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Vemlidy 25 mg film-coated tablets.

Each film-coated tablet contains tenofovir alafenamide fumarate equivalent to 25 mg of tenofovir alafenamide.

Excipient with known effect

Each tablet contains 95 mg lactose (as monohydrate).

For the full list of excipients, see section 6.1.

Film-coated tablet.

Yellow, round, film-coated tablets, 8 mm in diameter, debossed with “GSI” on one side of the tablet and “25” on the other side of the tablet.

Vemlidy is indicated for the treatment of chronic hepatitis B in adults and adolescents (aged 12 years and older with body weight at least 35 kg) (see section 5.1).

Therapy should be initiated by a physician experienced in the management of chronic hepatitis B.

Posology

Adults and adolescents (aged 12 years and older with body weight at least 35 kg): one tablet once daily.

Treatment discontinuation

Treatment discontinuation may be considered as follows (see section 4.4):

• In HBeAg-positive patients without cirrhosis, treatment should be administered for at least 6-12 months after HBe seroconversion (HBeAg loss and HBV DNA loss with anti-HBe detection) is confirmed or until HBs seroconversion or until there is loss of efficacy (see section 4.4). Regular reassessment is recommended after treatment discontinuation to detect virological relapse.

• In HBeAg-negative patients without cirrhosis, treatment should be administered at least until HBs seroconversion or until there is evidence of loss of efficacy. With prolonged treatment for more than 2 years, regular reassessment is recommended to confirm that continuing the selected therapy remains appropriate for the patient.

Missed dose

If a dose is missed and less than 18 hours have passed from the time it is usually taken, the patient should take Vemlidy as soon as possible and then resume their normal dosing schedule. If more than 18 hours have passed from the time it is usually taken, the patient should not take the missed dose and should simply resume the normal dosing schedule.

If the patient vomits within 1 hour of taking Vemlidy, the patient should take another tablet. If the patient vomits more than 1 hour after taking Vemlidy, the patient does not need to take another tablet.

Special populations

Elderly

No dose adjustment of Vemlidy is required in patients aged 65 years and older (see section 5.2).

Renal impairment

No dose adjustment of Vemlidy 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, Vemlidy should be administered after completion of haemodialysis treatment (see section 5.2).

No dosing recommendations can be given for patients with CrCl < 15 mL/min who are not receiving haemodialysis (see section 4.4).

Hepatic impairment

No dose adjustment of Vemlidy is required in patients with hepatic impairment (see sections 4.4 and 5.2).

Paediatric population

The safety and efficacy of Vemlidy in children younger than 12 years of age, or weighing < 35 kg, have not yet been established. No data are available.

Method of administration

Oral administration. Vemlidy film-coated tablets should be taken with food.

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

HBV transmission

Patients must be advised that Vemlidy 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.

Patients with decompensated liver disease

There are limited data on the safety and efficacy of Vemlidy 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 chronic hepatitis B 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 hepatitis B, 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 hepatitis B. 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 hepatitis B. 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 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 Vemlidy once daily in patients with CrCl ≥ 15 mL/min and < 30 mL/min is based on Week 24 interim data on the efficacy and safety of switching from another antiviral regimen to tenofovir alafenamide in an ongoing open-label clinical study of virologically suppressed chronic HBV-infected patients (see sections 4.8 and 5.1). There are very limited data on the safety and efficacy of Vemlidy in HBV-infected patients with CrCl < 15 mL/min on chronic haemodialysis (see sections 4.8, 5.1 and 5.2).

The use of Vemlidy is not recommended in patients with CrCl < 15 mL/min who are not receiving haemodialysis (see section 4.2).

Nephrotoxicity

A potential risk of nephrotoxicity resulting from chronic exposure to low levels of tenofovir due to dosing with tenofovir alafenamide cannot be excluded (see section 5.3).

It is recommended that renal function is assessed in all patients prior to, or when initiating, therapy with Vemlidy and that it is also monitored during therapy in all patients as clinically appropriate. In patients who develop clinically significant decreases in renal function, or evidence of proximal renal tubulopathy, discontinuation of Vemlidy should be considered.

Patients co-infected with HBV and hepatitis C or D virus

There are no data on the safety and efficacy of Vemlidy in patients co-infected with hepatitis C or D virus. Co-administration guidance for the treatment of hepatitis C should be followed (see section 4.5).

Hepatitis B and HIV co-infection

HIV antibody testing should be offered to all HBV infected patients whose HIV-1 infection status is unknown before initiating therapy with Vemlidy. In patients who are co-infected with HBV and HIV, Vemlidy should be co-administered with other antiretroviral agents to ensure that the patient receives an appropriate regimen for treatment of HIV (see section 4.5).

