Tenofovir alafenamide

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT TENOFOVIR ALAFENAMIDE (Tenofovir alafenamide)

Composition:

Active substance: tenofovir alafenamide;

One film-coated tablet contains tenofovir alafenamide fumarate 28.043 mg, equivalent to tenofovir alafenamide 25 mg;

Excipients: lactose monohydrate; microcrystalline cellulose; sodium croscarmellose; magnesium stearate; film coating: Opadry II White 85F18422 (partially hydrolyzed polyvinyl alcohol, titanium dioxide (E 171), macrogol, talc).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: round, biconvex, film-coated tablet, white to almost white, with the imprint «M» on one side and «TFI» on the other side.

Pharmacotherapeutic group. Antiviral agents for systemic use. Direct-acting antiviral agents. Nucleoside and nucleotide reverse transcriptase inhibitors. ATC code J05AF13.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Tenofovir alafenamide is a phosphonamidate prodrug of tenofovir (a 2'-deoxyadenosine monophosphate analog). Tenofovir alafenamide initially enters hepatocytes via passive diffusion and uptake by hepatic transporters OATP1B1 and OATP1B3. Tenofovir alafenamide is primarily hydrolyzed to tenofovir by carboxylesterase 1 in primary hepatocytes. Intracellular tenofovir is subsequently phosphorylated to the pharmacologically active metabolite tenofovir diphosphate. Tenofovir diphosphate inhibits hepatitis B virus (HBV) replication by incorporation into viral DNA by HBV reverse transcriptase, resulting in DNA chain termination.

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

Antiviral activity

The antiviral activity of tenofovir alafenamide was evaluated in HepG2 cells against a panel of clinical isolates of HBV representing genotypes A–H. The EC50 (50% effective concentration) values of tenofovir alafenamide ranged from 34.7 to 134.4 nM, with an overall mean EC50 of 86.6 nM. The CC50 (50% cytotoxic 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 from patients who experienced virologic breakthrough (two consecutive visits with HBV DNA ≥ 69 IU/mL after having been < 69 IU/mL, or a 1.0 log10 or greater increase in HBV DNA from nadir), or from patients with HBV DNA ≥ 69 IU/mL at week 48 or 96, or at early discontinuation at week 24 or later.

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

In patients with virologic suppression who switched to tenofovir alafenamide from tenofovir disoproxil fumarate in study 4018, no patient experienced virologic flare (one visit with HBV DNA ≥ 69 IU/mL), virologic breakthrough, or persistent viremia during treatment, and 0 of 243 (0.0%) patients met criteria for resistance analysis during 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 substitutions rtV173L, rtL180M, and rtM204V/I, associated with lamivudine resistance, remained sensitive to tenofovir alafenamide (< 2-fold change in EC50). HBV isolates expressing substitutions rtL180M, rtM204V plus rtT184G, rtS202G, or rtM250V, associated with entecavir resistance, remained sensitive to tenofovir alafenamide. HBV isolates expressing single substitutions rtA181T, rtA181V, or rtN236T, associated with adefovir resistance, remained sensitive to tenofovir alafenamide; however, an HBV isolate expressing rtA181V plus rtN236T showed reduced sensitivity to tenofovir alafenamide (3.7-fold change in EC50). The clinical significance of these substitutions is unknown.

Pharmacokinetics.

Absorption

Following oral administration of tenofovir alafenamide under fasting conditions in adult patients with chronic hepatitis B, peak plasma concentrations of tenofovir alafenamide were observed approximately 0.48 hours after dosing. Based on population pharmacokinetic analysis from phase 3 studies in patients with chronic hepatitis B, the mean AUC0–24 at steady state for tenofovir alafenamide (N = 698) and tenofovir (N = 856) was 0.22 µg•h/mL and 0.32 µg•h/mL, respectively. The maximum concentration (Cmax) of tenofovir alafenamide and tenofovir at steady state was 0.18 µg/mL and 0.02 µg/mL, respectively. Administration of a single dose of tenofovir alafenamide with a high-fat meal increased exposure to tenofovir alafenamide by 65%.

Distribution

Plasma protein binding of tenofovir alafenamide in human plasma samples collected during clinical studies was approximately 80%. Plasma protein binding of tenofovir is less than 0.7% and is independent of concentration within the range of 0.01–25 µg/mL.

