Biktarvy · 4.1 Therapeutic indications · 1

HOS-098321 · has-adverse-reaction-information · PDF-Seite 13

Summary of the safety profile In clinical studies of treatment-naïve patients receiving Biktarvy, the most frequently reported adverse reactions in the double-blind phase (Week 144) were headache (5%), diarrhoea (5%) and nausea (4%). 13 Tabulated list of adverse reactions The assessment of adverse reactions is based on safety data from across all Phase 2 and 3 studies with Biktarvy and from post-marketing experience. The adverse reactions in Table 2 are listed by system organ class and frequency. Frequencies are defined as follows: common (≥ 1/100 to < 1/10) uncommon (≥ 1/1 000 to < 1/100) and rare (≥ 1/10 000 to < 1/1 000). Table 2: Tabulated list of adverse reactions1 Frequency Adverse reaction Blood and lymphatic system disorders Uncommon: anaemia2 Psychiatric disorders Common: depression, abnormal dreams suicidal ideation, suicide attempt (particularly in patients with a pre-existing history Uncommon: of depression or psychiatric illness), anxiety, sleep disorders Nervous system disorders Common: headache, dizziness Gastrointestinal disorders Common: diarrhoea, nausea Uncommon: vomiting, abdominal pain, dyspepsia, flatulence Hepatobiliary disorders Uncommon: hyperbilirubinaemia Skin and subcutaneous tissue disorders Uncommon: angioedema3,4, rash, pruritus, urticaria4 Rare: Stevens-Johnson syndrome5 Musculoskeletal and connective tissue disorders Uncommon: arthralgia General disorders and administration site conditions Common: Fatigue Investigations Common: weight increased 1 With the exception of angioedema, anaemia, urticaria and Stevens-Johnson syndrome (see footnotes 2-5), all adverse reactions were identified from Biktarvy clinical studies. The frequencies were derived from the double-blind phase (Week 144) of Phase 3 Biktarvy clinical studies in treatment-naïve patients (GS-US-380-1489 and GS-US-380-1490). 2 This adverse reaction was not observed in the clinical studies of emtricitabine + tenofovir alafenamide-containing products but identified from clinical studies or post-marketing experience for emtricitabine when used with other antiretrovirals. 3 This adverse reaction was identified

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HOS-098317 · 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 rifampicin and St. John’s wort (Hypericum perforatum) (see section 4.5). 3

HOS-098316 · has-indication-information · PDF-Seite 2

Biktarvy is indicated for the treatment of human immunodeficiency virus-1 (HIV-1) infection in adults and paediatric patients at least 2 years of age and weighing at least 14 kg without present or past evidence of viral resistance to the integrase inhibitor class, emtricitabine or tenofovir (see section 5.1).

HOS-098319 · has-interaction-information · PDF-Seite 6

Interaction studies have only been performed in adults. Biktarvy should not be administered concomitantly with medicinal products containing tenofovir alafenamide, tenofovir disoproxil, lamivudine or adefovir dipivoxil used for the treatment of HBV infection. Bictegravir Bictegravir is a substrate of CYP3A and UGT1A1. Co-administration of bictegravir and medicinal products that potently induce both CYP3A and UGT1A1, such as rifampicin or St. John’s wort, may significantly decrease plasma concentrations of bictegravir, which may result in a loss of therapeutic effect of Biktarvy and development of resistance, therefore co-administration is contraindicated (see section 4.3). Co-administration of bictegravir with medicinal products that potently inhibit both CYP3A and UGT1A1, such as atazanavir, may significantly increase plasma concentrations of bictegravir, therefore co-administration is not recommended. Bictegravir is both a P-gp and a BCRP substrate. The clinical relevance of this feature is not established. Therefore, caution is recommended when bictegravir is combined with medicinal products known to inhibit P-gp and/or BCRP (e.g. macrolides, ciclosporin, verapamil, dronedarone, glecaprevir/pibrentasvir) (see also table below). Bictegravir inhibits organic cation transporter 2 (OCT2) and multidrug and toxin extrusion transporter 1 (MATE1) in vitro. Co-administration of Biktarvy with the OCT2 and MATE1 substrate metformin did not result in a clinically significant increase in metformin exposure. Biktarvy may be co-administered with substrates of OCT2 and MATE1. Bictegravir is not an inhibitor or inducer of CYP in vivo. Emtricitabine In vitro and clinical pharmacokinetic drug-drug interaction studies have shown that the potential for CYP-mediated interactions involving emtricitabine with other medicinal products is low. Co-administration of emtricitabine with medicinal products that are eliminated by active tubular secretion may increase concentrations of emtricitabine, and/or the co-administered medicinal product. Medicinal products that decrease renal function may increase concentrations of emtricitabine. 6 Tenofovir alafenamide Tenofovir alafenamide is transported by P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Co-administration of Biktarvy with medicinal products that strongly affect P-gp and BCRP activity may lead to changes in tenofovir alafenamide absorption. Medici