Co-administration with other medicinal products

Vemlidy should not be co-administered with medicinal products containing tenofovir alafenamide, tenofovir disoproxil or adefovir dipivoxil.

Co-administration of Vemlidy with certain anticonvulsants (e.g. carbamazepine, oxcarbazepine, phenobarbital and phenytoin), antimycobacterials (e.g. rifampicin, rifabutin and rifapentine) or St. John's wort, all of which are inducers of P-glycoprotein (P-gp) and may decrease tenofovir alafenamide plasma concentrations, is not recommended.

Co-administration of Vemlidy with strong inhibitors of P-gp (e.g. itraconazole and ketoconazole) may increase tenofovir alafenamide plasma concentrations. Co-administration is not recommended.

Lactose intolerance

Vemlidy contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Excipients

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'.

Interaction studies have only been performed in adults.

Vemlidy 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 Vemlidy 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.

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.”; and intravenously as “IV”). 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

a All interaction studies are conducted in healthy volunteers.

b All No Effect Boundaries are 70%-143%.

c Study conducted with emtricitabine/tenofovir alafenamide fixed-dose combination tablet.

d A sensitive CYP3A4 substrate.

e Study conducted with elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide fixed-dose combination tablet.

f Study conducted with emtricitabine/rilpivirine/tenofovir alafenamide fixed-dose combination tablet.

g The predominant circulating nucleoside metabolite of sofosbuvir.

h Study conducted with tenofovir alafenamide 40 mg and emtricitabine 200 mg.

i Study conducted with additional voxilaprevir 100 mg to achieve voxilaprevir exposures expected in HCV infected patients.

Pregnancy

There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of tenofovir alafenamide in pregnant women. However, a large amount of data on pregnant women (more than 1,000 exposed outcomes) indicate no malformative nor feto/neonatal toxicity associated with the use of tenofovir disoproxil.

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

It is not known whether tenofovir alafenamide is secreted in human milk. However, in animal studies it has been shown that tenofovir is secreted into milk. 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.

Vemlidy has no or negligible 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 pooled safety data from 2 controlled Phase 3 studies (GS-US-320-0108 and GS-US-320-0110; “Study 108” and “Study 110”, respectively) in which 866 HBV infected viremic patients with elevated serum ALT levels received 25 mg tenofovir alafenamide once daily in a double-blind fashion through Week 96 (median duration of blinded study drug exposure of 104 weeks) and from post-marketing experience. The most frequently reported adverse reactions were headache (12%), nausea (6%), and fatigue (6%). After Week 96, patients either remained on their original blinded treatment or received open-label tenofovir alafenamide. Changes in lipid laboratory tests were observed in Study 108 and Study 110. No additional adverse reactions to tenofovir alafenamide were identified from Week 96 through Week 144 in the double-blind phase and in the subset of subjects receiving open-label tenofovir alafenamide treatment (see section 5.1).

In an ongoing double-blind, randomized, active-controlled study (GS-US-320-4018; “Study 4018”) in virologically suppressed subjects who switched from tenofovir disoproxil to 25 mg tenofovir alafenamide (N=243), changes in lipid laboratory tests were observed. No additional adverse reactions to tenofovir alafenamide were identified through Week 48.

Tabulated summary of adverse reactions

The following adverse drug reactions have been identified with tenofovir alafenamide in patients with chronic hepatitis B (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 drug reactions identified with

tenofovir alafenamide

1 Adverse reaction identified through post-marketing surveillance for tenofovir alafenamide-containing products.

Changes in lipid laboratory tests

In a pooled analysis of Studies 108 and 110, median changes in fasting lipid parameters from baseline to Week 96 were observed in both treatment groups. In the tenofovir alafenamide group, decreases in median fasting total cholesterol and HDL, and increases in median fasting direct LDL and triglycerides were observed, while the tenofovir disoproxil group demonstrated median reductions in all parameters (see Table 6). In patients randomised initially to tenofovir alafenamide and switched to receive open-label tenofovir alafenamide at Week 96, the median (Q1, Q3) changes from double-blind baseline to Week 144 were as follows (mg/dL): total cholesterol was 0 (-16, 18); LDL was 8 (-6, 24); HDL was -5 (-12, 2); triglycerides were 11 (-11, 40); total cholesterol to HDL ratio was 0.3 (0.0, 0.7). In patients randomised initially to tenofovir disoproxil and switched to open-label tenofovir alafenamide at Week 96, the median (Q1, Q3) changes from double-blind baseline to Week 144 were as follows (mg/dL): total cholesterol was 1 (-17, 20); LDL was 9 (-5, 26); HDL was -8 (-15, -1); triglycerides were 14 (-10, 43); total cholesterol to HDL ratio was 0.4 (0.0, 1.0).

