Tenofovir disoproxil Zentiva · 4.5 Interaction with other medicinal products and other forms of interaction · 1

HOS-217275 · has-adverse-reaction-information · PDF-Seite 27

Summary of the safety profile HIV-1 and hepatitis B: 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 Tenofovir disoproxil Zentiva (see section 4.4). HIV-1: Approximately one third of patients can be expected to experience adverse reactions following treatment with tenofovir disoproxil in combination with other antiretroviral agents. These reactions are usually mild to moderate gastrointestinal events. Approximately 1% of tenofovir disoproxil -treated adult patients discontinued treatment due to the gastrointestinal events. Hepatitis B: Approximately one quarter of patients can be expected to experience adverse reactions following treatment with tenofovir disoproxil, most of which are mild. In clinical trials of HBV infected patients, the most frequently occurring adverse reaction to tenofovir disoproxil was nausea (5.4%). Acute exacerbation of hepatitis has been reported in patients on treatment as well as in patients who have discontinued hepatitis B therapy (see section 4.4). Tabulated summary of adverse reactions Assessment of adverse reactions for tenofovir disoproxil is based on safety data from clinical studies 27 and post-marketing experience. All adverse reactions are presented in Table 2. HIV-1 clinical studies: Assessment of adverse reactions from HIV-1 clinical study data is based on experience in two studies in 653 treatment-experienced patients receiving treatment with tenofovir disoproxil (n = 443) or placebo (n = 210) in combination with other antiretroviral medicinal products for 24 weeks and also in a double-blind comparative controlled study in which 600 treatment-naïve patients received treatment with tenofovir disoproxil 245 mg (n = 299) or stavudine (n = 301) in combination with lamivudine and efavirenz for 144 weeks. Hepatitis B clinical studies: Assessment of adverse reactions from HBV clinical study data is primarily based on experience in two double-blind comparative controlled studies in which 641 adult patients with chronic hepatitis B and compensated liver disease received treatment with tenofovir disoproxil 245 mg daily (n = 426) or adefovir dipivoxil 10 mg daily (n = 215) for 48 we

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HOS-217271 · has-contraindication-information · PDF-Seite 6

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

HOS-217270 · has-indication-information · PDF-Seite 2

HIV-1 infection Tenofovir disoproxil Zentiva is indicated in combination with other antiretroviral medicinal products for the treatment of HIV-1 infected adults. In adults, the demonstration of the benefit of tenofovir disoproxil in HIV-1 infection is based on results of one study in treatment-naïve patients, including patients with a high viral load (> 100,000 copies/ml) and studies in which tenofovir disoproxil was added to stable background therapy (mainly tritherapy) in antiretroviral pre-treated patients experiencing early virological failure (< 10,000 copies/ml, with the majority of patients having < 5,000 copies/ml). Tenofovir disoproxil Zentiva is also indicated for the treatment of HIV-1 infected adolescents, with NRTI resistance or toxicities precluding the use of first line agents, aged 12 to < 18 years. The choice of Tenofovir disoproxil Zentiva to treat antiretroviral-experienced patients with HIV-1 infection should be based on individual viral resistance testing and/or treatment history of patients. 2 Hepatitis B infection Tenofovir disoproxil Zentiva is indicated for the treatment of chronic hepatitis B in adults with: - compensated liver disease, with evidence of active viral replication, persistently elevated serum alanine aminotransferase (ALT) levels and histological evidence of active inflammation and/or fibrosis (see section 5.1). - evidence of lamivudine-resistant hepatitis B virus (see sections 4.8 and 5.1). - decompensated liver disease (see sections 4.4, 4.8 and 5.1). Tenofovir disoproxil Zentiva is indicated for the treatment of chronic hepatitis B in adolescents 12 to < 18 years of age with: - compensated liver disease and evidence of immune active disease, i.e. active viral replication and persistently elevated serum ALT levels, or histological evidence of moderate to severe inflammation and/or fibrosis. With respect to the decision to initiate treatment in paediatric patients, see sections 4.2, 4.4, 4.8 and 5.1.

