elvitegravir;cobicistat;emtricitabine;tenofovir disoproxil fumarate

HOS-216214 · has-adverse-reaction-information · PDF-Seite 22

Summary of the safety profile The most frequently reported adverse reactions considered possibly or probably related to Stribild in clinical studies through 144 weeks in treatment-naïve adult patients were nausea (16%) and diarrhoea (12%). The most frequently reported adverse reactions to Stribild in clinical studies through 48 weeks in virologically-suppressed adult patients were nausea (3% to 5%) and fatigue (6%). In patients receiving tenofovir disoproxil, rare events of renal impairment, renal failure and uncommon events of proximal renal tubulopathy (including Fanconi syndrome) sometimes leading to bone abnormalities (infrequently contributing to fractures) have been reported. Monitoring of renal function is recommended for patients receiving Stribild (see section 4.4). Discontinuation of Stribild therapy in patients co-infected with HIV and HBV may be associated with severe acute exacerbations of hepatitis (see section 4.4). Tabulated summary of adverse reactions Adverse reactions to Stribild from Phase 3 clinical studies GS-US-236-0102 and GS-US-236-0103 and adverse reactions to treatment with emtricitabine and tenofovir disoproxil from clinical studies and post-marketing experience, when used with other antiretrovirals, are listed in Table 2, below, by body system organ class and highest frequency observed. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Frequencies are defined as very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100) or rare (≥ 1/10,000 to < 1/1,000). 22 Table 2: Tabulated summary of adverse reactions associated with Stribild based on experience from Phase 3 studies GS-US-236-0102 and GS-US-236-0103 and adverse reactions to treatment with emtricitabine and tenofovir disoproxil from clinical studies and post-marketing experience, when used with other antiretrovirals Frequency Adverse reaction Blood and lymphatic system disorders: Common: neutropenia1 Uncommon: anaemia1,2 Immune system disorders: Common: allergic reaction1 Metabolism and nutrition disorders: Very common: hypophosphataemia1,3 Common: hyperglycaemia1, hypertriglyceridaemia1, decreased appetite Uncommon: hypokalaemia1,3 Rare: lactic acidosis1 Psychiatric disorders: Common:

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HOS-216210 · has-contraindication-information · PDF-Seite 3

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1. Patients who have previously discontinued treatment with tenofovir disoproxil due to renal toxicity, with or without reversal of the effects post-discontinuation. Co-administration is contraindicated with medicinal products that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events. Therefore, Stribild should not be co-administered with medicinal products that include, but are not limited to, the following (see section 4.5): • alpha 1-adrenoreceptor antagonists: alfuzosin • antiarrhythmics: amiodarone, quinidine • ergot derivatives: dihydroergotamine, ergometrine, ergotamine • gastrointestinal motility agents: cisapride • HMG Co-A reductase inhibitors: lovastatin, simvastatin 3 • neuroleptics/antipsychotics: pimozide, lurasidone • PDE-5 inhibitors: sildenafil for treatment of pulmonary arterial hypertension • sedatives/hypnotics: orally administered midazolam, triazolam Co-administration is contraindicated with medicinal products that are strong inducers of CYP3A due to the potential for loss of virologic response and possible resistance to Stribild. Therefore, Stribild should not be co-administered with medicinal products that include, but are not limited to, the following (see section 4.5): • anticonvulsants: carbamazepine, phenobarbital, phenytoin • antimycobacterials: rifampicin • herbal products: St. John’s wort (Hypericum perforatum) Co-administration with dabigatran etexilate, a P-glycoprotein (P-gp) substrate, is contraindicated (see section 4.5).

HOS-216209 · has-indication-information · PDF-Seite 2

Stribild is indicated for the treatment of human immunodeficiency virus-1 (HIV-1) infection in adults aged 18 years and over who are antiretroviral treatment-naïve or are infected with HIV-1 without known mutations associated with resistance to any of the three antiretroviral agents in Stribild (see sections 4.2, 4.4 and 5.1). Stribild is also indicated for the treatment of HIV-1 infection in adolescents aged 12 to < 18 years weighing ≥ 35 kg who are infected with HIV-1 without known mutations associated with resistance to any of the three antiretroviral agents in Stribild and who have experienced toxicities which preclude the use of other regimens that do not contain tenofovir disoproxil (see sections 4.2, 4.4 and 5.1).