In the open-label phase of Studies 108 and 110, where patients switched to open-label tenofovir alafenamide at Week 96, lipid parameters at Week 144 in patients who remained on tenofovir alafenamide were similar to those at Week 96, whereas median increases in fasting total cholesterol, direct LDL, HDL, and triglycerides were observed in patients who switched from tenofovir disoproxil to tenofovir alafenamide at Week 96. In the open label phase, median (Q1, Q3) change from Week 96 to Week 144 in total cholesterol to HDL ratio was 0.0 (-0.2, 0.4) in patients who remained on tenofovir alafenamide and 0.2 (-0.2, 0.6) in patients who switched from tenofovir disoproxil to tenofovir alafenamide at Week 96.

In Study 4018, median changes in fasting lipid parameters from baseline to Week 48 were observed in both treatment groups. In the group that switched from tenofovir disoproxil to tenofovir alafenamide, increases in median fasting total cholesterol, LDL, HDL, and triglycerides were observed, while the group continuing treatment with tenofovir disoproxil demonstrated reductions in median fasting total cholesterol, HDL, and triglycerides, and a minimal median increase in LDL (p < 0.001 for the difference between treatment groups in all parameters). Median (Q1, Q3) change from baseline at Week 48 in total cholesterol to HDL ratio was 0.2 (-0.1, 0.5) in the tenofovir alafenamide group and 0.0 (-0.3, 0.3) in the tenofovir disoproxil group (p < 0.001 for the difference between treatment groups).

Metabolic parameters

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

Other Special Populations

In an ongoing open-label Phase 2 study (GS-US-320-4035; “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 24.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system:

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard

or search for MHRA Yellow Card in the Google Play or Apple App Store

Ireland

HPRA Pharmacovigilance

Website: www.hpra.ie

Malta

ADR Reporting

Website: www.medicinesauthority.gov.mt/adrportal

If overdose occurs the patient must be monitored for evidence of toxicity (see section 4.8).

Treatment of overdose with tenofovir alafenamide consists of general supportive measures including monitoring of vital signs as well as observation of the clinical status of the patient.

Tenofovir is efficiently removed by haemodialysis with an extraction coefficient of approximately 54%. It is not known whether tenofovir can be removed by peritoneal dialysis.

Pharmacotherapeutic group: Antiviral for systemic use, nucleoside and nucleotide reverse transcriptase inhibitors; ATC code: J05AF13.

Mechanism of action

Tenofovir alafenamide is a phosphonamidate prodrug of tenofovir (2'-deoxyadenosine monophosphate analogue). Tenofovir alafenamide enters primary hepatocytes by passive diffusion and by the hepatic uptake transporters OATP1B1 and OATP1B3. Tenofovir alafenamide is primarily hydrolysed to form tenofovir by carboxylesterase 1 in primary hepatocytes. Intracellular tenofovir is subsequently phosphorylated to the pharmacologically active metabolite tenofovir diphosphate. Tenofovir diphosphate inhibits HBV replication through incorporation into viral DNA by the HBV reverse transcriptase, which results in DNA chain termination.

Tenofovir has activity that is specific to hepatitis B virus and human immunodeficiency virus (HIV-1 and HIV-2). Tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerases that include mitochondrial DNA polymerase γ and there is no evidence of mitochondrial toxicity in vitro based on several assays including mitochondrial DNA analyses.

Antiviral activity

The antiviral activity of tenofovir alafenamide was assessed in HepG2 cells against a panel of HBV clinical isolates representing genotypes A-H. The EC₅₀ (50% effective concentration) values for tenofovir alafenamide ranged from 34.7 to 134.4 nM, with an overall mean EC₅₀ of 86.6 nM. The CC₅₀ (50% cytotoxicity concentration) in HepG2 cells was > 44,400 nM.

Resistance

In patients receiving tenofovir alafenamide, sequence analysis was performed on paired baseline and on-treatment HBV isolates for patients who either experienced virologic breakthrough (2 consecutive visits with HBV DNA ≥ 69 IU/mL after having been < 69 IU/mL, or 1.0 log₁₀ or greater increase in HBV DNA from nadir) or patients with HBV DNA ≥ 69 IU/mL at Week 48, or Week 96 or at early discontinuation at or after Week 24.

In a pooled analysis of patients receiving tenofovir alafenamide in Study 108 and Study 110 at Week 48 (N = 20) and Week 96 (N = 72), no amino acid substitutions associated with resistance to tenofovir alafenamide were identified in these isolates (genotypic and phenotypic analyses).

