Odefsey · 4.1 Therapeutic indications · 1

HOS-217315 · has-adverse-reaction-information · PDF-Seite 17

Summary of the safety profile The most frequently reported adverse reactions in clinical studies of treatment-naïve patients taking emtricitabine + tenofovir alafenamide in combination with elvitegravir + cobicistat were nausea (11%), diarrhoea (7%), and headache (6%). The most frequently reported adverse reactions in clinical studies of treatment-naïve patients taking rilpivirine hydrochloride in combination with emtricitabine + tenofovir disoproxil fumarate were nausea (9%), dizziness (8%), abnormal dreams (8%), headache (6%), diarrhoea (5%) and insomnia (5%). Tabulated summary of adverse reactions Assessment of adverse reactions is based on safety data from across all Phase 2 and 3 studies in which patients received emtricitabine + tenofovir alafenamide given with elvitegravir + cobicistat as a fixed-dose combination tablet, pooled data from patients who received rilpivirine 25 mg once daily in combination with other antiretroviral medicinal products in the controlled studies TMC278-C209 and TMC278-C215, patients who received Odefsey in Studies GS-US-366-1216 and GS-US-366-1160, and post-marketing experience. The adverse reactions in Table 2 are listed by system organ class and highest frequency observed. Frequencies are defined as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10) or uncommon (≥ 1/1,000 to < 1/100). 17 Table 2: Tabulated list of adverse reactions Frequency Adverse reaction Blood and lymphatic system disorders Common: decreased white blood cell count1, decreased haemoglobin1, decreased platelet count1 Uncommon: anaemia2 Immune system disorders Uncommon: immune reactivation syndrome1 Metabolism and nutrition disorders Very common: increased total cholesterol (fasted)1, increased LDL-cholesterol (fasted)1 Common: decreased appetite1, increased triglycerides (fasted)1 Psychiatric disorders Very common: insomnia1 Common: depression1, abnormal dreams1, 3, sleep disorders1, depressed mood1 Nervous system disorders Very common: headache1, 3, dizziness1, 3 Common: somnolence1 Gastrointestinal disorders Very common: nausea1, 3, increased pancreatic amylase1 abdominal pain1, 3, vomiting1, 3, increased lipase1, abdominal discomfort1, dry Common:

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HOS-217311 · has-contraindication-information · PDF-Seite 3

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1. Odefsey should not be co-administered with medicinal products that can result in significant decreases in rilpivirine plasma concentrations (due to cytochrome P450 [CYP]3A enzyme induction or gastric pH increase), which may result in loss of therapeutic effect of Odefsey (see section 4.5), including: • carbamazepine, oxcarbazepine, phenobarbital, phenytoin • rifabutin, rifampicin, rifapentine • omeprazole, esomeprazole, dexlansoprazole, lansoprazole, pantoprazole, rabeprazole • dexamethasone (oral and parenteral doses), except as a single dose treatment • St. John’s wort (Hypericum perforatum)

HOS-217310 · has-indication-information · PDF-Seite 2

Odefsey is indicated for the treatment of adults and adolescents (aged 12 years and older with body weight at least 35 kg) infected with human immunodeficiency virus-1 (HIV-1) without known mutations associated with resistance to the non-nucleoside reverse transcriptase inhibitor (NNRTI) class, tenofovir or emtricitabine and with a viral load ≤ 100,000 HIV-1 RNA copies/mL (see sections 4.2, 4.4 and 5.1).

HOS-217313 · has-interaction-information · PDF-Seite 6

Odefsey is indicated for use as a complete regimen for the treatment of HIV-1 infection and should not be co-administered with other antiretroviral medicinal products. Therefore, information regarding drug-drug interactions with other antiretroviral medicinal products is not provided. Interaction studies have only been performed in adults. 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 Rilpivirine Rilpivirine is primarily metabolised by CYP3A. Medicinal products that induce or inhibit CYP3A may thus affect the clearance of rilpivirine (see section 5.2). Rilpivirine inhibits P-glycoprotein (P-gp) in vitro (50% inhibitory concentration [IC50] is 9.2 µM). In a clinical study, rilpivirine did not significantly affect the pharmacokinetics of digoxin. Additionally, in a clinical drug-drug interaction study with tenofovir alafenamide, which is more sensitive to intestinal P-gp inhibition, rilpivirine did not affect tenofovir alafenamide exposures when administered concurrently, indicating that rilpivirine is not a P-gp inhibitor in vivo. Rilpivirine is an in vitro inhibitor of the transporter MATE-2K with an IC50 of < 2.7 nM. The clinical implications of this finding are currently unknown. Tenofovir alafenamide Tenofovir alafenamide is transported by P-gp and breast cancer resistance protein (BCRP). Medicinal products that affect P-gp and BCRP activity may lead to changes in tenofovir alafenamide absorption (see Table 1). Medicinal products that induce P-gp activity (e.g., rifampicin, rifabutin, carbamazepine, phenobarbital) are expected to decrease the absorption of tenofovir alafenamide, resulting in decreased plasma concentration of tenofovir alafenamide, which may lead to loss of therapeutic effect of Odefsey and development of resistance. Co-administration of Odefsey with other medicinal products that inhibit P-gp and BCRP activity (e.g., ketoconazole, fluconazole, itraconazole, posaconazole, voriconazole, ciclosporin) is expected to increase the absorption