Biological transformation

Metabolism is the major route of elimination of tenofovir alafenamide in humans, accounting for > 80% of the oral dose. In vitro studies showed that tenofovir alafenamide is metabolized to tenofovir (the major metabolite) by carboxylesterase-1 in hepatocytes and cathepsin A in peripheral blood mononuclear cells and macrophages. In vivo, tenofovir alafenamide is hydrolyzed intracellularly to form tenofovir (the major metabolite), which is then phosphorylated to the active metabolite tenofovir diphosphate.

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

Elimination

Renal excretion of intact tenofovir alafenamide is a minor pathway, with < 1% of the dose excreted in urine. Tenofovir alafenamide is primarily eliminated after metabolism to tenofovir. The mean elimination half-life of tenofovir alafenamide and tenofovir in plasma is 0.51 and 32.37 hours, respectively. Tenofovir is eliminated by the kidneys through both glomerular filtration and active tubular secretion.

Linearity/non-linearity

Exposure to tenofovir alafenamide is dose-proportional over the dose range of 8 mg to 125 mg.

Pharmacokinetics in special populations

Age, sex, and ethnicity

No clinically significant differences in pharmacokinetics were observed based on age or ethnicity. Differences in pharmacokinetics based on sex were not considered clinically significant.

Hepatic impairment

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

Renal impairment

No clinically significant differences in the pharmacokinetics of tenofovir alafenamide or tenofovir were observed between healthy volunteers and patients with severe renal impairment (estimated creatinine clearance (CrCl) > 15 but < 30 mL/min) in tenofovir alafenamide studies.

Pediatric population

The pharmacokinetics of tenofovir alafenamide and tenofovir were evaluated in previously untreated HIV-1-infected adolescents who received tenofovir alafenamide (10 mg) as a fixed-dose combination tablet with elvitegravir/cobicistat and emtricitabine. No clinically significant differences in the pharmacokinetics of tenofovir alafenamide or tenofovir were observed between adolescents and HIV-1-infected adults.

Clinical characteristics.

Indications.

The medicinal product Tenofovir alafenamide 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 "Pharmacological properties").

Contraindications.

Hypersensitivity to the active substance or to any of the excipients of the medicinal product.

Interaction with other medicinal products and other forms of interaction.

Interaction studies have been conducted only in adults.

The medicinal product Tenofovir alafenamide must not be used concomitantly with medicinal products containing tenofovir disoproxil, tenofovir alafenamide, or adefovir dipivoxil.

Medicinal products that may affect tenofovir alafenamide

Tenofovir alafenamide is transported by P-glycoprotein (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 reduce plasma concentrations of tenofovir alafenamide, which may lead to loss of therapeutic effect. Concomitant use of such medicinal products with Tenofovir alafenamide is not recommended.

Concomitant administration of Tenofovir alafenamide with medicinal products that inhibit P-gp and BCRP may increase plasma concentrations of tenofovir alafenamide. Concomitant use of potent P-gp inhibitors 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 influenced 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 neither an inhibitor nor an inducer of CYP3A in vivo.

Tenofovir alafenamide is not an inhibitor of human uridine diphosphate-glucuronosyltransferase (UGT) 1A1 in vitro. It is unknown whether tenofovir alafenamide inhibits other UGT enzymes.

Information on interactions of 25 mg tenofovir alafenamide tablets with potential concomitant medicinal products is summarized in Table 1 (increases are indicated as "↑", decreases as "↓", and no change as "↔"). The described drug interactions were observed during studies with tenofovir alafenamide or are potential drug interactions that may occur when using 25 mg tenofovir alafenamide tablets.

Table 1

Interaction between 25 mg tenofovir alafenamide tablets and other medicinal products