In virologically suppressed patients receiving tenofovir alafenamide following switch from tenofovir disoproxil treatment in Study 4018, no patient experienced a virologic blip (one visit with HBV DNA ≥ 69 IU/mL), virologic breakthrough or persistent viremia during treatment, and 0 of 243 (0.0%) patients qualified for resistance analysis through 48 weeks of tenofovir alafenamide treatment.

Cross-resistance

The antiviral activity of tenofovir alafenamide was evaluated against a panel of isolates containing nucleos(t)ide reverse transcriptase inhibitor mutations in HepG2 cells. HBV isolates expressing the rtV173L, rtL180M, and rtM204V/I substitutions associated with resistance to lamivudine remained susceptible to tenofovir alafenamide (< 2-fold change in EC₅₀). HBV isolates expressing the rtL180M, rtM204V plus rtT184G, rtS202G, or rtM250V substitutions associated with resistance to entecavir remained susceptible to tenofovir alafenamide. HBV isolates expressing the rtA181T, rtA181V, or rtN236T single substitutions associated with resistance to adefovir remained susceptible to tenofovir alafenamide; however, the HBV isolate expressing rtA181V plus rtN236T exhibited reduced susceptibility to tenofovir alafenamide (3.7-fold change in EC₅₀). The clinical relevance of these substitutions is not known.

Clinical data

The efficacy and safety of tenofovir alafenamide in patients with chronic hepatitis B are based on 48- and 96-week data from two randomised, double-blind, active-controlled studies, Study 108 and Study 110. The safety of tenofovir alafenamide is also supported by pooled data from patients in Studies 108 and 110 who remained on blinded treatment from Week 96 through Week 144 and additionally from patients in the open-label phase of Studies 108 and 110 from Week 96 through Week 144 (N = 360 remained on tenofovir alafenamide; N = 180 switched from tenofovir disoproxil to tenofovir alafenamide at Week 96).

In Study 108, HBeAg-negative treatment-naïve and treatment-experienced patients with compensated liver function were randomised in a 2:1 ratio to receive tenofovir alafenamide (25 mg; N = 285) once daily or tenofovir disoproxil (245 mg; N = 140) once daily. The mean age was 46 years, 61% were male, 72% were Asian, 25% were White and 2% (8 subjects) were Black. 24%, 38%, and 31% had HBV genotype B, C, and D, respectively. 21% were treatment-experienced (previous treatment with oral antivirals, including entecavir (N = 41), lamivudine (N = 42), tenofovir disoproxil (N = 21), or other (N = 18)). At baseline, mean plasma HBV DNA was 5.8 log₁₀ IU/mL, mean serum ALT was 94 U/L, and 9% of patients had a history of cirrhosis.

In Study 110, HBeAg-positive treatment-naïve and treatment-experienced patients with compensated liver function were randomised in a 2:1 ratio to receive tenofovir alafenamide (25 mg; N = 581) once daily or tenofovir disoproxil (245 mg; N = 292) once daily. The mean age was 38 years, 64% were male, 82% were Asian, 17% were White and < 1% (5 subjects) were Black. 17%, 52%, and 23% had HBV genotype B, C, and D, respectively. 26% were treatment-experienced (previous treatment with oral antivirals, including adefovir (N = 42), entecavir (N = 117), lamivudine (N = 84), telbivudine (N = 25), tenofovir disoproxil (N = 70), or other (N = 17)). At baseline, mean plasma HBV DNA was 7.6 log₁₀ IU/mL, mean serum ALT was 120 U/L, and 7% of patients had a history of cirrhosis.

The primary efficacy endpoint in both studies was the proportion of patients with plasma HBV DNA levels below 29 IU/mL at Week 48. Tenofovir alafenamide met the non-inferiority criteria in achieving HBV DNA less than 29 IU/mL when compared to tenofovir disoproxil. Treatment outcomes of Study 108 and Study 110 through Week 48 are presented in Table 3 and Table 4.

Table 3: HBV DNA efficacy parameters at Week 48^a

N/A = not applicable

TDF = tenofovir disoproxil

TAF = tenofovir alafenamide

a Missing = failure analysis.

b Adjusted by baseline plasma HBV DNA categories and oral antiviral treatment status strata.

c Treatment-naïve subjects received < 12 weeks of oral antiviral treatment with any nucleoside or nucleotide analogue including tenofovir disoproxil or tenofovir alafenamide.

d Includes patients who discontinued for reasons other than an adverse event (AE), death or lack or loss of efficacy, e.g. withdrew consent, loss to follow-up, etc.