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HOS-217314 · has-pregnancy-information · PDF-Seite 16

Women of childbearing potential/contraception in males and females The use of Odefsey should be accompanied by the use of effective contraception. Pregnancy There are no adequate and well-controlled studies of Odefsey or its components in pregnant women. There is a limited amount of data (less than 300 pregnancy outcomes) from the use of tenofovir alafenamide in pregnant women. A moderate amount of data on pregnant women (between 300-1,000 pregnancy outcomes) indicate no malformative or foetal/neonatal toxicity of rilpivirine (see sections 4.4, 5.1 and 5.2). Lower exposures of rilpivirine were observed during pregnancy; therefore viral load should be monitored closely. A large amount of data on pregnant women (more than 1,000 exposed outcomes) indicate no malformative nor foetal/neonatal toxicity associated with emtricitabine. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3) with the components of Odefsey. Odefsey should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus. Breast-feeding Emtricitabine is excreted in human milk. It is not known whether rilpivirine or tenofovir alafenamide are excreted in human milk. In animal studies it has been shown that tenofovir is excreted in milk. Rilpivirine is excreted in the milk of rats. There is insufficient information on the effects of all the components of Odefsey in newborns/infants. Because of the potential for adverse reactions in breastfed infants, women should be instructed not to breast-feed if they are receiving Odefsey. 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 Odefsey on fertility are available. Animal studies do not indicate harmful effects of emtricitabine, rilpivirine hydrochloride or tenofovir alafenamide on fertility (see section 5.3).

HOS-217312 · has-warning-information · PDF-Seite 3

Virologic failure and development of resistance There are insufficient data to justify the use in patients with prior NNRTI failure. Resistance testing and/or historical resistance data should guide the use of Odefsey (see section 5.1). 3 In the pooled efficacy analysis from the two Phase 3 clinical studies in adults (C209 [ECHO] and C215 [THRIVE]) through 96 weeks, patients treated with emtricitabine/tenofovir disoproxil fumarate + rilpivirine with a baseline viral load > 100,000 HIV-1 RNA copies/mL had a greater risk of virologic failure (17.6% with rilpivirine versus 7.6% with efavirenz) compared to patients with a baseline viral load ≤ 100,000 HIV-1 RNA copies/mL (5.9% with rilpivirine versus 2.4% with efavirenz). The virologic failure rate in patients treated with emtricitabine/tenofovir disoproxil fumarate + rilpivirine at Week 48 and Week 96 was 9.5% and 11.5% respectively, and 4.2% and 5.1% in the emtricitabine/tenofovir disoproxil fumarate + efavirenz arm. The difference in the rate of new virologic failures from the Week 48 to Week 96 analysis between rilpivirine and efavirenz arms was not statistically significant. Patients with a baseline viral load > 100,000 HIV-1 RNA copies/mL who experienced virologic failure exhibited a higher rate of treatment-emergent resistance to the NNRTI class. More patients who failed virologically on rilpivirine than who failed virologically on efavirenz developed lamivudine/emtricitabine associated resistance (see section 5.1). Findings in adolescents (12 to less than 18 years of age) in Study C213 were generally in line with these data (for details see section 5.1). Only adolescents deemed likely to have good adherence to antiretroviral therapy should be treated with rilpivirine, as suboptimal adherence can lead to development of resistance and the loss of future treatment options. Cardiovascular At supratherapeutic doses (75 mg once daily and 300 mg once daily), rilpivirine has been associated with prolongation of the QTc interval of the electrocardiogram (ECG) (see sections 4.5 and 4.9). Rilpivirine at the recommended dose of 25 mg once daily is not associated with a clinically relevant effect on QTc. Odefsey should be used with caution when co-administered with medicinal products with a known risk of Torsade de Pointes. Patients co-infected with HIV and hepatitis B or C virus Patients with chronic hepatitis B or C treated with antiretroviral therapy ar

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