Medicinal products by therapeutic areas	Effect on drug levelsa,b Mean ratio (90 % confidence interval) for AUC, Cmax, Cmin	Recommendations for concomitant use
ANTICONVULSANTS
Carbamazepine (300 mg orally, twice daily) Tenofovir alafenamidec (25 mg orally, single dose)	Tenofovir alafenamide ↓ Cmax 0.43 (0.36; 0.51) ↓ AUC 0.45 (0.40; 0.51) Tenofovir ↓ Cmax 0.70 (0.65; 0.74) ↔ AUC 0.77 (0.74; 0.81)	Concomitant use is not recommended.
Oxcarbazepine Phenobarbital	Interaction not studied. Expected: ↓ Tenofovir alafenamide	Concomitant use is not recommended.
Phenytoin	Interaction not studied. Expected: ↓ Tenofovir alafenamide	Concomitant use is not recommended.
Midazolamd (2.5 mg orally, single dose) Tenofovir alafenamide (25 mg orally, once daily)	Midazolam ↔ Cmax 1.02 (0.92; 1.13) ↔ AUC 1.13 (1.04; 1.23)	No need to adjust the dose of midazolam (oral or intravenous).
Midazolamd (1 mg intravenous, single dose) Tenofovir alafenamidec (25 mg orally, once daily)	Midazolam ↔ Cmax 0.99 (0.89; 1.11) ↔ AUC 1.08 (1.04; 1.14)
ANTIDEPRESSANTS
Sertraline (50 mg orally, single dose) Tenofovir alafenamidee (10 mg orally, once daily)	Tenofovir alafenamide ↔ Cmax 1.00 (0.86; 1.16) ↔ AUC 0.96 (0.89; 1.03) Tenofovir ↔ Cmax 1.10 (1.00; 1.21) ↔ AUC 1.02 (1.00; 1.04) ↔ Cmin 1.01 (0.99; 1.03)	No need to adjust the dose of tenofovir alafenamide or sertraline.
Sertraline (50 mg orally, single dose) Tenofovir alafenamidee (10 mg orally, once daily)	Sertraline ↔ Cmax 1.14 (0.94; 1.38) ↔ AUC 0.93 (0.77; 1.13)
ANTIFUNGAL AGENTS
Itraconazole Ketoconazole	Interaction not studied. Expected: ↑ Tenofovir alafenamide	Concomitant use is not recommended.
ANTIMYCOTIC AGENTS
Rifampicin Rifapentine	Interaction not studied. Expected: ↓ Tenofovir alafenamide	Concomitant use is not recommended.
Rifabutin	Interaction not studied. Expected: ↓ Tenofovir alafenamide	Concomitant use is not recommended.
ANTIVIRAL AGENTS FOR TREATMENT OF HEPATITIS C VIRUS (HCV) INFECTION
Sofosbuvir (400 mg orally, once daily)	Interaction not studied. Expected: ↔ Sofosbuvir ↔ GS-331007	No need to adjust the dose of tenofovir alafenamide or sofosbuvir.
Ledipasvir/sofosbuvir (90 mg/400 mg orally, once daily) Tenofovir alafenamidef (25 mg orally, once daily)	Ledipasvir ↔ Cmax 1.01 (0.97; 1.05) ↔ AUC 1.02 (0.97; 1.06) ↔ Cmin 1.02 (0.98; 1.07) Sofosbuvir ↔ Cmax 0.96 (0.89; 1.04) ↔ AUC 1.05 (1.01; 1.09) GS-331007g ↔ Cmax 1.08 (1.05; 1.11) ↔ AUC 1.08 (1.06; 1.10) ↔ Cmin 1.10 (1.07; 1.12) Tenofovir alafenamide ↔ Cmax 1.03 (0.94; 1.14) ↔ AUC 1.32 (1.25; 1.40) Tenofovir ↑ Cmax 1.62 (1.56; 1.68) ↑ AUC 1.75 (1.69; 1.81) ↑ Cmin 1.85 (1.78; 1.92)	No need to adjust the dose of tenofovir alafenamide or ledipasvir/sofosbuvir.
Sofosbuvir/velpatasvir (400 mg/100 mg orally, once daily)	Interaction not studied. Expected: ↔ Sofosbuvir ↔ GS-331007 ↔ Velpatasvir ↑ Tenofovir alafenamide	No need to adjust the dose of tenofovir alafenamide or sofosbuvir/velpatasvir.
Sofosbuvir/velpatasvir/ voxilaprevir (400 mg/100 mg/100 mg + 100 mgi orally, once daily) Tenofovir alafenamidef (25 mg orally, once daily)	Sofosbuvir ↔ Cmax 0.95 (0.86; 1.05) ↔ AUC 1.01 (0.97; 1.06) GS-331007g ↔ Cmax 1.02 (0.98; 1.06) ↔ AUC 1.04 (1.01; 1.06) Velpatasvir ↔ Cmax 1.05 (0.96; 1.16) ↔ AUC 1.01 (0.94; 1.07) ↔ Cmin 1.01 (0.95; 1.09) Voxilaprevir ↔ Cmax 0.96 (0.84; 1.11) ↔ AUC 0.94 (0.84; 1.05) ↔ Cmin 1.02 (0.92; 1.12) Tenofovir alafenamide ↑ Cmax 1.32 (1.17; 1.48) ↑ AUC 1.52 (1.43; 1.61)	No need to adjust the dose of tenofovir alafenamide or sofosbuvir/velpatasvir/voxilaprevir.
ANTIRETROVIRAL AGENTS — HIV PROTEASE INHIBITORS
Atazanavir/cobicistat (300 mg/150 mg orally, once daily) Tenofovir alafenamidec (10 mg orally, once daily)	Tenofovir alafenamide ↑ Cmax 1.80 (1.48; 2.18) ↑ AUC 1.75 (1.55; 1.98) Tenofovir ↑ Cmax 3.16 (3.00; 3.33) ↑ AUC 3.47 (3.29; 3.67) ↑ Cmin 3.73 (3.54; 3.93) Atazanavir ↔ Cmax 0.98 (0.94; 1.02) ↔ AUC 1.06 (1.01; 1.11) ↔ Cmin 1.18 (1.06; 1.31) Cobicistat ↔ Cmax 0.96 (0.92; 1.00) ↔ AUC 1.05 (1.00; 1.09) ↑ Cmin 1.35 (1.21; 1.51)	Concomitant use is not recommended.