Table 4: Additional efficacy parameters at Week 48^a

N/A = not applicable

TDF = tenofovir disoproxil

TAF = tenofovir alafenamide

a Missing = failure analysis.

b The population used for analysis of ALT normalisation included only patients with ALT above upper limit of normal (ULN) of the central laboratory range at baseline. Central laboratory ULN for ALT are as follows: ≤ 43 U/L for males aged 18 to < 69 years and ≤ 35 U/L for males ≥ 69 years; ≤ 34 U/L for females 18 to < 69 years and ≤ 32 U/L for females ≥ 69 years.

c The population used for analysis of ALT normalisation included only patients with ALT above ULN of the 2016 American Association of the Study of Liver Diseases (AASLD) criteria (> 30 U/L males and > 19 U/L females) at baseline.

d The population used for serology analysis included only patients with antigen (HBeAg) positive and antibody (HBeAb) negative or missing at baseline.

Experience beyond 48 weeks in Study 108 and Study 110

At Week 96, viral suppression as well as biochemical and serological responses were maintained with continued tenofovir alafenamide treatment (see Table 5).

Table 5: HBV DNA and additional efficacy parameters at Week 96^a

N/A = not applicable

TDF = tenofovir disoproxil

TAF = tenofovir alafenamide

a Missing = failure analysis

b Treatment-naïve subjects received < 12 weeks of oral antiviral treatment with any nucleoside or nucleotide analogue including tenofovir disoproxil or tenofovir alafenamide.

c The population used for analysis of ALT normalisation included only patients with ALT above ULN of the central laboratory range at baseline. Central laboratory ULN for ALT are as follows: ≤ 43 U/L for males aged 18 to < 69 years and ≤ 35 U/L for males ≥ 69 years; ≤ 34 U/L for females 18 to < 69 years and ≤ 32 U/L for females ≥ 69 years.

d The population used for analysis of ALT normalisation included only patients with ALT above ULN of the 2016 AASLD criteria (> 30 U/L males and > 19 U/L females) at baseline.

e The population used for serology analysis included only patients with antigen (HBeAg) positive and antibody (HBeAb) negative or missing at baseline.

Changes in measures of bone mineral density in Study 108 and Study 110

In both studies tenofovir alafenamide was associated with smaller mean percentage decreases in bone mineral density (BMD; as measured by hip and lumbar spine dual energy X ray absorptiometry [DXA] analysis) compared to tenofovir disoproxil after 96 weeks of treatment.

In patients who remained on blinded treatment beyond Week 96, mean percentage change in BMD in each group at Week 144 was similar to that at Week 96. In the open-label phase of both studies, mean percentage change in BMD from Week 96 to Week 144 in patients who remained on tenofovir alafenamide was +0.4% at the lumbar spine and -0.3% at the total hip, compared to +2.0% at the lumbar spine and +0.9% at the total hip in those who switched from tenofovir disoproxil to tenofovir alafenamide at Week 96.

Changes in measures of renal function in Study 108 and Study 110

In both studies tenofovir alafenamide was associated with smaller changes in renal safety parameters (smaller median reductions in estimated CrCl by Cockcroft-Gault and smaller median percentage increases in urine retinol binding protein to creatinine ratio and urine beta-2-microglobulin to creatinine ratio) compared to tenofovir disoproxil after 96 weeks of treatment (see also section 4.4).

In patients who remained on blinded treatment beyond Week 96 in Studies 108 and 110, changes from baseline in renal laboratory parameter values in each group at Week 144 were similar to those at Week 96. In the open-label phase of Studies 108 and 110, the mean (SD) change in serum creatinine from Week 96 to Week 144 was +0.002 (0.0924) mg/dL in those who remained on tenofovir alafenamide, compared to -0.018 (0.0691) mg/dL in those who switched from tenofovir disoproxil to tenofovir alafenamide at Week 96. In the open-label phase, the median change in eGFR from Week 96 to Week 144 was -1.2 mL/min in patients who remained on tenofovir alafenamide, compared to +4.2 mL/min in patients who switched from tenofovir disoproxil to tenofovir alafenamide at Week 96.

Changes in lipid laboratory tests in Study 108 and Study 110

For patients who switched to open label tenofovir alafenamide at Week 96, changes from double-blind baseline for patients randomised initially to tenofovir alafenamide and tenofovir disoproxil at Week 96 and Week 144 in total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides, and total cholesterol to HDL ratio are presented in Table 6.

Table 6: Median changes from double-blind baseline in lipid laboratory tests at Weeks 96 and 144 for patients who switched to open-label tenofovir alafenamide at Week 96

TAF = tenofovir alafenamide

TDF = tenofovir disoproxil

a. P-value was calculated for change from double blind baseline at Week 96, from Wilcoxon Signed Rank test and was statistically significant (p < 0.001).

b. P-value was calculated for change from double blind baseline at Week 144, from Wilcoxon Signed Rank test and was statistically significant (p < 0.001).

