Eviplera · 4.3 Contraindications · 1

HOS-155333 · has-adverse-reaction-information · PDF-Seite 21

Summary of the safety profile The combination of emtricitabine, rilpivirine and tenofovir disoproxil has been studied as the component products in treatment-naïve patients (Phase III studies C209 and C215). The single-tablet regimen (STR), Eviplera, has been studied in virologically suppressed patients who switched from a regimen containing a ritonavir-boosted PI (Phase III study GS-US-264-0106) or from efavirenz/emtricitabine/tenofovir disoproxil (Phase IIb study GS-US-264-0111). In treatment-naïve patients, the most frequently reported adverse reactions considered possibly or probably related to rilpivirine hydrochloride and emtricitabine/tenofovir disoproxil were nausea (9%), dizziness (8%), abnormal dreams (8%), headache (6%), diarrhoea (5%) and insomnia (5%) (pooled data from the Phase III clinical studies C209 and C215, see section 5.1). In virologically suppressed patients switching to Eviplera, the most frequently reported adverse reactions considered possibly or probably related to Eviplera were fatigue (3%), diarrhoea (3%), nausea (2%) and insomnia (2%) (48 week data from the Phase III study GS-US-264-0106). The safety profile of emtricitabine and tenofovir disoproxil in these studies was consistent with the previous experience with these agents when each was administered with other antiretroviral agents. 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 Eviplera (see section 4.4). Discontinuation of Eviplera 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 The adverse reactions considered at least possibly related to treatment with the components of Eviplera from clinical study and post-marketing experience are listed in Table 2, below, by body system organ class and frequency. Within each frequency grouping, undesirable effects are presented 21 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). Table 2: Tabulated summary of adverse reactions to Eviplera based o

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HOS-155329 · has-contraindication-information · PDF-Seite 4

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1. Eviplera should not be co-administered with the following medicinal products as significant decreases in rilpivirine plasma concentrations may occur (due to cytochrome P450 [CYP]3A enzyme induction or gastric pH increase), which may result in loss of therapeutic effect of Eviplera: • the anticonvulsants carbamazepine, oxcarbazepine, phenobarbital, phenytoin • the antimycobacterials rifampicin, rifapentine • proton pump inhibitors, such as omeprazole, esomeprazole, lansoprazole, pantoprazole, rabeprazole • the systemic glucocorticoid dexamethasone, except as a single dose treatment • St. John’s wort (Hypericum perforatum)

HOS-155328 · has-indication-information · PDF-Seite 2

Eviplera is indicated for the treatment of adults infected with human immunodeficiency virus type 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). Genotypic resistance testing and/or historical resistance data should guide the use of Eviplera (see sections 4.4 and 5.1).

HOS-155331 · has-interaction-information · PDF-Seite 8

As Eviplera contains emtricitabine, rilpivirine hydrochloride and tenofovir disoproxil, any interactions that have been identified with these active substances individually may occur with Eviplera. Interaction studies with these active substances have only been performed in adults. Rilpivirine is primarily metabolised by CYP3A Medicinal products that induce or inhibit CYP3A may thus affect the clearance of rilpivirine (see section 5.2). Concomitant use contraindicated Co-administration of Eviplera and medicinal products that induce CYP3A has been observed to decrease the plasma concentrations of rilpivirine which could potentially lead to loss of therapeutic effect of Eviplera (see section 4.3). Co-administration of Eviplera with proton pump inhibitors has been observed to decrease the plasma concentrations of rilpivirine (due to an increase in gastric pH) which could potentially lead to loss of therapeutic effect of Eviplera (see section 4.3). Concomitant use not recommended Eviplera should not be administered concomitantly with other medicinal products containing emtricitabine, tenofovir disoproxil or tenofovir alafenamide. Eviplera should not be administered concomitantly with rilpivirine hydrochloride unless needed for dose adjustment with rifabutin (see section 4.2). Due to similarities with emtricitabine, Eviplera should not be administered concomitantly with other cytidine analogues, such as lamivudine (see section 4.4). Eviplera should not be administered concomitantly with adefovir dipivoxil. Didanosine The co-administration of Eviplera and didanosine is not recommended (see section 4.4 and Table 1). Renally eliminated medicinal products Since emtricitabine and tenofovir are primarily eliminated by the kidneys, co-administration of Eviplera with medicinal products that reduce renal function or compete for active tubular secretion (e.g. cidofovir) may increase serum concentrations of emtricitabine, tenofovir and/or the co-administered medicinal products. Use of Eviplera should be avoided with concurrent or recent use of a nephrotoxic medicinal product. Some examples include, but are not limited to, aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine, vancomycin, cidofovir or interleukin-2 (also called aldesleukin). Other NNRTIs It is not recommended to co-administer Eviplera with other NNRTIs. 8 Concomitant use where caution is recommended Cytochrome P450 enzyme inhi

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HOS-155332 · has-pregnancy-information · PDF-Seite 20

Women of childbearing potential / contraception in males and females The use of Eviplera must be accompanied by the use of effective contraception. Pregnancy There are no adequate and well-controlled studies of Eviplera or its components 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 pregnancy outcomes) indicate no malformative nor 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) with the components of Eviplera. The use of Eviplera may be considered during pregnancy, if necessary. 20 Breast-feeding Emtricitabine and tenofovir disoproxil are excreted in human milk. It is not known whether rilpivirine is excreted in human milk. Rilpivirine is excreted in the milk of rats. There is insufficient information on the effects of Eviplera 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 Eviplera. 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 Eviplera on fertility are available. Animal studies do not indicate harmful effects of emtricitabine, rilpivirine hydrochloride or tenofovir disoproxil on fertility.

HOS-155330 · has-warning-information · PDF-Seite 4

Virologic failure and development of resistance Eviplera has not been evaluated in patients with previous virologic failure to any other antiretroviral therapy. There is not sufficient data to justify the use in patients with prior NNRTI failure. Resistance testing and/or historical resistance data should guide the use of Eviplera (see section 5.1). In the pooled efficacy analysis from the two Phase III clinical studies (C209 [ECHO] and C215 [THRIVE]) through 96 weeks, patients treated with emtricitabine/tenofovir disoproxil + 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 + 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 + 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). Cardiovascular At supratherapeutic doses (75 mg and 300 mg once daily), rilpivirine has been associated with prolongation of the QTc interval of the electrocardiogram (ECG) (see sections 4.5 and 5.1). Rilpivirine at the recommended dose of 25 mg once daily is not associated with a clinically relevant effect on QTc. Eviplera should be used with caution when co-administered with medicinal products with a known risk of Torsade de Pointes. Co-administration of other medicinal products Eviplera should not be administered concomitantly with other medicinal products containing emtricitabine, tenofovir disoproxil, tenofovir alafenamide, or other cytidine analogues, such as lamivudine (see section 4.5). Eviplera should not be administered concomitantly with rilpivirine hydrochloride unless needed for dose adjustment with rifabutin (see sections 4.2 and 4.5). Eviplera should not be administered concomitantly with adefo

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