Atazanavir/ritonavir (300 mg/100 mg orally, once daily) Tenofovir alafenamidec (10 mg orally, single dose)	Tenofovir alafenamide ↑ Cmax 1.77 (1.28; 2.44) ↑ AUC 1.91 (1.55; 2.35) Tenofovir ↑ Cmax 2.12 (1.86; 2.43) ↑ AUC 2.62 (2.14; 3.20) Atazanavir ↔ Cmax 0.98 (0.89; 1.07) ↔ AUC 0.99 (0.96; 1.01) ↔ Cmin 1.00 (0.96; 1.04)	Concomitant use is not recommended.
Darunavir/cobicistat (800 mg/150 mg orally, once daily) Tenofovir alafenamidec (25 mg orally, once daily)	Tenofovir alafenamide ↔ Cmax 0.93 (0.72; 1.21) ↔ AUC 0.98 (0.80; 1.19) Tenofovir ↑ Cmax 3.16 (3.00; 3.33) ↑ AUC 3.24 (3.02; 3.47) ↑ Cmin 3.21 (2.90; 3.54) Darunavir ↔ Cmax 1.02 (0.96; 1.09) ↔ AUC 0.99 (0.92; 1.07) ↔ Cmin 0.97 (0.82; 1.15) Cobicistat ↔ Cmax 1.06 (1.00; 1.12) ↔ AUC 1.09 (1.03; 1.15) ↔ Cmin 1.11 (0.98; 1.25)	Concomitant use is not recommended.
Darunavir/ritonavir (800 mg/100 mg orally, once daily) Tenofovir alafenamidec (10 mg orally, single dose)	Tenofovir alafenamide ↑ Cmax 1.42 (0.96; 2.09) ↔ AUC 1.06 (0.84; 1.35) Tenofovir ↑ Cmax 2.42 (1.98; 2.95) ↑ AUC 2.05 (1.54; 2.72) Darunavir ↔ Cmax 0.99 (0.91; 1.08) ↔ AUC 1.01 (0.96; 1.06) ↔ Cmin 1.13 (0.95; 1.34)	Concomitant use is not recommended.
Lopinavir/ritonavir (800 mg/200 mg orally, once daily) Tenofovir alafenamidec (10 mg orally, single dose)	Tenofovir alafenamide ↑ Cmax 2.19 (1.72; 2.79) ↑ AUC 1.47 (1.17; 1.85) Tenofovir ↑ Cmax 3.75 (3.19; 4.39) ↑ AUC 4.16 (3.50; 4.96) Lopinavir ↔ Cmax 1.00 (0.95; 1.06) ↔ AUC 1.00 (0.92; 1.09) ↔ Cmin 0.98 (0.85; 1.12)	Concomitant use is not recommended.
Tipranavir/ritonavir	Interaction not studied. Expected: ↓ Tenofovir alafenamide	Concomitant use is not recommended.
ANTIRETROVIRAL AGENTS — HIV INTEGRASE INHIBITORS
Dolutegravir (50 mg orally, once daily) Tenofovir alafenamidec (10 mg orally, single dose)	Tenofovir alafenamide ↑ Cmax 1.24 (0.88; 1.74) ↑ AUC 1.19 (0.96; 1.48) Tenofovir ↔ Cmax 1.10 (0.96; 1.25) ↑ AUC 1.25 (1.06; 1.47) Dolutegravir ↔ Cmax 1.15 (1.04; 1.27) ↔ AUC 1.02 (0.97; 1.08) ↔ Cmin 1.05 (0.97; 1.13)	No need to adjust the dose of tenofovir alafenamide or dolutegravir.
Raltegravir	Interaction not studied. Expected: ↔ Tenofovir alafenamide ↔ Raltegravir	No need to adjust the dose of tenofovir alafenamide or raltegravir.
ANTIRETROVIRAL AGENTS — NON-NUCLEOSIDE HIV REVERSE TRANSCRIPTASE INHIBITORS
Efavirenz (600 mg orally, once daily) Tenofovir alafenamideh (40 mg orally, once daily)	Tenofovir alafenamide ↓ Cmax 0.78 (0.58; 1.05) ↔ AUC 0.86 (0.72; 1.02) Tenofovir ↓ Cmax 0.75 (0.67; 0.86) ↔ AUC 0.80 (0.73; 0.87) ↔ Cmin 0.82 (0.75; 0.89) Expected: ↔ Efavirenz	No need to adjust the dose of tenofovir alafenamide or efavirenz.
Nevirapine	Interaction not studied. Expected: ↔ Tenofovir alafenamide ↔ Nevirapine	No need to adjust the dose of tenofovir alafenamide or nevirapine.
Rilpivirine (25 mg orally, once daily) Tenofovir alafenamide (25 mg orally, once daily)	Tenofovir alafenamide ↔ Cmax 1.01 (0.84; 1.22) ↔ AUC 1.01 (0.94; 1.09) Tenofovir ↔ Cmax 1.13 (1.02; 1.23) ↔ AUC 1.11 (1.07; 1.14) ↔ Cmin 1.18 (1.13; 1.23) Rilpivirine ↔ Cmax 0.93 (0.87; 0.99) ↔ AUC 1.01 (0.96; 1.06) ↔ Cmin 1.13 (1.04; 1.23)	No need to adjust the dose of tenofovir alafenamide or rilpivirine.
ANTIRETROVIRAL AGENTS — CCR5 RECEPTOR ANTAGONISTS
Maraviroc	Interaction not studied. Expected: ↔ Tenofovir alafenamide ↔ Maraviroc	No need to adjust the dose of tenofovir alafenamide or maraviroc.
HERBAL PRODUCTS
St. John's wort (Hypericum perforatum)	Interaction not studied. Expected: ↓ Tenofovir alafenamide	Concomitant use is not recommended.
ORAL CONTRACEPTIVES
Norgestimate (0.180 mg/0.215 mg/0.250 mg orally, once daily) Ethinylestradiol (0.025 mg orally, once daily) Tenofovir alafenamidec (25 mg orally, once daily)	Norelgestromin ↔ Cmax 1.17 (1.07; 1.26) ↔ AUC 1.12 (1.07; 1.17) ↔ Cmin 1.16 (1.08; 1.24) Norgestrel ↔ Cmax 1.10 (1.02; 1.18) ↔ AUC 1.09 (1.01; 1.18) ↔ Cmin 1.11 (1.03; 1.20) Ethinylestradiol ↔ Cmax 1.22 (1.15; 1.29) ↔ AUC 1.11 (1.07; 1.16) ↔ Cmin 1.02 (0.93; 1.12)	No need to adjust the dose of tenofovir alafenamide or norgestimate/ethinylestradiol.