Virologically suppressed adult patients in Study 4018

The efficacy and safety of tenofovir alafenamide in virologically suppressed adults with chronic hepatitis B is based on 48-week data from an ongoing randomized, double-blind, active-controlled study, Study 4018.

In Study 4018 virologically suppressed adults with chronic hepatitis B (N=488) were enrolled who had been previously maintained on 245 mg tenofovir disoproxil once daily for at least 12 months, with HBV DNA < lower limit of quantification (LLOQ) by local laboratory assessment for at least 12 weeks prior to screening and HBV DNA < 20 IU/mL at screening. Patients were stratified by HBeAg status (HBeAg-positive or HBeAg-negative) and age (≥ 50 or < 50 years) and randomized in a 1:1 ratio to switch to 25 mg tenofovir alafenamide (N=243) or remain on 245 mg tenofovir disoproxil once daily (N=245). Mean age was 51 years (22% were ≥ 60 years), 71% were male, 82% were Asian, 14% were White, and 68% were HBeAg-negative. At baseline, median duration of prior tenofovir disoproxil treatment was 220 and 224 weeks in the tenofovir alafenamide and tenofovir disoproxil groups, respectively. Previous treatment with antivirals also included interferon (N=63), lamivudine (N=191), adefovir dipivoxil (N=185), entecavir (N=99), telbivudine (N=48), or other (N=23). At baseline, mean serum ALT was 27 U/L, median eGFR by Cockcroft-Gault was 90.5 mL/min; 16% of patients had a history of cirrhosis.

The primary efficacy endpoint was the proportion of patients with plasma HBV DNA levels ≥ 20 IU/mL at Week 48 (as determined by the modified US FDA Snapshot algorithm). Additional efficacy endpoints included the proportion of patients with HBV DNA levels < 20 IU/mL, ALT normal and ALT normalization, HBsAg loss and seroconversion, and HBeAg loss and seroconversion. Tenofovir alafenamide was non-inferior in the proportion of subjects with HBV DNA ≥ 20 IU/mL at Week 48 when compared to tenofovir disoproxil as assessed by the modified US FDA Snapshot algorithm. Treatment outcomes (HBV DNA < 20 IU/mL by missing=failure) at Week 48 between treatment groups were similar across subgroups by age, sex, race, baseline HBeAg status, and ALT.

Treatment outcomes of Study 4018 at Week 48 are presented in Table 7 and Table 8.

Table 7: HBV DNA efficacy parameters at Week 48^a,b

TDF = tenofovir disoproxil

TAF = tenofovir alafenamide

a. Week 48 window was between Day 295 and 378 (inclusive).

b. As determined by the modified US FDA-defined snapshot algorithm.

c. No patient discontinued treatment due to lack of efficacy.

d. Adjusted by baseline age groups (< 50, ≥ 50 years) and baseline HBeAg status strata.

e. Includes patients who discontinued for reasons other than an AE, death or lack of efficacy, e.g., withdrew consent, loss to follow-up, etc.

Table 8: Additional efficacy parameters at Week 48^a

TDF = tenofovir disoproxil

TAF = tenofovir alafenamide

a. Missing = failure analysis

b. The population used for analysis of ALT normalization included only patients with ALT above upper limit of normal (ULN) of the central laboratory range (> 43 U/L males 18 to < 69 years and > 35 U/L males ≥ 69 years; > 34 U/L females 18 to < 69 years and > 32 U/L females ≥ 69 years) at baseline.

c. Proportion of patients at Week 48: TAF, 16/32; TDF, 7/19.

d. The population used for analysis of ALT normalization included only patients with ALT above ULN of the 2018 American Association of the Study of Liver Diseases (AASLD) criteria (35 U/L males and 25 U/L females) at baseline.

e. Proportion of patients at Week 48: TAF, 26/52; TDF, 14/53.

f. The population used for serology analysis included only patients with antigen (HBeAg) positive and anti-body (HBeAb) negative or missing at baseline.

Changes in bone mineral density in Study 4018

The mean percentage change in BMD from baseline to Week 48 as assessed by DXA was +1.7% with tenofovir alafenamide compared to −0.1% with tenofovir disoproxil at the lumbar spine and +0.7% compared to −0.5% at the total hip. BMD declines of greater than 3% at the lumbar spine were experienced by 4% of tenofovir alafenamide patients and 17% of tenofovir disoproxil patients at Week 48. BMD declines of greater than 3% at the total hip were experienced by 2% of tenofovir alafenamide patients and 12% of tenofovir disoproxil patients at Week 48.

