cardiac disorders uncommon torsades de pointesa rare QTc prolongationa, oedema, palpitation Vascular disorders uncommon hypertension Respiratory, thoracic and mediastinal disorders uncommon dysp

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HOS-216859 · has-contraindication-information · PDF-Seite 3

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1. Co-administration with medicinal products that are strong inducers of the CYP3A4 isoform of cytochrome P450 due to the potential for loss of therapeutic effect and development of possible resistance (see section 4.5); co-administration is contraindicated with, but not limited to, the following medicines:  carbamazepine, phenobarbital, phenytoin (antiepileptics)  St John's wort (Hypericum perforatum) (herbal product)  rifampicin (antimycobacterial)  apalutamide, encorafenib, ivosidenib (antineoplastics) Co-administration with the following medicinal products due to the potential for serious and/or life- threatening adverse reactions (see section 4.5); co-administration is contraindicated with, but not limited to, the following medicines:  colchicine, when used in patients with renal and/or hepatic impairment (antigout) (see section 4.5)  sildenafil - when used for the treatment of pulmonary arterial hypertension (see sections 4.5 and 4.4) for co-administration for the treatment of erectile dysfunction), avanafil (PDE5 inhibitors) 3  dabigatran (anticoagulant)  simvastatin and lovastatin (HMG-CoA reductase inhibitors) (see section 4.5)  lomitapide (lipid-modifying agent)  grazoprevir-containing products, including elbasvir/grazoprevir fixed dose combination (used to treat chronic hepatitis C infection) (see section 4.5)  glecaprevir/pibrentasvir fixed dose combination (see section 4.5)  substrates of CYP3A4 or the UGT1A1 isoform of UDP-glucuronyltransferase and have narrow therapeutic windows; co-administration is contraindicated with, but not limited to, the following medicines:  alfuzosin (alpha-1-adrenoreceptor antagonist)  amiodarone, bepridil, dronedarone, quinidine, systemic lidocaine (antiarrhythmics/antianginals)  astemizole, terfenadine (antihistamines)  cisapride (gastrointestinal motility agent)  ergot derivatives (e.g. dihydroergotamine, ergometrine, ergotamine, methylergonovine)  pimozide, quetiapine, lurasidone (antipsychotics/neuroleptics) (see section 4.5)  ticagrelor (platelet aggregation inhibitor)  triazolam, midazolam administered orally (sedatives/hypnotics) (for caution on

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HOS-216858 · has-indication-information · PDF-Seite 2

EVOTAZ is indicated in combination with other antiretroviral medicinal products for the treatment of HIV-1 infected adults and adolescents (aged 12 years and older weighing at least 35 kg) without known mutations associated with resistance to atazanavir (see sections 4.4 and 5.1).