a All interaction studies were conducted in healthy volunteers.

b No effect on drug levels within 70–143%.

c Studies were conducted with the fixed-dose combination of emtricitabine/tenofovir alafenamide tablets.

d Sensitive CYP3A4 substrate.

e Studies were conducted with the fixed-dose combination of elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide tablets.

f Studies were conducted with the fixed-dose combination of emtricitabine/rilpivirine/tenofovir alafenamide tablets.

g Predominant circulating nucleoside metabolite of sofosbuvir.

h Studies were conducted with tenofovir alafenamide 40 mg and emtricitabine 200 mg.

i Study conducted with an additional dose of voxilaprevir 100 mg to achieve voxilaprevir exposure expected in HCV-infected patients.

Special precautions for use.

HBV transmission

Patients should be advised that the medicinal product Tenofovir alafenamide does not prevent the risk of transmitting HBV to others through sexual contact or blood exposure. Appropriate preventive measures should continue to be used.

Patients with decompensated liver disease

There are no data on the safety and efficacy of tenofovir alafenamide in HBV-infected patients with decompensated liver disease who have a Child–Pugh–Turcotte score > 9 (i.e., Class C). In these patients, there is an increased risk of developing serious hepatic or renal adverse reactions. Therefore, hepatic and renal parameters should be closely monitored in this patient population (see section "Pharmacokinetics").

