Vemlidy

HOS-097799 · has-adverse-reaction-information · PDF-Seite 11

Summary of the safety profile Assessment of adverse reactions is based on clinical study data and postmarketing data. In pooled safety data from 2 controlled Phase 3 studies (GS-US-320-0108 and GS-US-320-0110; “Study 108” and “Study 110”, respectively), the most frequently reported adverse reactions at Week 96 analysis were headache (12%), nausea (6%), and fatigue (6%). After Week 96, patients either remained on their original blinded treatment up to Week 144 or received open-label tenofovir alafenamide. The safety profile of tenofovir alafenamide was similar in virologically suppressed patients switching from tenofovir disoproxil to tenofovir alafenamide in Study 108, Study 110 and a controlled Phase 3 study GS-US-320-4018 (“Study 4018”). Changes in lipid laboratory tests were observed in these studies following a switch from tenofovir disoproxil (see section 5.1). 11 Tabulated summary of adverse reactions The following adverse reactions have been identified with tenofovir alafenamide in patients with CHB (Table 2). The adverse reactions are listed below by body system organ class and frequency based on the Week 96 analysis. Frequencies are defined as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10) or uncommon (≥ 1/1,000 to < 1/100). Table 2: Adverse Reactions Identified with Tenofovir Alafenamide System organ class Frequency Adverse reaction Nervous system disorders Very common Headache Common Dizziness Gastrointestinal disorders Common Diarrhoea, vomiting, nausea, abdominal pain, abdominal distension, flatulence Hepatobiliary disorders Common Increased ALT Skin and subcutaneous tissue disorders Common Rash, pruritus Uncommon Angioedema1, urticaria1 Musculoskeletal and connective tissue disorders Common Arthralgia General disorders and administration site conditions Common Fatigue 1 Adverse reaction identified through post-marketing surveillance for tenofovir alafenamide-containing products. In the open-label Phase 2 study (GS-US-320-4035; “Study 4035”) to evaluate the efficacy and safety of switching from another antiviral regimen to tenofovir alafenamide in virologically suppressed HBV infected patients, small median increases in fasting total cholesterol, direct low density lipoprotein (LDL), high density lipoprotein (HDL), and triglycerides from baseline

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HOS-097795 · has-contraindication-information · PDF-Seite 3

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

HOS-097794 · has-indication-information · PDF-Seite 2

Vemlidy is indicated for the treatment of chronic hepatitis B (CHB) in adults and paediatric patients 6 years of age and older weighing at least 25 kg (see section 5.1).

HOS-097797 · has-interaction-information · PDF-Seite 5

Interaction studies have only been performed in adults. This medicinal product should not be co-administered with medicinal products containing tenofovir disoproxil, tenofovir alafenamide or adefovir dipivoxil. Medicinal products that may affect tenofovir alafenamide Tenofovir alafenamide is transported by P-gp and breast cancer resistance protein (BCRP). Medicinal products that are P-gp inducers (e.g., rifampicin, rifabutin, carbamazepine, phenobarbital or St. John’s wort) are expected to decrease plasma concentrations of tenofovir alafenamide, which may lead to loss of therapeutic effect of Vemlidy. Co-administration of such medicinal products with tenofovir alafenamide is not recommended. 5 Co-administration of tenofovir alafenamide with medicinal products that inhibit P-gp and BCRP may increase plasma concentrations of tenofovir alafenamide. Co-administration of strong inhibitors of P-gp with tenofovir alafenamide is not recommended. Tenofovir alafenamide is a substrate of OATP1B1 and OATP1B3 in vitro. The distribution of tenofovir alafenamide in the body may be affected by the activity of OATP1B1 and/or OATP1B3. Effect of tenofovir alafenamide on other medicinal products Tenofovir alafenamide is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6 in vitro. It is not an inhibitor or inducer of CYP3A in vivo. Tenofovir alafenamide is not an inhibitor of human uridine diphosphate glucuronosyltransferase (UGT) 1A1 in vitro. It is not known whether tenofovir alafenamide is an inhibitor of other UGT enzymes. Drug interaction information for Vemlidy with potential concomitant medicinal products is summarised in Table 1 below (increase is indicated as “↑”, decrease as “↓”, no change as “↔”; twice daily as “b.i.d.”, single dose as “s.d.”, once daily as “q.d.”). The drug interactions described are based on studies conducted with tenofovir alafenamide, or are potential drug interactions that may occur with Vemlidy. Table 1: Interactions Between Vemlidy and Other Medicinal Products Medicinal product by Effects on drug levels.a,b Recommendation concerning co-administration therapeutic areas Mean ratio (90% with Vemlidy confidence interval) for AUC, Cmax, Cmin ANTICONVULSANTS Carbamazepine Tenofovir alafenamide Co-administration is not recommended. (300 mg orally, b.i.d.)

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HOS-097798 · has-pregnancy-information · PDF-Seite 11

Pregnancy A moderate amount of data on pregnant women exposed to tenofovir alafenamide (between 300-1000 pregnancy outcomes) indicate no malformative or feto/neonatal toxicity. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). The use of tenofovir alafenamide may be considered during pregnancy, if necessary. Breast-feeding Based on published data, tenofovir alafenamide and tenofovir are excreted in human milk at low levels in women administered with tenofovir alafenamide. There is insufficient information on the effects of tenofovir in newborns/infants. A risk to the breast-fed newborns/infants cannot be excluded; therefore, tenofovir alafenamide should not be used during breast-feeding. Fertility No human data on the effect of tenofovir alafenamide on fertility are available. Animal studies do not indicate harmful effects of tenofovir alafenamide on fertility.

HOS-097796 · has-warning-information · PDF-Seite 3

Hepatitis B Virus (HBV) transmission Patients must be advised that this medicinal product does not prevent the risk of transmission of HBV to others through sexual contact or contamination with blood. Appropriate precautions must continue to be used. 3 Patients with decompensated liver disease There are limited data on the safety and efficacy of tenofovir alafenamide in HBV infected patients with decompensated liver disease and who have a Child Pugh Turcotte (CPT) score > 9 (i.e. class C). These patients may be at higher risk of experiencing serious hepatic or renal adverse reactions. Therefore, hepatobiliary and renal parameters should be closely monitored in this patient population (see section 5.2). Exacerbation of hepatitis Flares on treatment Spontaneous exacerbations in CHB are relatively common and are characterised by transient increases in serum alanine aminotransferase (ALT). After initiating antiviral therapy, serum ALT may increase in some patients. In patients with compensated liver disease, these increases in serum ALT are generally not accompanied by an increase in serum bilirubin concentrations or hepatic decompensation. Patients with cirrhosis may be at a higher risk for hepatic decompensation following hepatitis exacerbation, and therefore should be monitored closely during therapy. Flares after treatment discontinuation Acute exacerbation of hepatitis has been reported in patients who have discontinued treatment for CHB, usually in association with rising HBV DNA levels in plasma. The majority of cases are self-limited but severe exacerbations, including fatal outcomes, may occur after discontinuation of treatment for CHB. Hepatic function should be monitored at repeated intervals with both clinical and laboratory follow-up for at least 6 months after discontinuation of treatment for CHB. If appropriate, resumption of CHB 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 flares are especially serious, and sometimes fatal in patients with decompensated liver disease. Renal impairment Patients with creatinine clearance < 30 mL/min The use of tenofovir alafenamide once daily in patients with CrCl ≥ 15 mL/min and < 30 mL/min is based on Week 96 data on the efficacy and safety of switching from another antiviral regim

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