HOS-216212 · has-interaction-information · PDF-Seite 9

As Stribild contains elvitegravir, cobicistat, emtricitabine and tenofovir disoproxil, any interactions that have been identified with these active substances individually may occur with Stribild. Stribild is indicated for use as a complete regimen for the treatment of HIV-1 infection and must not be administered with other antiretroviral products. Therefore, information regarding drug-drug interactions with other antiretroviral products (including protease inhibitors and non-nucleoside reverse transcriptase inhibitors) is not provided (see section 4.4). Interaction studies have only been performed in adults. Cobicistat is a strong mechanism-based CYP3A inhibitor and a CYP3A substrate. Cobicistat is also a weak CYP2D6 inhibitor and is metabolised, to a minor extent, by CYP2D6. The transporters that cobicistat inhibits include P-gp, BCRP, OATP1B1 and OATP1B3. Co-administration of Stribild with medicinal products that are primarily metabolised by CYP3A or CYP2D6, or are substrates of P-gp, BCRP, OATP1B1 or OATP1B3 may result in increased plasma concentrations of those products, which could increase or prolong their therapeutic effect and adverse reactions (see Concomitant use contraindicated and section 4.3). Co-administration of Stribild with medicinal products that have active metabolite(s) formed by CYP3A may result in reduced plasma concentrations of these active metabolite(s). Co-administration of Stribild with medicinal products that inhibit CYP3A may decrease the clearance of cobicistat, resulting in increased cobicistat plasma concentrations. Elvitegravir is a modest inducer and may have the potential to induce CYP2C9 and/or inducible UGT enzymes; as such it may decrease the plasma concentration of substrates of these enzymes. Elvitegravir is metabolised by CYP3A and, to a minor extent, by UGT1A1. Medicinal products that induce CYP3A activity are expected to increase the clearance of elvitegravir, resulting in decreased plasma concentration of elvitegravir which may lead to loss of therapeutic effect of Stribild and development of resistance (see Concomitant use contraindicated and section 4.3). Concomitant use contraindicated Co-administration of Stribild and some medicinal products that are primarily metabolised by CYP3A may result in increased plasma concentrations of these products, which are associated with the potential for serious and/or life-threatening reactions such as peripheral vasospasm or ischaemia (e.g., dihydroergotamine, ergota

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HOS-216213 · has-pregnancy-information · PDF-Seite 21

Women of childbearing potential / contraception in males and females The use of Stribild must be accompanied by the use of effective contraception (see section 4.5). Pregnancy There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of Stribild in pregnant women. However, a large amount of data in pregnant women (more than1,000 pregnancy outcomes) indicate no malformations or foetal/neonatal toxicity associated with emtricitabine and tenofovir disoproxil. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). Treatment with cobicistat and elvitegravir during the second and third trimesters of pregnancy has been shown to result in lower elvitegravir exposure (see section 5.2). Cobicistat levels decrease and may not provide sufficient boosting. The substantial reduction in elvitegravir exposure may result in virological failure and an increased risk of mother-to-child transmission of HIV infection. Therefore, 21 therapy with Stribild should not be initiated during pregnancy, and women who become pregnant during therapy with Stribild should be switched to an alternative regimen (see section 4.4). Breast-feeding It is not known whether elvitegravir or cobicistat are excreted in human milk. Emtricitabine and tenofovir have been shown to be excreted in human milk. In animal studies it has been shown that elvitegravir, cobicistat and tenofovir are excreted in milk. There is insufficient information on the effects of elvitegravir, cobicistat, emtricitabine and tenofovir disoproxil in newborns/infants. Therefore Stribild 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 Stribild on fertility are available. Animal studies do not indicate harmful effects of elvitegravir, cobicistat, emtricitabine or tenofovir disoproxil on fertility.

HOS-216211 · has-warning-information · PDF-Seite 4

Renal and bone effects in adults Renal effects Emtricitabine and tenofovir are primarily excreted by the kidneys by a combination of glomerular filtration and active tubular secretion. Renal failure, renal impairment, elevated creatinine, hypophosphataemia and proximal tubulopathy (including Fanconi syndrome) have been reported with the use of tenofovir disoproxil (see section 4.8). There are currently inadequate data to determine whether co-administration of tenofovir disoproxil and cobicistat is associated with a greater risk of renal adverse reactions compared with regimens that include tenofovir disoproxil without cobicistat. Patients who have previously discontinued treatment with tenofovir disoproxil due to renal toxicity, with or without reversal of the effects post-discontinuation, should not be treated with Stribild (see section 4.3). Renal monitoring Before initiating treatment with Stribild Creatinine clearance should be calculated and urine glucose and urine protein should be determined in all patients. Stribild should not be initiated in patients with creatinine clearance < 70 mL/min. It is recommended that Stribild is not initiated in patients with creatinine clearance < 90 mL/min unless, after review of the available treatment options, it is considered that Stribild is the preferred treatment for the individual patient. During treatment with Stribild Creatinine clearance, serum phosphate, urine glucose and urine protein should be monitored every four weeks during the first year and then every three months during Stribild therapy. In patients at risk for renal impairment a more frequent monitoring of renal function is required. Cobicistat inhibits the tubular secretion of creatinine and may cause modest increases in serum creatinine and modest declines in creatinine clearance (see section 4.8). Patients who experience a confirmed increase in serum creatinine of greater than 26.5 µmol/L (0.3 mg/dL) from baseline should be closely monitored for renal safety. See also under Co-administration of other medicinal products below. Renal management If serum phosphate is < 0.48 mmol/L (1.5 mg/dL) or creatinine clearance is decreased to < 70 mL/min, renal function should be re-evaluated within one week, including measurements of blood glucose, 4 blood potassium and urine glucose concentrations (see section 4.8). It is recommended that Stribild is discontinued in patients with creatinine clearan

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