Hepatitis flare

Flare during treatment

Spontaneous flares in chronic hepatitis B are relatively common and are characterized by a transient increase in serum alanine aminotransferase (ALT) levels. After initiation of antiviral therapy, serum ALT levels may increase in some patients. In patients with compensated liver disease, these ALT elevations are usually not associated with increased serum bilirubin levels or hepatic decompensation. Patients with cirrhosis have a higher risk of hepatic decompensation following hepatitis flare and should therefore be carefully monitored during therapy.

Flare after discontinuation of treatment

Rapid hepatitis flare has been reported in patients who discontinued treatment for hepatitis B, usually associated with increased HBV DNA levels in plasma. Most cases do not require intervention, but severe flares, including fatal cases, may occur after discontinuation of HBV treatment. Liver function should be monitored periodically by clinical and laboratory follow-up for at least 6 months after stopping hepatitis B treatment. Resumption of hepatitis B therapy may be necessary.

Discontinuation of treatment is not recommended in patients with advanced liver disease or cirrhosis, as post-treatment hepatitis flare may lead to hepatic decompensation. Flares in patients with decompensated liver disease are particularly serious and sometimes fatal.

Renal function impairment

Patients with creatinine clearance < 30 mL/min

The use of tenofovir alafenamide once daily in patients with creatinine clearance ≥ 15 mL/min but < 30 mL/min, and in patients with creatinine clearance < 15 mL/min receiving hemodialysis, is based on very limited pharmacokinetic data and modeling and simulation. There are no data on the safety of tenofovir alafenamide for the treatment of HBV-infected patients with creatinine clearance < 30 mL/min.

The use of tenofovir alafenamide is not recommended in patients with creatinine clearance < 15 mL/min who are not receiving hemodialysis (see section "Dosage and administration").

Nephrotoxicity

The potential risk of nephrotoxicity due to chronic low-level exposure to tenofovir from tenofovir alafenamide cannot be excluded (based on preclinical study data).

Renal function should be assessed in all patients prior to or at initiation of tenofovir alafenamide 25 mg tablets and monitored during therapy in all patients as clinically indicated. In patients who develop clinically significant reduction in renal function or signs of proximal renal tubulopathy, discontinuation of the medicinal product Tenofovir alafenamide should be considered.

Patients coinfected with hepatitis B and hepatitis C or D virus

There are no data on the safety and efficacy of tenofovir alafenamide in patients coinfected with hepatitis C or D virus. Recommendations for concomitant use in the treatment of hepatitis C should be followed (see section "Interaction with other medicinal products and other forms of interaction").

Hepatitis B and HIV coinfection

HIV antibody testing should be offered to all HBV-infected patients whose HIV-1 status is unknown prior to starting therapy with the medicinal product Tenofovir alafenamide. In patients coinfected with HBV and HIV, the product should be used concomitantly with other antiretroviral agents to ensure appropriate HIV treatment (see section "Interaction with other medicinal products and other forms of interaction").

Concomitant use with other medicinal products

The medicinal product Tenofovir alafenamide should not be used together with medicinal products containing tenofovir alafenamide, tenofovir disoproxil, or adefovir dipivoxil.

Concomitant use of the medicinal product Tenofovir alafenamide with certain anticonvulsants (e.g., carbamazepine, oxcarbazepine, phenobarbital, and phenytoin), antimycobacterial agents (e.g., rifampicin, rifabutin, and rifapentine), or St John’s wort, which are P-gp inducers and may reduce plasma concentrations of tenofovir alafenamide, is not recommended.

Concomitant use of the medicinal product Tenofovir alafenamide with potent P-gp inhibitors (e.g., itraconazole and ketoconazole) may increase plasma concentrations of tenofovir alafenamide. Concomitant use is not recommended.

Lactose intolerance

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

Use during pregnancy or breastfeeding.

Pregnancy

Data on the use of tenofovir alafenamide in pregnant women are limited (fewer than 300 pregnancy outcomes). However, there is a large amount of data from pregnant women (over 1000 outcomes) indicating no malformative or fetotoxic/neonatal toxicity associated with the use of tenofovir disoproxil.

Animal studies do not indicate a direct or indirect harmful effect on reproductive performance.

If necessary, tenofovir alafenamide may be considered for use during pregnancy.

