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.

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.

No dose adjustment of this medicinal product is required in adults or adolescents (aged at least 12 years and of at least 35 kg body weight) with estimated creatinine clearance (CrCl) ≥15 mL/min or in patients with CrCl <15 mL/min who are receiving haemodialysis.

On days of haemodialysis, this medicinal product should be administered after completion of haemodialysis treatment.

No dosing recommendations can be given for patients with CrCl <15 mL/min who are not receiving haemodialysis.

Co-administration is not recommended.

Co-administration is not recommended.

Co-administration is not recommended.

Co-administration is not recommended.

Co-administration is not recommended.

Interaction not studied. Co-administration is not recommended.

There are no data on the safety and efficacy of tenofovir alafenamide in patients co-infected with hepatitis C or D virus. Co-administration guidance for the treatment of hepatitis C should be followed.

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.

HIV antibody testing should be offered to all HBV infected patients whose HIV-1 infection status is unknown before initiating therapy with this medicinal product. In patients who are co-infected with HBV and HIV, tenofovir alafenamide should be co-administered with other antiretroviral medicinal products to ensure that the patient receives an appropriate regimen for treatment of HIV.

No data are available to make dose recommendations in children aged less than 12 years and of less than 35 kg body weight with renal impairment.

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.

The use of tenofovir alafenamide may be considered during pregnancy, if necessary.

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.

Tenofovir alafenamide may have minor influence on the ability to drive and use machines. Patients should be informed that dizziness has been reported during treatment with tenofovir alafenamide.

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.

Tabulated summary of adverse reactions

The following adverse drug reactions have been identified with tenofovir alafenamide in patients with CHB (table). 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).

Adverse drug reactions identified with tenofovir alafenamide:

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 to Week 96 were observed in patients with moderate or severe renal impairment (Part A Cohort 1) and patients with moderate or severe hepatic impairment (Part B), consistent with changes observed in Studies 108 and 110. Small median decreases in total cholesterol, LDL and triglycerides were observed in patients with ESRD on hemodialysis in Part A Cohort 2, while small median increases were observed in HDL from baseline to Week 96. Median (Q1, Q3) change from baseline at Week 96 in total cholesterol to HDL ratio was 0.1 (-0.4, 0.4) in the moderate or severe renal impairment group, and -0.4 (-0.8,-0.1) in patients with ESRD on hemodialysis and 0.1 (-0.2, 0.4) in patients with moderate or severe hepatic impairment.

Metabolic parameters

Body weight and levels of blood lipids and glucose may increase during therapy.

Other special populations

In Study 4035 in virologically suppressed patients with moderate to severe renal impairment (eGFR by Cockcroft-Gault method 15 to 59 mL/min; Part A, Cohort 1, N=78), end stage renal disease (ESRD) (eGFR <15 mL/min) on haemodialysis (Part A, Cohort 2, N=15), and/or moderate to severe hepatic impairment (Child-Pugh Class B or C at screening or by history; Part B, N=31) who switched from another antiviral regimen to tenofovir alafenamide, no additional adverse reactions to tenofovir alafenamide were identified through Week 96.

Paediatric population

The safety of tenofovir alafenamide was evaluated in 88 HBV-infected treatment-naïve and treatmentexperienced paediatric patients between the ages of 12 to <18 years weighing ≥35 kg (tenofovir alafenamide group N=47, placebo group N=23) and 6 to <12 years weighing ≥ 25 kg (tenofovir alafenamide group N=12, placebo group N=6) through Week 24 in a randomised, double-blind, placebo-controlled clinical study GS-US-320-1092 (“Study 1092”). After the double-blind phase, patients were switched to open-label tenofovir alafenamide at Week 24. The safety profile of tenofovir alafenamide in paediatric patients was comparable to that in adults. Reductions in bone mineral density (BMD ≥4%) of the lumbar spine and of whole body have been reported in some paediatric patients 6 years of age and older weighing at least 25 kg who received tenofovir alafenamide for up to 48 weeks.