Efavirenz/Emtricitabine/Tenofovir disoproxil Zentiva · 4.3 Contraindications · 1

HOS-217447 · has-adverse-reaction-information · PDF-Seite 35

Summary of the safety profile The combination of efavirenz, emtricitabine and tenofovir disoproxil has been studied in 460 patients either as the fixed-dose combination tablet containing efavirenz/emtricitabine/tenofovir disoproxil (study AI266073) or as the component products (study GS-01-934). Adverse reactions were generally consistent with those seen in previous studies of the individual components. The most frequently reported adverse reactions considered possibly or probably related to efavirenz/emtricitabine/tenofovir disoproxil among patients treated up to 48 weeks in study AI266073 were psychiatric disorders (16%), nervous system disorders (13%), and gastrointestinal disorders (7%). Severe skin reactions such as Stevens-Johnson syndrome and erythema multiforme; neuropsychiatric adverse reactions (including severe depression, death by suicide, psychosis-like behaviour, seizures); severe hepatic events; pancreatitis and lactic acidosis (sometimes fatal) have been reported. 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 also been reported. Monitoring of renal function is recommended for patients receiving efavirenz/emtricitabine/tenofovir disoproxil (see section 4.4). Discontinuation of efavirenz/emtricitabine/tenofovir disoproxil therapy in patients co-infected with HIV and HBV may be associated with severe acute exacerbations of hepatitis (see section 4.4). The administration of efavirenz/emtricitabine/tenofovir disoproxil with food may increase efavirenz exposure and may lead to an increase in the frequency of adverse reactions (see sections 4.4 and 5.2). Tabulated list of adverse reactions The adverse reactions from clinical study and post-marketing experience with the combination efavirenz/emtricitabine/tenofovir disoproxil and the individual components of the combination efavirenz/emtricitabine/tenofovir disoproxil in antiretroviral combination therapy are listed in Table 2 below by body system organ class, frequency and the component(s) efavirenz/emtricitabine/tenofovir disoproxil to which the adverse reactions are attributable. 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). Adver

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HOS-217443 · has-contraindication-information · PDF-Seite 4

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1. Severe hepatic impairment (CPT, Class C) (see section 5.2). Co-administration with terfenadine, astemizole, cisapride, midazolam, triazolam, pimozide, bepridil, or ergot alkaloids (for example, ergotamine, dihydroergotamine, ergonovine, and methylergonovine). Competition for cytochrome P450 (CYP) 3A4 by efavirenz could result in inhibition of metabolism and create the potential for serious and/or life-threatening adverse reactions (for example, cardiac arrhythmias, prolonged sedation or respiratory depression) (see section 4.5). Co-administration with elbasvir/grazoprevir due to the expected significant decreases in plasma concentrations of elbasvir and grazoprevir. This effect is due to induction of CYP3A4 or P-gp by efavirenz and may result in loss of therapeutic effect of elbasvir/grazoprevir (see section 4.5). Co-administration with voriconazole. Efavirenz significantly decreases voriconazole plasma concentrations while voriconazole also significantly increases efavirenz plasma concentrations. Since Efavirenz/Emtricitabine/Tenofovir disoproxil Zentiva is a fixed-dose combination product, the dose of efavirenz cannot be altered (see section 4.5). Co-administration with herbal preparations containing St. John’s wort (Hypericum perforatum) due to the risk of decreased plasma concentrations and reduced clinical effects of efavirenz (see section 4.5). Administration to patients with: • a family history of sudden death or of congenital prolongation of the QTc interval on electrocardiograms, or with any other clinical condition known to prolong the QTc interval. • a history of symptomatic cardiac arrhythmias or with clinically relevant bradycardia or with congestive cardiac failure accompanied by reduced left ventricle ejection fraction. • severe disturbances of electrolyte balance e.g. hypokalemia or hypomagnesemia. Co-administration with drugs that are known to prolong the QTc interval (proarrhythmic). These drugs include: • antiarrhythmics of classes IA and III, • neuroleptics, antidepressive agents, • certain antibiotics including some agents of the following classes: macrolides, fluoroquinolones, imidazole and triazole antifungal agents, • certain non-sedating antihistamines (terfenadine, astemizole), • cisapride, • flecainide, • certain antimalarials, • methadone (see sections 4.4, 4.5 and 5.1).