Breastfeeding period

It is not known whether tenofovir alafenamide is excreted in human breast milk. However, studies in animals have shown that tenofovir is excreted in milk. There is insufficient information on the effects of tenofovir on neonates/infants.

Risk to breastfed neonates/infants cannot be excluded; therefore, the medicinal product should not be used during breastfeeding.

Fertility

There are no data on the effect of tenofovir alafenamide on human fertility. Animal studies do not indicate a harmful effect of tenofovir alafenamide on fertility.

Ability to influence the speed of reactions while driving or operating machinery.

Tenofovir alafenamide has no or negligible effect on the ability to drive or operate machinery. Patients should be informed that dizziness has been reported during treatment with tenofovir alafenamide.

Dosage and Administration

Treatment should be initiated by a physician experienced in managing chronic hepatitis B.

Adults and adolescents (aged 12 years and older with body weight at least 35 kg): 1 tablet once daily.

Discontinuation of treatment

Discontinuation of treatment may be considered as follows (see section "Special precautions"):

• For HBeAg-positive patients without cirrhosis, treatment should be continued for at least 6–12 months after confirmed HBe seroconversion (loss of HBeAg and HBV DNA, with detection of anti-HBe) or until HBs seroconversion or loss of response occurs (see section "Special precautions"). Regular reassessment after treatment discontinuation is recommended to monitor for virological relapse.
• For HBeAg-negative patients without cirrhosis, treatment should be continued at least until HBs seroconversion or until evidence of loss of response. For prolonged treatment exceeding 2 years, regular reassessment is recommended to confirm that continuation of the chosen therapy remains appropriate for the patient.

Missed dose

If a dose is missed and less than 18 hours have passed, the patient should take the medication as soon as possible, then resume the normal dosing schedule. If more than 18 hours have passed, the patient should not take the missed dose and should simply resume the regular dosing schedule.

If vomiting occurs within 1 hour after taking tenofovir alafenamide, the patient should take another tablet. If vomiting occurs more than 1 hour after taking this medication, the patient does not need to take another tablet.

Special patient populations

Elderly patients

No dose adjustment is required for patients aged 65 years and older (see section "Pharmacokinetics").

Renal impairment

No dose adjustment is required for adults or adolescents (aged 12 years and older with body weight at least 35 kg) with a calculated creatinine clearance (CrCl) ≥15 mL/min, or for patients with CrCl <15 mL/min who are receiving hemodialysis.

On hemodialysis days, tenofovir alafenamide should be administered after completion of the hemodialysis procedure (see section "Pharmacokinetics").

Dosage recommendations cannot be provided for patients with CrCl <15 mL/min who are not receiving hemodialysis (see section "Special precautions").

Hepatic impairment

No dose adjustment is required for patients with hepatic impairment (see sections "Pharmacokinetics" and "Special precautions").

Paediatric population

The safety and efficacy of tenofovir alafenamide in children under 12 years of age or with body weight <35 kg have not yet been established. No data are available.

Administration method

Oral use. Tenofovir alafenamide film-coated tablets should be taken with food.

Children

Tenofovir alafenamide is not recommended for use in children under 12 years of age or with body weight <35 kg, as safety and efficacy have not been established in this population.

Overdose

In case of overdose, the patient should be monitored for signs of toxicity (see section "Adverse reactions").

Management of tenofovir alafenamide overdose consists of general supportive measures, including monitoring of vital signs and observation of the patient's clinical status.

Tenofovir is efficiently removed by hemodialysis with an extraction coefficient of approximately 54%. It is unknown whether tenofovir can be removed by peritoneal dialysis.

Adverse reactions

The assessment of adverse reactions is based on pooled safety data from 2 phase 3 controlled studies in which 866 hepatitis B virus (HBV)-infected patients received tenofovir alafenamide 25 mg once daily in double-blind studies for 96 weeks (mean duration of exposure in the blinded portion of the study was 104 weeks), as well as on postmarketing experience. The most commonly reported adverse reactions were headache (12%), nausea (6%), and fatigue (6%). After week 96, patients either remained on the initial blinded treatment or were switched to open-label tenofovir alafenamide. In both studies, changes in lipid laboratory parameters were observed. No additional adverse reactions were identified from week 96 to week 144 in the double-blind phase or in the subgroup of patients receiving open-label tenofovir alafenamide.

