Tenofovir Alafenamide Fumarate Tablets

Pharmacological action Tenofovir alafenamide fumarate is an anti-hepatitis B virus drug. Mechanism of action Tenofovir alafenamide fumarate is a phosphoramidated prodrug of tenofovir (2-deoxyadenosine monophosphate analog). As a lipophilic cell-permeable compound, tenofovir alafenamide fumarate enters primary hepatocytes through passive diffusion and liver uptake transporters OATP1B1 and OATP1B3, where it is hydrolyzed by carboxylic acid esterase 1 and converted into tenofovir, which is then phosphorylated by intracellular cellular kinases to form the pharmacologically active metabolite tenofovir diphosphate. Tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerases (including mitochondrial DNA polymerase gamma) through HBV reverse transcriptase, and no toxicity to mitochondria has been observed in cell culture. Antiviral activity The antiviral activity of tenofovir alafenamide fumarate against HBV clinical isolates representing genotypes A-H was evaluated in transient transfection assays in HepG2 cells. The EC50 (half effective concentration) of tenofovir alafenamide fumarate is between 34.7-134.4nM, with an overall mean of 86.6nM. The CC50 (half cytotoxic concentration) is higher than 44400nM. In the cell-based study of the combination of tenofovir and HBV nucleoside reverse transcriptase inhibitors (entecavir, lamivudine, telbivudine), no antagonistic effect was observed. Resistance In the pooled analysis of Trials 108 and 110 in treatment-naive or previously treated subjects treated with tenofovir alafenamide, genotypic resistance analysis was performed on paired baseline and on-treatment HBV isolates in subjects who experienced virologic breakthrough at Week 48 (HBV DNA > 69 IU/mL [400 copies/mL] for 2 consecutive visits after HBV DNA was already < 69 IU/mL, or an increase of 1.0 log10 or greater from nadir) or HBV DNA > 69 IU/mL at early discontinuation at Week 24 or later. Treatment-emergent HBV reverse transcriptase domain amino acid substitutions (all at polymorphic positions) were seen in some HBV isolates (5/20); however, no specific substitutions were seen at a sufficiently high incidence to be associated with resistance to tenofovir alafenamide. Cross-resistance The antiviral activity of tenofovir alafenamide was determined in a transient transfection assay in HepG2 cells against a panel of HBV isolates harboring mutations associated with resistance to ribonucleic acid reverse transcriptase inhibitors. HBV isolates harboring the lamivudine resistance-associated mutations rtM204V/I (±rtL180M±rtV173L) and the tecavir resistance-associated mutations rtT184G, rtS202G, or rtM250V (in the case of rtL180M and rtM204V mutations) showed a less than 2-fold decrease in sensitivity to tenofovir alafenamide. HBV isolates harboring any of the adefovir resistance-associated mutations rtA181T, HA181V, or HN236T also showed a less than 2-fold decrease in EC50 values to tenofovir alafenamide, but the double mutation of rtA181V and rtN236T reduced sensitivity to tenofovir alafenamide by 3.7-fold. The clinical relevance of these mutations is unclear.Toxicology studies Genotoxicity Tenofovir alafenamide fumarate showed no genotoxicity in the Ames test, mouse lymphoma test, and rat micronucleus test.Reproductive toxicity Male rats were given tenofovir alafenamide fumarate equivalent to 155 times the human dose (based on body surface area) from 28 days before mating to the mating period, and female rats were given tenofovir alafenamide