Tafnat

Tenofovir alafenamide.

Each 1 film-coated tablet contains Tenofovir alafenamide fumarate 28.50 mg equivalent to Tenofovir Alafenamide 25 mg.
Excipients/Inactive Ingredients: Lactose Monohydrate, Microcrystalline Cellulose, Croscarmellose sodium, Magnesium stearate, Opadry II Blue Opadry II Blue contains polyvinyl alcohol, Titanium dioxide, Polyethylene glycol, Talc and Brilliant Blue FCF Aluminum Lake.

Pharmacotherapeutic group: Antiviral for systemic use, nucleoside and nucleotide reverse transcriptase inhibitors. ATC code: J05AF13.
Pharmacology: Pharmacodynamics: 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 hydrolyzed 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 > 44400 nM.
Resistance: In a pooled analysis of patients receiving Tenofovir Alafenamide tablets, 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) through Week 48, or had HBV DNA ≥ 69 IU/mL at early discontinuation at or after Week 24. No amino acid substitutions associated with resistance to Tenofovir Alafenamide tablets were identified in 20 paired isolates.
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: From the clinical study of Vemlidy (tenofovir alafenamide): The efficacy and safety of tenofovir alafenamide tablets in patients with chronic hepatitis B are based on 48-week data from two randomized, double-blind, active-controlled studies, GS-US-320-0108 ("Study 108") and GS-US-320-0110 ("Study 110"): In Study 108, HBeAg-negative treatment-naïve and treatment-experienced patients with compensated liver function were randomized in a 2:1 ratio to receive tenofovir alafenamide tablets (25 mg; N = 285) once daily or tenofovir disoproxil fumarate (300 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 fumarate (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 story of cirrhosis.
In Study 110, HBeAg-positive treatment-naïve and treatment-experienced patients with compensated liver function were randomized in a 2:1 ratio to receive tenofovir alafenamide tablets (25 mg; N = 581) once daily or tenofovir disoproxil fumarate (300 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 fumarate (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 trials was the proportion of patients with plasma HBV DNA levels below 29 IU/mL Tenofovir alafenamide tablets met the non-inferiority criteria in achieving HBV DNA less than 29 IU/mL when compared to tenofovir disoproxil fumarate.
Treatment outcomes of Study 108 and Study 110 through Week 48 are presented in Table 1 and Table 2. Additional outcomes through Week 72 are presented in Table 3. (See Table 1 and Table 2.)

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Experience beyond 48 weeks in Study 108 and Study 110: At week 72, viral suppression as well as biochemical and serological responses were maintained with continued tenofovir alafenamide treatment (see Table 3). Serological data were not collected at the Week 72 timepoint. (See Table 3.)

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Changes in measures of bone mineral density: In both studies tenofovir alafenamide was associated with smaller 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 fumarate after 72 weeks of treatment.
Changes in measures of renal function: In both studies tenofovir alafenamide was associated with smaller changes in renal safety parameters (smaller reductions in estimated CrCl by Cockcroft-Gault and smaller percentage increases in urine protein to creatinine ratio and urine albumin to creatinine ratio) compared to tenofovir disoproxil fumarate after 72 weeks of treatment (see also Precautions).
Pharmacokinetics: Absorption: Following oral administration of Tenofovir Alafenamide tablets 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 CHB, mean steady state AUC _0-24 for tenofovir alafenamide (N = 698) and tenofovir (N = 856) were 0.22 μg•hr/mL and 0.32 μg•hr/mL, respectively. Steady state Cmax for tenofovir alafenamide and tenofovir were 0.18 and 0.02 μg•hr/mL, respectively. Relative to fasting conditions, the administration of a single dose of Tenofovir Alafenamide tablets 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 trials 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 metabolized 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 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 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.
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.
Toxicology: Preclinical safety data: Nonclinical 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 fumarate, carcinogenicity studies and a rat peri-postnatal study were conducted only with tenofovir disoproxil fumarate. 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 fumarate 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.

Tenofovir Alafenamide tablets are 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 Pharmacology: Pharmacodynamics under Actions).

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 Precautions): 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 Precautions). 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 Tenofovir Alafenamide tablets 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 Tenofovir Alafenamide tablets, the patient should take another tablet. If the patient vomits more than 1 hour after taking Tenofovir Alafenamide tablets, the patient does not need to take another tablet.
Special populations: Elderly: No dose adjustment of Tenofovir Alafenamide tablets is required in patients aged 65 years and older (see Pharmacology: Pharmacokinetics under Actions).
Renal impairment: No dose adjustment of Tenofovir Alafenamide tablets 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, Tenofovir Alafenamide tablets should be administered after completion of haemodialysis treatment (see Pharmacology: Pharmacokinetics under Actions).
No dosing recommendations can be given for patients with CrCl <15 mL/min who are not receiving haemodialysis (see Precautions).
Hepatic impairment: No dose adjustment of Tenofovir Alafenamide tablets is required in patients with hepatic impairment (see Precautions and Pharmacology: Pharmacokinetics under Actions).
Paediatric population: The safety and efficacy of Tenofovir Alafenamide tablets 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. Tenofovir Alafenamide film-coated tablets should be taken with food.