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HOS-217442 · has-indication-information · PDF-Seite 2

Efavirenz/Emtricitabine/Tenofovir disoproxil Zentiva is a fixed-dose combination of efavirenz, emtricitabine and tenofovir disoproxil. It is indicated for the treatment of human immunodeficiency virus-1 (HIV-1) infection in adults aged 18 years and over with virologic suppression to HIV-1 RNA levels of < 50 copies/ml on their current combination antiretroviral therapy for more than three months. Patients must not have experienced virological failure on any prior antiretroviral therapy and must be known not to have harboured virus strains with mutations conferring significant resistance to any of the three components contained in Efavirenz/Emtricitabine/Tenofovir disoproxil Zentiva prior to initiation of their first antiretroviral treatment regimen (see sections 4.4 and 5.1). The demonstration of the benefit of the combination efavirenz/emtricitabine/tenofovir disoproxil is primarily based on 48-week data from a clinical study in which patients with stable virologic suppression on a combination antiretroviral therapy changed to efavirenz/emtricitabine/tenofovir disoproxil (see section 5.1). No data are currently available from clinical studies with combination efavirenz/emtricitabine/tenofovir disoproxil in treatment-naïve or in heavily pretreated patients. No data are available to support the combination of efavirenz/emtricitabine/tenofovir disoproxil and other antiretroviral agents.

HOS-217445 · has-interaction-information · PDF-Seite 9

As Efavirenz/Emtricitabine/Tenofovir disoproxil Zentiva contains efavirenz, emtricitabine and tenofovir disoproxil, any interactions that have been identified with these agents individually may occur with Efavirenz/Emtricitabine/Tenofovir disoproxil Zentiva. Interaction studies with these agents have only been performed in adults. As a fixed combination, Efavirenz/Emtricitabine/Tenofovir disoproxil Zentiva should not be administered concomitantly with other medicinal products containing the components, emtricitabine or tenofovir disoproxil. Efavirenz/Emtricitabine/Tenofovir disoproxil Zentiva should not be co-administered with products containing efavirenz unless needed for dose adjustment e.g. with 9 rifampicin (see section 4.2). Due to similarities with emtricitabine, Efavirenz/Emtricitabine/Tenofovir disoproxil Zentiva should not be administered concomitantly with other cytidine analogues, such as lamivudine. Efavirenz/Emtricitabine/Tenofovir disoproxil Zentiva should not be administered concomitantly with adefovir dipivoxil or with medicinal products containing tenofovir alafenamide. Efavirenz is an in vivo inducer of CYP3A4, CYP2B6 and UGT1A1. Compounds that are substrates of these enzymes may have decreased plasma concentrations when co-administered with efavirenz. Efavirenz may be an inducer of CYP2C19 and CYP2C9; however, inhibition has also been observed in vitro and the net effect of co-administration with substrates of these enzymes is not clear (see section 5.2). Co-administration of efavirenz with metamizole, which is an inducer of metabolising enzymes including CYP2B6 and CYP3A4 may cause a reduction in plasma concentrations of efavirenz with potential decrease in clinical efficacy. Therefore, caution is advised when metamizole and efavirenz are administered concurrently; clinical response and/or drug levels should be monitored as appropriate. Efavirenz exposure may be increased when given with medicinal products (for example ritonavir) or food (for example, grapefruit juice) which inhibit CYP3A4 or CYP2B6 activity. Compounds or herbal preparations (for example Ginkgo biloba extracts and St. John’s wort) which induce these enzymes may give rise to decreased plasma concentrations of efavirenz. Concomitant use of St. John’s wort is contraindicated (see section 4.3). Concomitant use of Ginkgo biloba extracts is not recommended (see section 4.4). In vitro and clinical pharmacokinetic inter

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HOS-217446 · has-pregnancy-information · PDF-Seite 34