fumarate from 14 days before mating to the 7th day of pregnancy. No effects on rat fertility, mating behavior, and early embryonic development were observed. In the embryo-fetal developmental toxicity test, pregnant rats and rabbits were orally administered 25, 100, 250 mg/kg/day and 10, 30, 100 mg/kg/day of tenofovir alafenamide fumarate during the organogenesis period (6-17 days of gestation in rats and 7-20 days of gestation in rabbits), respectively. No fertility damage or embryo-fetal toxicity was observed. The exposure of tenofovir alafenamide fumarate at the NOAEL (no adverse effect level) of embryo-fetal toxicity in rats and rabbits was equivalent to 1 times and 51 times the exposure at the recommended daily dose for humans, respectively. Tenofovir alafenamide fumarate is rapidly converted to tenofovir; the tenofovir exposure measured in rats and rabbits was 54 times and 85 times the exposure of tenofovir at the recommended daily dose for humans, respectively. Because tenofovir alafenamide fumarate is rapidly converted to tenofovir, and the tenofovir exposure measured after administration of tenofovir alafenamide fumarate to rats and mice is lower than that to tenofovir disoproxil fumarate (TDF), only the perinatal toxicity study of TDF in rats was conducted. The maximum dose during lactation was 600 mg/kg/day; no adverse reactions were observed in the offspring when the tenofovir exposure on the 7th day of pregnancy and the 20th day of lactation was approximately 12 times and 18 times the tenofovir exposure at the recommended daily dose of tenofovir alafenamide fumarate in humans, respectively. Studies in rats and monkeys have shown that tenofovir can be secreted into breast milk. On the 11th day after oral administration of TDF (maximum dose of 600 mg/kg/day) to lactating rats, the highest milk concentration was approximately 24% of the median plasma concentration of animals in the high-dose group. After a single subcutaneous injection of tenofovir 30 mg/kg in lactating monkeys, the concentration in milk was about 4% of the plasma concentration, and the exposure (AUC) was about 20% of the plasma exposure. Carcinogenic tenofovir alafenamide fumarate is rapidly converted to tenofovir in rats and mice after administration, and the latter's exposure is lower than the exposure of tenofovir after TDF administration, so only TDF is used for carcinogenicity testing. In the long-term oral administration carcinogenicity test, the highest tenofovir exposure was about 10 times (mice) and 4 times (rats) at the human chronic hepatitis B infection treatment dose (300 mg) of tenofovir disoproxil fumarate, and this exposure was about 151 times (mice) and 50 times (rats) at the human treatment dose of tenofovir alafenamide fumarate. The incidence of hepatic adenoma increased in female mice at high doses (about 151 times the exposure of tenofovir at the human treatment dose of tenofovir alafenamide fumarate). The results of the rat carcinogenicity test were negative. After dogs were given tenofovir alafenamide fumarate for 3 and 9 months, slight to mild infiltration of mononuclear cells in the posterior uveal tract of similar severity was observed; this was reversible after a three-month recovery period. At the NOAEL for ocular toxicity, the systemic exposure of tenofovir alafenamide fumarate and tenofovir in dogs was 5 times and 4 times the exposure of tenofovir alafenamide fumarate and tenofovir at the recommended daily dose of tenofovir alafenamide fumarate in humans, respectively.

