Emtricitabine/Tenofovir disoproxil Krka d.d. · 4.4 Special warnings and precautions for use · 1

HOS-287259 · has-adverse-reaction-information · PDF-Seite 19

Summary of the safety profile The most frequently reported adverse reactions considered possibly or probably related to emtricitabine and/or tenofovir disoproxil were nausea (12%) and diarrhoea (7%) in an open-label randomised clinical study in adults (GS-01-934, see section 5.1). The safety profile of emtricitabine and tenofovir disoproxil in this study was consistent with the previous experience with these agents when each was administered with other antiretroviral agents. Tabulated summary of adverse reactions The adverse reactions considered at least possibly related to treatment with the tenofovir disoproxil and emtricitabine from clinical study and post-marketing experience in HIV-1 infected patients are listed in Table 3, below, by body system organ class and frequency. 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). Table 3: Tabulated summary of adverse reactions associated with tenofovir disoproxil and emtricitabine based on clinical study and post-marketing experience Frequency Emtricitabine Tenofovir disoproxil Blood and lymphatic system disorders: Common: neutropenia Uncommon: anaemia2 Immune system disorders: Common: allergic reaction Metabolism and nutrition disorders: Very common: hypophosphataemia1 19 Common: hyperglycaemia, hypertriglyceridaemia Uncommon: hypokalaemia1 Rare: lactic acidosis Psychiatric disorders: Common: insomnia, abnormal dreams Nervous system disorders: Very common: headache dizziness Common: dizziness headache Gastrointestinal disorders: Very common: diarrhoea, nausea diarrhoea, vomiting, nausea Common: elevated amylase including elevated abdominal pain, abdominal

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HOS-287255 · has-contraindication-information · PDF-Seite 3

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.

HOS-287254 · has-indication-information · PDF-Seite 2

Emtricitabine/Tenofovir disoproxil Krka d.d. is indicated in antiretroviral combination therapy for the treatment of HIV-1 infected adults (see section 5.1). Emtricitabine/Tenofovir disoproxil Krka d.d. is also indicated for the treatment of HIV-1 infected adolescents, with NRTI resistance or toxicities precluding the use of first line agents (see section 4.2, 4.4 and 5.1).

HOS-287257 · has-interaction-information · PDF-Seite 9

Interaction studies have only been performed in adults. As Emtricitabine/Tenofovir disoproxil Krka d.d. contains emtricitabine and tenofovir disoproxil, any interactions that have been identified with these agents individually may occur with Emtricitabine/Tenofovir disoproxil Krka d.d.. Interaction studies have only been performed in adults. The steady-state pharmacokinetics of emtricitabine and tenofovir were unaffected when emtricitabine and tenofovir disoproxil were administered together versus each medicinal product dosed alone. In vitro and clinical pharmacokinetic interaction studies have shown the potential for CYP450 mediated interactions involving emtricitabine and tenofovir disoproxil with other medicinal products is low. Concomitant use not recommended Emtricitabine/Tenofovir disoproxil Krka d.d. should not be administered concomitantly with other medicinal products containing emtricitabine, tenofovir disoproxil, tenofovir alafenamide or other cytidine analogues, such as lamivudine (see section 4.4). Emtricitabine/Tenofovir disoproxil Krka d.d. should not be administered concomitantly with adefovir dipivoxil. Didanosine: The co-administration of Emtricitabine/Tenofovir disoproxil Krka d.d. and didanosine is not recommended (see section 4.4 and Table 2). Renally eliminated medicinal products: Since emtricitabine and tenofovir are primarily eliminated by the kidneys, co-administration of Emtricitabine/Tenofovir disoproxil Krka d.d. 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 Emtricitabine/Tenofovir disoproxil Krka d.d. 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 (see section 4.4). Other interactions Interactions between emtricitabine/tenofovir disoproxil or its individual component(s) and other medicinal products are listed in Table 2 below (increase is indicated as “↑”, decrease as “↓”, no change as “↔”, twice daily as “b.i.d.” and once daily as “q.d.”). If available, 90% confidence intervals are shown in parentheses. Table 2: Interactions between the individual components of emtricitabine/tenofovir disoproxil and other medicinal products Medicinal product by therape

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HOS-287258 · has-pregnancy-information · PDF-Seite 18

Pregnancy A large amount of data on pregnant women (more than 1 000 pregnancy outcomes) indicate no malformations or foetal/neonatal toxicity associated with emtricitabine and tenofovir disoproxil. 18 Animal studies on emtricitabine and tenofovir disoproxil do not indicate reproductive toxicity (see section 5.3). Therefore the use of Emtricitabine/Tenofovir disoproxil Krka d.d. may be considered during pregnancy, if necessary. Breast-feeding Emtricitabine and tenofovir have been shown to be excreted in human milk. There is insufficient information on the effects of emtricitabine and tenofovir in newborns/infants. Therefore Emtricitabine/Tenofovir disoproxil Krka d.d. 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 emtricitabine/tenofovir disoproxil are available. Animal studies do not indicate harmful effects of emtricitabine or tenofovir disoproxil on fertility.

HOS-287256 · has-warning-information · PDF-Seite 3

Patients with HIV-1 harbouring mutations 3 Emtricitabine/Tenofovir disoproxil Krka d.d. should be avoided in antiretroviral-experienced patients with HIV-1 harbouring the K65R mutation (see section 5.1). Patients with hepatitis B or C virus infection HIV-1 infected patients with chronic hepatitis B or C treated with antiretroviral therapy are at an increased risk for severe and potentially fatal hepatic adverse reactions. Physicians should refer to current HIV treatment guidelines for the management of HIV infection in patients co-infected with hepatitis B virus (HBV) or hepatitis C virus (HCV). In case of concomitant antiviral therapy for hepatitis B or C, please refer also to the relevant Summary of Product Characteristics for these medicinal products. See also under Use with ledipasvir and sofosbuvir or sofosbuvir and velpatasvir below. Tenofovir disoproxil is indicated for the treatment of HBV and emtricitabine has shown activity against HBV in pharmacodynamic studies but the safety and efficacy of emtricitabine/tenofovir disoproxil have not been specifically established in patients with chronic HBV infection. Discontinuation of Emtricitabine/Tenofovir disoproxil Krka d.d. therapy in patients infected with HBV may be associated with severe acute exacerbations of hepatitis. Patients infected with HBV who discontinue Emtricitabine/Tenofovir disoproxil Krka d.d. should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. If appropriate, resumption of hepatitis B therapy may be warranted. In patients with advanced liver disease or cirrhosis, treatment discontinuation is not recommended since post-treatment exacerbation of hepatitis may lead to hepatic decompensation. Liver disease The safety and efficacy of emtricitabine/tenofovir disoproxil have not been established in patients with significant underlying liver disorders. The pharmacokinetics of tenofovir has been studied in patients with hepatic impairment and no dose adjustment is required. The pharmacokinetics of emtricitabine has not been studied in patients with hepatic impairment. Based on minimal hepatic metabolism and the renal route of elimination for emtricitabine, it is unlikely that a dose adjustment would be required for Emtricitabine/Tenofovir disoproxil Krka d.d. in patients with hepatic impairment (see sections 4.2 and 5.2). HIV-1infected patients with pre-existin

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