Changes in renal laboratory tests in Study 4018

The median change from baseline to Week 48 in eGFR by Cockcroft-Gault method was +0.9 mL per minute in the tenofovir alafenamide group and −2.7 mL per minute in those receiving tenofovir disoproxil. At Week 48, there was a median increase from baseline in serum creatinine among patients randomized to continue treatment with tenofovir disoproxil (0.02 mg/dL) compared with no median change from baseline among those who were switched to tenofovir alafenamide (0.00 mg/dL). Further, median percentage decreases from baseline were observed in the tenofovir alafenamide group at Week 48 in urine retinol binding protein to creatinine ratio and urine beta-2-microglobulin to creatinine ratio, compared with median percentage increases from baseline for both of these renal parameters in the tenofovir disoproxil group.

Changes in lipid laboratory tests in Study 4018

Changes from baseline to Week 48 in total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides, and total cholesterol to HDL ratio among subjects treated with tenofovir alafenamide and tenofovir disoproxil are presented in Table 9.

Table 9: Median changes in lipid laboratory tests at Week 48

TDF = tenofovir disoproxil

TAF = tenofovir alafenamide

a. P-value was calculated for the difference between the TAF and TDF groups, from Wilcoxon Rank Sum test and was statistically significant (p < 0.001) for median changes (Q1, Q3) from baseline in total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides and total cholesterol to HDL ratio.

Renal and/or hepatic impairment Study 4035

Study 4035 is an ongoing open-label clinical study to evaluate the efficacy and safety of switching from another antiviral regimen to tenofovir alafenamide in virologically suppressed chronic HBV-infected patients. Part A of the study includes patients with moderate to severe renal impairment (eGFR by Cockcroft-Gault method between 15 and 59 mL/min; Cohort 1, N = 78) or ESRD (eGFR by Cockcroft-Gault method < 15 mL/min) on hemodialysis (Cohort 2, N = 15). Part B of the study includes patients (N = 31) with moderate to severe hepatic impairment (Child-Pugh Class B or C at screening or a history of CPT score ≥ 7 with any CPT score ≤ 12 at screening). The final clinical and laboratory outcomes will be reported following study completion at Week 96.

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with Vemlidy in one or more subsets of the paediatric population in the treatment of chronic hepatitis B (see sections 4.2 and 5.2 for information on paediatric use).

Absorption

Following oral administration of tenofovir alafenamide under fasted conditions in adult patients with chronic hepatitis B, peak plasma concentrations of tenofovir alafenamide were observed approximately 0.48 hours post-dose. Based on Phase 3 population pharmacokinetic analysis in subjects with chronic hepatitis B, mean steady state AUC_0-24 for tenofovir alafenamide (N = 698) and tenofovir (N = 856) were 0.22 µg•h/mL and 0.32 µg•h/mL, respectively. Steady state C_max for tenofovir alafenamide and tenofovir were 0.18 and 0.02 µg/mL, respectively. Relative to fasting conditions, the administration of a single dose of tenofovir alafenamide with a high fat meal resulted in a 65% increase in tenofovir alafenamide exposure.

Distribution

The binding of tenofovir alafenamide to human plasma proteins in samples collected during clinical studies was approximately 80%. The binding of tenofovir to human plasma proteins is less than 0.7% and is independent of concentration over the range of 0.01-25 µg/mL.

Biotransformation

Metabolism is a major elimination pathway for tenofovir alafenamide in humans, accounting for > 80% of an oral dose. In vitro studies have shown that tenofovir alafenamide is metabolised to tenofovir (major metabolite) by carboxylesterase-1 in hepatocytes; and by cathepsin A in peripheral blood mononuclear cells (PBMCs) and macrophages. In vivo, tenofovir alafenamide is hydrolysed within cells to form tenofovir (major metabolite), which is phosphorylated to the active metabolite, tenofovir diphosphate.

In vitro, tenofovir alafenamide is not metabolised by CYP1A2, CYP2C8, CYP2C9, CYP2C19, or CYP2D6. Tenofovir alafenamide is minimally metabolised by CYP3A4.

Elimination

Renal excretion of intact tenofovir alafenamide is a minor pathway with < 1% of the dose eliminated in urine. Tenofovir alafenamide is mainly eliminated following metabolism to tenofovir. Tenofovir alafenamide and tenofovir have a median plasma half-life of 0.51 and 32.37 hours, respectively. Tenofovir is renally eliminated from the body by the kidneys by both glomerular filtration and active tubular secretion.

Linearity/non-linearity

Tenofovir alafenamide exposures are dose proportional over the dose range of 8 to 125 mg.

Pharmacokinetics in special populations

Age, gender and ethnicity

No clinically relevant differences in pharmacokinetics according to age or ethnicity have been identified. Differences in pharmacokinetics according to gender were not considered to be clinically relevant.