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HOS-098320 · has-pregnancy-information · PDF-Seite 13

Pregnancy A large amount of data on pregnant women (more than 1,000 exposed outcomes) indicate no malformative or foeto/neonatal toxicity associated with emtricitabine or tenofovir alafenamide. A moderate amount of data on pregnant women (between 300-1000 pregnancy outcomes) indicate no malformative or foeto/neonatal toxicity associated with bictegravir. Animal studies do not indicate direct or indirect harmful effects of emtricitabine with respect to fertility parameters, pregnancy, foetal development, parturition or postnatal development. Studies of bictegravir and tenofovir alafenamide, administered separately, in animals have shown no evidence of harmful effects on fertility parameters, pregnancy, or foetal development (see section 5.3). In a study performed in pregnant women receiving Biktarvy, exposures of bictegravir, emtricitabine and tenofovir alafenamide were lower during pregnancy (see section 5.2). Therefore, Biktarvy may be used during pregnancy if the potential benefit justifies the potential risk to the foetus. Moreover, viral load should all the more be monitored closely in accordance with established treatment guidelines. Breast-feeding It is not known whether bictegravir is excreted in human milk. Emtricitabine is excreted in human milk. Based on published data, tenofovir alafenamide is excreted in human milk at low levels. The relative infant dose (RID) is estimated to be below 0.1% of the maternal weight-adjusted dose.In animal studies, bictegravir was detected in the plasma of nursing rat pups likely due to the presence of bictegravir in milk, without effects on nursing pups. There is insufficient information on the effects of all the components of Biktarvy in newborns/infants, therefore Biktarvy should not be used during breast-feeding. 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 No human data on the effect of Biktarvy on fertility are available. Animal studies indicate no effects of bictegravir, emtricitabine or tenofovir alafenamide on mating or fertility (see section 5.3).

HOS-098318 · has-warning-information · PDF-Seite 4

Patients co-infected with HIV and hepatitis B or C virus Patients with chronic hepatitis B or C treated with antiretroviral therapy are at an increased risk for severe and potentially fatal hepatic adverse reactions. There are limited safety and efficacy data for Biktarvy in patients co-infected with HIV-1 and hepatitis C virus (HCV). Biktarvy contains tenofovir alafenamide, which is active against hepatitis B virus (HBV). Discontinuation of Biktarvy therapy in patients co-infected with HIV and HBV may be associated with severe acute exacerbations of hepatitis. Patients co-infected with HIV and HBV who discontinue Biktarvy should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. Liver disease The safety and efficacy of Biktarvy in patients with significant underlying liver disorders have not been established. Patients with pre-existing liver dysfunction, including chronic active hepatitis, have an increased frequency of liver function abnormalities during combination antiretroviral therapy (CART) 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. 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 disease control and lifestyle. For lipids and weight, there is in some cases evidence for a treatment effect. For monitoring of blood lipids and glucose, reference is made to established HIV treatment guidelines. Lipid disorders should be managed as clinically appropriate. Mitochondrial dysfunction following exposure in utero Nucleos(t)ide analogues may impact mitochondrial function to a variable degree, which is most pronounced with stavudine, didanosine and zidovudine. There have been reports of mitochondrial dysfunction in HIV negative infants exposed in utero and/or postnatally to nucleoside analogues; these have predominantly concerned treatment with regimens containing zidovudine. The main adverse reactions reported are haematological disorders (anaemia, neutropenia) and metabolic disorders (hyperlactatemia, hyperlipasemia). These events have often been transitory. Late onset neurological disorders have been reported rarely (hypertonia, convulsion, abnormal behaviour). Whether such neurological disorders are transient or per

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