Women of childbearing potential (see below and section 5.3) Pregnancy should be avoided in women receiving Efavirenz/Emtricitabine/Tenofovir disoproxil Zentiva. Women of childbearing potential should undergo pregnancy testing before initiation of Efavirenz/Emtricitabine/Tenofovir disoproxil Zentiva. Contraception in males and females Barrier contraception should always be used in combination with other methods of contraception (for example, oral or other hormonal contraceptives, see section 4.5) while on therapy with Efavirenz/Emtricitabine/Tenofovir disoproxil Zentiva. Because of the long half-life of efavirenz, use of adequate contraceptive measures for 12 weeks after discontinuation of Efavirenz/Emtricitabine/Tenofovir disoproxil Zentiva is recommended. Pregnancy Efavirenz There have been seven retrospective reports of findings consistent with neural tube defects, including meningomyelocele, all in mothers exposed to efavirenz-containing regimens (excluding any efavirenz- containing fixed-dose combination tablets) in the first trimester. Two additional cases (1 prospective and 1 retrospective) including events consistent with neural tube defects have been reported with the fixed-dose combination tablet containing efavirenz, emtricitabine, and tenofovir disoproxil. A causal relationship of these events to the use of efavirenz has not been established, and the denominator is unknown. As neural tube defects occur within the first 4 weeks of foetal development (at which time neural tubes are sealed), this potential risk would concern women exposed to efavirenz during the first trimester of pregnancy. As of July 2013, the Antiretroviral Pregnancy Registry (APR) has received prospective reports of 904 pregnancies with first trimester exposure to efavirenz-containing regimens, resulting in 766 live births. One child was reported to have a neural tube defect, and the frequency and pattern of other birth defects were similar to those seen in children exposed to non-efavirenz-containing regimens, as well as those in HIV negative controls. The incidence of neural tube defects in the general population ranges from 0.5-1 case per 1,000 live births. Malformations have been observed in foetuses from efavirenz-treated monkeys (see section 5.3). Emtricitabine and tenofovir disoproxil A large amount of data on pregnant women (more than 1000 pregnancy outcomes) indicates no malformations or foetal/neonatal toxicity associated with emtricitabine and tenofovir disoprox

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HOS-217444 · has-warning-information · PDF-Seite 5

Co-administration with other medicinal products As a fixed combination, Efavirenz/Emtricitabine/Tenofovir disoproxil Zentiva should not be administered concomitantly with other medicinal products containing the same active components, emtricitabine or tenofovir disoproxil. Efavirenz/Emtricitabine/Tenofovir disoproxil Zentiva should not be co-administered with products containing efavirenz unless needed for dose adjustment e.g. with rifampicin (see section 4.2). Due to similarities with emtricitabine, Efavirenz/Emtricitabine/Tenofovir disoproxil Zentiva should not be administered concomitantly with other cytidine analogues, such as lamivudine (see section 4.5). Efavirenz/Emtricitabine/Tenofovir disoproxil Zentiva should not be administered concomitantly with adefovir dipivoxil or with medicinal products containing tenofovir alafenamide. Co-administration of efavirenz/emtricitabine/tenofovir disoproxil and didanosine is not recommended (see section 4.5). Co-administration of efavirenz/emtricitabine/tenofovir disoproxil and sofosbuvir/velpatasvir or sofosbuvir/velpatasvir/voxilaprevir is not recommended since plasma concentrations of velpatasvir and voxilaprevir are expected to decrease following co-administration with efavirenz leading to reduced therapeutic effect of sofosbuvir/velpatasvir or sofosbuvir/velpatasvir/voxilaprevir (see section 4.5). No data are available on the safety and efficacy of efavirenz/emtricitabine/tenofovir disoproxil in combination with other antiretroviral agents. Concomitant use of Ginkgo biloba extracts is not recommended (see section 4.5). Switching from a PI-based antiretroviral regimen Currently available data indicate a trend that in patients on a PI-based antiretroviral regimen the switch to efavirenz/emtricitabine/tenofovir disoproxil may lead to a reduction of the response to the therapy (see section 5.1). These patients should be carefully monitored for rises in viral load and, since the safety profile of efavirenz differs from that of protease inhibitors, for adverse reactions. Opportunistic infections Patients receiving efavirenz/emtricitabine/tenofovir disoproxil or any other antiretroviral therapy may continue to develop opportunistic infections and other complications of HIV infection, and therefore should remain under close clinical observation by physicians experienced in the treatment of patients with HIV associated diseases. Effect of food The administration of efavirenz/emtricitabine/tenofovir disopro

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