In an ongoing double-blind, randomized, active-controlled study (GS-US-320-4018; study 4018) in patients with virologic suppression who switched from tenofovir disoproxil to tenofovir alafenamide 25 mg (N = 243), lipid parameter changes were observed during laboratory testing. No additional adverse reactions to tenofovir alafenamide were observed through week 48.

The adverse reactions observed during administration of tenofovir alafenamide to patients with chronic hepatitis B are listed below (see Table 2). Adverse reactions are categorized below by system organ class and frequency, based on analysis at week 96. Frequencies are defined as follows: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100).

Table 2
Adverse reactions observed during administration of tenofovir alafenamide

Frequency	Adverse reactions
Nervous system disorders
Very common	Headache
Common	Dizziness
Gastrointestinal disorders
Common	Diarrhea, vomiting, nausea, abdominal pain, bloating, flatulence
Hepatobiliary disorders
Common	Elevated ALT levels
Skin and subcutaneous tissue disorders
Common	Rash, pruritus
Uncommon	Angioneurotic edema1, urticaria1
Musculoskeletal and connective tissue disorders
Common	Arthralgia
General disorders
Common	Fatigue

1 Adverse reaction identified during post-marketing surveillance of drugs containing tenofovir alafenamide.

Changes in lipid levels observed in laboratory tests

In a combined analysis of two studies, changes in mean lipid parameters were observed at week 96 compared to baseline levels in both treatment groups under fasting conditions. In the tenofovir alafenamide group, a decrease in median fasting total cholesterol and high-density lipoprotein cholesterol (HDL-C), along with an increase in median directly measured low-density lipoprotein cholesterol (LDL-C) and fasting triglycerides, was observed, whereas in the tenofovir disoproxil group, a decrease in median values of all parameters was observed. In patients initially randomized to receive tenofovir alafenamide and switched to open-label tenofovir alafenamide at week 96, the median changes from baseline of the double-blind study to week 144 were (mg/dL): total cholesterol 0 (-16; 18); LDL-C 8 (-6; 24); HDL-C -5 (-12; 2); triglycerides 11 (-11; 40); total cholesterol to HDL-C ratio 0.3 (0.0; 0.7). In patients initially randomized to receive tenofovir disoproxil and switched to open-label tenofovir alafenamide at week 96, the median changes from baseline of the double-blind study to week 144 were (mg/dL): total cholesterol 1 (-17; 20); LDL-C 9 (-5; 26); HDL-C -8 (-15; -1); triglycerides 14 (-10; 43); total cholesterol to HDL-C ratio 0.4 (0.0; 1.0).

During the open-label phase of the studies, when patients switched to open-label tenofovir alafenamide at week 96, lipid parameters at week 144 in patients continuing tenofovir alafenamide remained similar to those at week 96, whereas median increases in fasting total cholesterol, directly measured LDL-C, HDL-C, and triglycerides were observed in patients switching from tenofovir disoproxil to tenofovir alafenamide at week 96. During the open-label phase, the median change in total cholesterol to HDL-C ratio from week 96 to week 144 was 0.0 (-0.2; 0.4) in patients continuing tenofovir alafenamide and 0.2 (-0.2; 0.6) in patients switching from tenofovir disoproxil to tenofovir alafenamide at week 96.

In one study, median changes in fasting lipid parameters from baseline to week 48 were observed in both treatment groups. In the group switching from tenofovir disoproxil to tenofovir alafenamide, an increase in median fasting total cholesterol, LDL-C, HDL-C, and triglycerides was observed, whereas in the group continuing tenofovir disoproxil treatment, a decrease in median fasting total cholesterol, HDL-C, and triglycerides and minimal median increase in LDL-C were observed (p < 0.001 for the difference between treatment groups for all parameters). The median change in total cholesterol to HDL-C ratio from baseline to week 48 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

During treatment, body weight, as well as blood lipid and glucose levels, may increase.

Reporting of suspected adverse reactions

Reporting of adverse reactions after drug registration is important. It allows continuous monitoring of the benefit-risk balance of the drug. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all cases of suspected adverse reactions and lack of drug efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 36 months.

Storage conditions.

Store in the original packaging at a temperature not exceeding 30 ºC. Keep out of reach of children.

Packaging. 30 tablets in a bottle with one or two desiccant containers; 1 bottle in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Mylan Laboratories Limited.

Manufacturer's address and location of business operations.

Plot No. 11, 12 and 13, Indore SEZ, Pharma Zone, Phase II, Sector III, District Dhar, Pithampur, Madhya Pradesh, 454775, India.

The medicinal product was manufactured under license from Gilead Sciences Inc.