HOS-216861 · has-interaction-information · PDF-Seite 8

Drug interaction trials were not conducted for EVOTAZ. As EVOTAZ contains atazanavir and cobicistat, any interactions that have been identified with these active substances individually may occur with EVOTAZ. Complex or unknown mechanisms of drug interaction preclude extrapolation of ritonavir drug interactions to certain cobicistat drug interactions. The recommendations given for concomitant use of atazanavir and other medicinal products may, therefore, differ depending on whether atazanavir is boosted with ritonavir or cobicistat. In particular, atazanavir boosted with cobicistat is more sensitive for CYP3A induction (see section 4.3 and the interaction table). Caution is also required during the first time of treatment if switching the pharmacoenhancer from ritonavir to cobicistat (see section 4.4). Medicinal products that affect atazanavir/cobicistat exposure Atazanavir is metabolised in the liver through CYP3A4. Cobicistat is a CYP3A substrate and is metabolised to a minor extent by CYP2D6. 8 Concomitant use contraindicated Co-administration of EVOTAZ with medicinal products that are strong inducers of CYP3A (such as carbamazepine, phenobarbital, phenytoin, rifampicin, apalutamide, encorafenib, ivosidenib and St. John’s wort [Hypericum perforatum]) may result in decreased plasma concentrations of atazanavir and/or cobicistat, leading to loss of therapeutic effect and possible development of resistance to atazanavir (see section 4.3 and Table 1). Concomitant use not recommended Co-administration of EVOTAZ with medicinal products containing ritonavir or cobicistat, which are strong inhibitors of CYP3A, may result in additional boosting and increased plasma concentration of atazanavir. Co-administration of EVOTAZ with medicinal products that inhibit CYP3A may result in increased plasma concentration of atazanavir and/or cobicistat. Some examples include, but are not limited to, itraconazole, ketoconazole and voriconazole (see Table 1). Co-administration of EVOTAZ with medicinal products that are moderate to weak inducers of CYP3A may result in decreased plasma concentration of atazanavir and/or cobicistat, leading to loss of therapeutic effect and possible development of resistance to atazanavir. Some examples include, but are not limited to etravirine, nevirapine, efavirenz, fluticasone and bosentan (see Table 1). Medicinal products that may be affected by atazanavir/cobicistat Atazanavir i

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HOS-216862 · has-pregnancy-information · PDF-Seite 32

Pregnancy EVOTAZ is not recommended during pregnancy nor should it be initiated in pregnant patients; an alternative regimen is recommended (see sections 4.2 and 4.4). This is due to substantially lower exposures of cobicistat and consequently, lower exposures of co-administered antiretroviral agents, including atazanavir, during the second and third trimesters, compared to postpartum. Animal studies with EVOTAZ are insufficient with respect to reproductive toxicity (see section 5.3). 32 Breast-feeding Atazanavir, an active component of EVOTAZ, has been detected in human milk. It is unknown if cobicistat/metabolites are excreted in human milk. Studies in animals have shown excretion of cobicistat/metabolites in milk. Because of both the potential for HIV transmission and the potential for serious adverse reactions in breast-feeding infants, women should be instructed not to breast-feed if they are receiving EVOTAZ. Fertility The effect of EVOTAZ on fertility in humans has not been studied. 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). No human data on the effect of cobicistat on fertility are available. Animal studies do not indicate harmful effects of cobicistat on fertility.

HOS-216860 · has-warning-information · PDF-Seite 4

The choice of EVOTAZ in patients should be based on individual viral resistance testing and the patient’s treatment history (see section 5.1). Pregnancy Treatment with atazanavir/cobicistat 300/150 mg during the second and third trimester has been shown to result in low atazanavir exposure. Cobicistat levels decrease and may not provide sufficient boosting. The substantial reduction in atazanavir exposure may result in virological failure and an increased risk of mother to child transmission of HIV infection. Therefore, therapy with EVOTAZ should not be initiated during pregnancy, and women who become pregnant during therapy with EVOTAZ should be switched to an alternative regimen (see sections 4.2 and 4.6). Patients with co-existing conditions Hepatic impairment The use of EVOTAZ is contraindicated in patients with moderate to severe hepatic impairment. EVOTAZ should be used with caution in patients with mild hepatic impairment (see sections 4.2, 4.3 and 5.2). Atazanavir Atazanavir is primarily hepatically metabolised and increased plasma concentrations were observed in patients with hepatic impairment (see sections 4.2 and 5.2). The safety and efficacy of atazanavir have 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 (see section 4.8). 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. Patients with previous liver dysfunction or patients with 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. 4 Cobicistat Cobicistat has not been studied in patients with severe hepatic impairment (Child-Pugh Class C). Renal impairment EVOTAZ is not recommended in patients undergoing haemodialysis (see sections 4.2 and 5.2). Effects on estimated creatinine clearance Cobicistat has been shown to decrease estimated creatinine clearance due to inhibition of tubular secretion of creatinine. This effect on serum creatinine, leading to a decrease in

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