If overdose occurs the patient must be monitored for evidence of toxicity (see Adverse Reactions).
Treatment of overdose with Tenofovir Alafenamide tablets 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.

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

HBV transmission: Patients must be advised that Tenofovir Alafenamide tablets do 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 no data on the safety and efficacy of Tenofovir Alafenamide tablets 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 Pharmacology: Pharmacokinetics under Actions).
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 Tenofovir Alafenamide tablets once daily in patients with CrCl ≥15 mL/min but <30 mL/min and in patients with CrCl <15 mL/min who are receiving haemodialysis is based on very limited pharmacokinetic data and on modelling and simulation. There are no safety data on the use of Tenofovir Alafenamide tablets to treat HBV-infected patients with CrCl <30 mL/min.
The use of Tenofovir Alafenamide tablets are not recommended in patients with CrCl <15 mL/min who are not receiving haemodialysis (see Dosage & Administration).
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 Pharmacology: Toxicology: Preclinical safety data under Actions).
Patients co-infected with HBV and hepatitis C or D virus: There are no data on the safety and efficacy of Tenofovir Alafenamide tablets in patients co- infected with hepatitis C or D virus. Co-administration guidance for the treatment of hepatitis C should be followed (see Interactions).
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 Tenofovir Alafenamide tablets. In patients who are co- infected with HBV and HIV, Tenofovir Alafenamide tablets should be co-administered with other antiretroviral agents to ensure that the patient receives an appropriate regimen for treatment of HIV (see Interactions).
Co-administration with other medicinal products: Tenofovir Alafenamide tablets should not be co-administered with products containing tenofovir alafenamide, tenofovir disoproxil fumarate or adefovir dipivoxil.
Co-administration of Tenofovir Alafenamide tablets 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 Tenofovir Alafenamide tablets with strong inhibitors of P-gp (e. g. itraconazole and ketoconazole) may increase tenofovir alafenamide plasma concentrations. Co- administration is not recommended.
Lactose intolerance: Tenofovir Alafenamide tablets contains lactose monohydrate. Consequently, patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.
Effects on ability to drive and use machines: Tenofovir Alafenamide Tablets have 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 Tablets.

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 1000 exposed outcomes) indicates no malformative nor feto/neonatal toxicity associated with the use of tenofovir disoproxil fumarate.
Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see Pharmacology: Toxicology: Preclinical safety data under Actions).
The use of Tenofovir Alafenamide tablets 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 breastfed child cannot be excluded; therefore, Tenofovir Alafenamide tablets should not be used during breast-feeding.
Fertility: No human data on the effect of Tenofovir Alafenamide tablets on fertility are available. Animal studies do not indicate harmful effects of tenofovir alafenamide on fertility.

Summary of the safety profile: Assessment of adverse reactions is based on safety data from the analysis performed through to the Week 72 analysis (median duration of exposure of 88 weeks), from 2 Phase 3 studies in which 866 HBV-infected patients received tenofovir alafenamide 25 mg once daily. The most frequently reported adverse reactions were headache (11%), nausea (6%), and fatigue (6%).
Tabulated summary of adverse reactions: The following adverse drug reactions have been identified with tenofovir alafenamide in patients with chronic hepatitis B (see Table 4). The adverse reactions are listed below by body system organ class and frequency.
Frequencies are defined as follows: very common (≥1/10), common (≥1/100 to < 1/10), uncommon (≥1/1,000 to < 1/100), rare (≥1/10,000 to <1/1,000) or very rare (<1/10,000). (See Table 4.)

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Interaction studies have only been performed in adults.
Tenofovir Alafenamide tablets should not be co-administered with medicinal products containing tenofovir disoproxil fumarate, 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 Tenofovir Alafenamide tablets. Co- administration of such medicinal products with Tenofovir Alafenamide tablets is not recommended.
Co-administration of Tenofovir Alafenamide tablets with medicinal products that inhibit P-gp and/or BCRP may increase plasma concentration of tenofovir alafenamide. Co-administration of strong inhibitors of P-gp with Tenofovir Alafenamide tablets 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 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 Tenofovir Alafenamide tablets with potential concomitant medicinal products is summarised in Table 5 as follows (increase is indicated as "↑", decrease as "↓", no change as "
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"; 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 Tenofovir Alafenamide tablets. (See Table 5.)

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Incompatibilities: Not applicable.

Do not store above 30°C.
Shelf life: 24 months.

Antivirals

J05AF13 - tenofovir alafenamide ; Belongs to the class of nucleoside and nucleotide reverse transcriptase inhibitors. Used in the systemic treatment of viral infections.

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