Hepatic impairment

In patients with severe hepatic impairment, total plasma concentrations of tenofovir alafenamide and tenofovir are lower than those seen in subjects with normal hepatic function. When corrected for protein binding, unbound (free) plasma concentrations of tenofovir alafenamide in severe hepatic impairment and normal hepatic function are similar.

Renal impairment

No clinically relevant differences in tenofovir alafenamide or tenofovir pharmacokinetics were observed between healthy subjects and patients with severe renal impairment (estimated CrCl > 15 but < 30 mL/min) in studies of tenofovir alafenamide (Table 10).

Exposures of tenofovir in subjects with ESRD (estimated creatinine clearance < 15 mL/min) on chronic haemodialysis who received tenofovir alafenamide (N = 5) were substantially higher than in subjects with normal renal function (Table 10). No clinically relevant differences in tenofovir alafenamide pharmacokinetics were observed in patients with ESRD on chronic haemodialysis as compared to those with normal renal function.

Table 10: Pharmacokinetics of tenofovir alafenamide and its metabolite tenofovir in subjects with renal impairment as compared to subjects with normal renal function

CV = coefficient of variation

a. By Cockcroft-Gault method.

b. PK assessed on a single dose of TAF 25 mg in subjects with normal renal function and in subjects with severe renal impairment in Study GS-US-120-0108.

c. PK assessed prior to haemodialysis following multiple-dose administration of TAF 25 mg in 5 HBV-infected subjects in Study GS-US-320-4035. These subjects had a median baseline eGFR by Cockcroft-Gault of 7.2 mL/min (range, 4.8 to 12.0).

d. AUC_inf.

e. AUC_last.

f. AUC_tau.

Paediatric population

The pharmacokinetics of tenofovir alafenamide and tenofovir were evaluated in HIV-1 infected, treatment-naïve adolescents who received tenofovir alafenamide (10 mg) given with elvitegravir, cobicistat and emtricitabine as a fixed-dose combination tablet (E/C/F/TAF; Genvoya). No clinically relevant differences in tenofovir alafenamide or tenofovir pharmacokinetics were observed between adolescent and adult HIV-1 infected subjects.

Non-clinical studies in rats and dogs revealed bone and kidney as the primary target organs of toxicity. Bone toxicity was observed as reduced BMD in rats and dogs at tenofovir exposures at least four times greater than those expected after administration of tenofovir alafenamide. A minimal infiltration of histiocytes was present in the eye in dogs at tenofovir alafenamide and tenofovir exposures of approximately 4 and 17 times greater, respectively, than those expected after administration of tenofovir alafenamide.

Tenofovir alafenamide was not mutagenic or clastogenic in conventional genotoxic assays.

Because there is a lower tenofovir exposure in rats and mice after tenofovir alafenamide administration compared to tenofovir disoproxil, carcinogenicity studies and a rat peri-postnatal study were conducted only with tenofovir disoproxil. No special hazard for humans was revealed in conventional studies of carcinogenic potential with tenofovir disoproxil (as fumarate) and toxicity to reproduction and development with tenofovir disoproxil (as fumarate) or tenofovir alafenamide. Reproductive toxicity studies in rats and rabbits showed no effects on mating, fertility, pregnancy or foetal parameters. However, tenofovir disoproxil reduced the viability index and weight of pups in a peri-postnatal toxicity study at maternally toxic doses. A long-term oral carcinogenicity study in mice showed a low incidence of duodenal tumours, considered likely related to high local concentrations in the gastrointestinal tract at the high dose of 600 mg/kg/day. The mechanism of tumour formation in mice and potential relevance for humans is uncertain.

Tablet core

Lactose monohydrate

Microcrystalline cellulose (E460(i))

Croscarmellose sodium (E468)

Magnesium stearate (E470b)

Film-coating

Polyvinyl alcohol (E1203)

Titanium dioxide (E171)

Macrogol (E1521)

Talc (E553b)

Iron oxide yellow (E172)

Not applicable.

4 years.

Store in the original package in order to protect from moisture. Keep the bottle tightly closed.

Vemlidy tablets are packaged in high density polyethylene (HDPE) bottles and enclosed with a polypropylene continuous-thread, child-resistant cap, lined with an induction-activated aluminium foil liner. Each bottle contains silica gel desiccant and polyester coil.

The following pack sizes are available: outer cartons containing 1 bottle of 30 film-coated tablets and outer cartons containing 90 (3 bottles of 30) film-coated tablets.

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Gilead Sciences Ireland UC

Carrigtohill

County Cork, T45 DP77

Ireland

EU/1/16/1154/001

EU/1/16/1154/002

Date of first authorisation: 09 January 2017

09/2020

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.