HOS-217273 · has-interaction-information · PDF-Seite 11

Interaction studies have only been performed in adults. Based on the results of in vitro experiments and the known elimination pathway of tenofovir, the potential for CYP450 mediated interactions involving tenofovir with other medicinal products is low. Concomitant use not recommended Tenofovir disoproxil Zentiva should not be administered concomitantly with other medicinal products containing tenofovir disoproxil or tenofovir alafenamide. Tenofovir disoproxil Zentiva should not be administered concomitantly with adefovir dipivoxil. Didanosine Co-administration of tenofovir disoproxil and didanosine is not recommended (see section 4.4 and Table 1). Renally eliminated medicinal products Since tenofovir is primarily eliminated by the kidneys, co-administration of tenofovir disoproxil with medicinal products that reduce renal function or compete for active tubular secretion via transport proteins hOAT 1, hOAT 3 or MRP 4 (e.g. cidofovir) may increase serum concentrations of tenofovir and/or the co-administered medicinal products. Use of tenofovir disoproxil 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). Given that tacrolimus can affect renal function, close monitoring is recommended when it is co-administered with tenofovir disoproxil. Other interactions Interactions between tenofovir disoproxil and other medicinal products are listed in Table 1 below (increase is indicated as “↑”, decrease as “↓”, no change as “↔”, twice daily as “b.i.d.”, and once daily as “q.d.”). 11 Table 1: Interactions between tenofovir disoproxil and other medicinal products Medicinal product by Effects on drug levels Recommendation therapeutic areas Mean percent change in AUC, Cmax, concerning (dose in mg) Cmin co-administration with 245 mg tenofovir disoproxil ANTI-INFECTIVES Antiretrovirals Protease inhibitors Atazanavir/Ritonavir Atazanavir: No dose adjustment is (300 mg q.d./100 mg q.d.) AUC: ↓ 25% recommended. The

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HOS-217274 · has-pregnancy-information · PDF-Seite 26

Pregnancy A large amount of data on pregnant women (more than 1,000 pregnancy outcomes) indicate no malformations or foetal/neonatal toxicity associated with tenofovir disoproxil. Animal studies do not indicate reproductive toxicity (see section 5.3). The use of tenofovir disoproxil may be considered during pregnancy, if necessary. 26 In the literature, exposure to tenofovir disoproxil in the third trimester of pregnancy has been shown to reduce the risk of HBV transmission from mother to infant if tenofovir disoproxil is given to mothers, in addition to hepatitis B immune globulin and hepatitis B vaccine in infants. In three controlled clinical trials, a total of 327 pregnant women with chronic HBV infection were administered tenofovir disoproxil (245 mg) once daily from 28 to 32 weeks gestation through 1 to 2 months postpartum; women and their infants were followed for up to 12 months after delivery. No safety signal has emerged from these data. Breast-feeding Generally, if the newborn is adequately managed for hepatitis B prevention at birth, a mother with hepatitis B may breast-feed her infant. Tenofovir is excreted in human milk at very low levels and exposure of infants through breast milk is considered negligible. Although long-term data is limited, no adverse reactions have been reported in breast-fed infants, and HBV-infected mothers using tenofovir disoproxil may breast-feed. 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 There are limited clinical data with respect to the effect of tenofovir disoproxil on fertility. Animal studies do not indicate harmful effects of tenofovir disoproxil on fertility.

HOS-217272 · has-warning-information · PDF-Seite 6

General HIV antibody testing should be offered to all HBV infected patients before initiating tenofovir disoproxil therapy (see below Co-infection with HIV-1 and hepatitis B). Hepatitis B Patients must be advised that tenofovir disoproxil has not been proven to prevent the risk of transmission of HBV to others through sexual contact or contamination with blood. Appropriate precautions must continue to be used. Co-administration of other medicinal products - Tenofovir disoproxil Zentiva should not be administered concomitantly with other medicinal products containing tenofovir disoproxil or tenofovir alafenamide. - Tenofovir disoproxil Zentiva should not be administered concomitantly with adefovir dipivoxil. - Co-administration of tenofovir disoproxil and didanosine is not recommended (see section 4.5). Triple therapy with nucleosides/nucleotides There have been reports of a high rate of virological failure and of emergence of resistance at an early stage in HIV patients when tenofovir disoproxil was combined with lamivudine and abacavir as well as with lamivudine and didanosine as a once daily regimen. Renal and bone effects in adult population Renal effects Tenofovir is principally eliminated via the kidney. Renal failure, renal impairment, elevated creatinine, hypophosphataemia and proximal tubulopathy (including Fanconi syndrome) have been reported with the use of tenofovir disoproxil in clinical practice (see section 4.8). Renal monitoring It is recommended that creatinine clearance is calculated in all patients prior to initiating therapy with tenofovir disoproxil and renal function (creatinine clearance and serum phosphate) is also monitored after two to four weeks of treatment, after three months of treatment and every three to six months thereafter in patients without renal risk factors. In patients at risk for renal impairment, a more frequent monitoring of renal function is required. Renal management If serum phosphate is < 1.5 mg/dl (0.48 mmol/l) or creatinine clearance is decreased to < 50 ml/min in any adult patient receiving tenofovir disoproxil, renal function should be re-evaluated within one week, including measurements of blood glucose, blood potassium and urine glucose concentrations (see section 4.8, proximal tubulopathy). Consideration should also be given to interrupting treatment with tenofovir disoproxil in adult patients with creatinine clearance decreased to < 50 ml/min or decreases in serum phosphate to < 1.0

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