The main ingredient of this product is tenofovir alafenamide fumarate. Chemical name: propan-2-yl N-[(S)-({[(2R)-1-(6-amino-9H-purine-9-yl)propan-2-yl]-oxidized}methyl)(phenoxy)phosphoryl]-1-alaninate, (2E)-but-2-enedioic acid (2:1) Molecular formula: C21H29O5N6P·1/2(C4H4O4) Molecular weight: 534.50

This product is a film-coated tablet, which appears white or off-white after removing the coating.

Tenofovir alafenamide fumarate tablets are suitable for the treatment of chronic hepatitis B in adults and adolescents (aged 12 years and above, weighing at least 35 kg) (see [Pharmacology and Toxicology]).

Treatment should be initiated by a physician experienced in the management of chronic hepatitis B. Adults and adolescents (age 12 years and older and weighing at least 35 kg): One tablet once daily. Oral. To be taken with food. Missed dose If a dose of tenofovir alafenamide is missed and it has been less than 18 hours since the usual time of taking the medication, the patient should take a dose as soon as possible and resume the normal dosing schedule. If it has been more than 18 hours since the usual time of taking the medication, the patient should not take the missed dose and should only resume the normal dosing schedule. If the patient vomits within 1 hour after taking tenofovir alafenamide, the patient should take another tablet. If the patient vomits more than 1 hour after taking tenofovir alafenamide, the patient does not need to take another tablet. Special populations Elderly No dose adjustment of tenofovir alafenamide tablets is required for patients aged 65 years and older (see [Pharmacology and Toxicology]). Renal impairment No dose adjustment is required for adults or adolescents (aged at least 12 years and weighing at least 35 kg) with an estimated creatinine clearance (CrCl) ≥ 15 mL/min or patients with CrCl < 15 mL/min who are receiving hemodialysis. On the day of hemodialysis, tenofovir alafenamide tablets should be given after the hemodialysis treatment is completed (see [Pharmacology and Toxicology]). No dosing recommendation is available for patients with CrCK 15 mL/min who are not receiving hemodialysis (see [Pharmacology and Toxicology]). Hepatic impairment No dose adjustment of tenofovir alafenamide tablets is required for patients with hepatic impairment (see [Precautions] and see [Pharmacology and Toxicology]). Pediatric population The safety and efficacy of tenofovir alafenamide tablets in children under 12 years of age or weighing < 35 kg have not been established. No data are available.

Summary of safety characteristics of overseas patients The adverse reaction assessment is based on pooled safety data from 2 controlled Phase 3 studies overseas in which 866 HBV-infected patients were treated with tenofovir alafenamide 25 mg once daily in a double-blind manner until week 96 (median duration of blinded study drug exposure was 104 weeks). The most commonly reported adverse reactions were headache (12%), nausea (6%), and fatigue (6%). After week 96, patients continued to receive their original blinded treatment or received open-label tenofovir alafenamide fumarate tablets. No other adverse reactions of tenofovir alafenamide fumarate tablets were found in the subgroup of subjects treated with open-label tenofovir alafenamide fumarate tablets from week 96 to week 120 of the double-blind period (see [Pharmacology and Toxicology]). Summary of adverse reactions The following adverse reactions have been found when tenofovir alafenamide is used in patients with chronic hepatitis B (Table 1). The following adverse reactions are listed by body system organ classification and frequency based on the analysis of week 96 of overseas studies. Frequency was defined as follows: very common (>1/10), common (>1/100 to <1/10), uncommon (>/1,000 to <1/100), rare (>1/10,000 to <1/1,000), or very rare (<1/10,000). Table 1: Adverse reactions found in overseas subjects using tenofovir alafenamide Changes in lipid laboratory tests In the pooled analysis of study 108110, 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 LDL and triglycerides were observed, while the tenofovir alafenamide group showed decreases in median values for all parameters. In patients initially randomized to tenofovir alafenamide 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 0 (-16, 18): DL 8 (-6, 24): HDL -5 (-12, 2) triglycerides 11 (-11, 40): total cholesterol HDL ratio 0.3 (0.0, 0.7). For patients in the open-label tenofovir alafenamide group, the median (Q1, Q3) changes from double-blind baseline to Week 144 were as follows (mg/dL): total cholesterol, 1 (-17, 20); LDL, 9 (-5, 26); HDL, -8 (-15, -1); triglycerides, 14 (-10, 43); total cholesterol to HDL ratio, 0.4 (0.0, 1.0). The lipid parameters at week 144 for patients receiving tenofovir alafenamide were similar to those at week 96: increases in median fasting total cholesterol, direct LDL, HDL, and triglycerides were observed in patients who switched from tenofovir alafenamide to tenofovir alafenamide at week 96. During the open-label period, the median changes in the ratio of total cholesterol to HDL from week 96 to week 144 were 0.0 (-0.1) and 0.2 (-1.0) for patients who continued to receive tenofovir alafenamide and those who switched from tenofovir alafenamide to tenofovir alafenamide at week 96, respectively. 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 to tenofovir alafenamide, increases in median fasting total cholesterol, LDL, HDL, and triglycerides were observed, while the group that continued to receive tenofovir showed decreases in median fasting total cholesterol, HDL, and triglycerides and minimal increases in median LDL (p<0.05 for between-treatment differences in all parameters).

Hypersensitivity to the active ingredients or any of the following excipients: lactose, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc and iron oxide yellow.

Precautions for children: The safety and efficacy of tenofovir alafenamide fumarate tablets in children under 12 years of age or weighing less than 35 kg have not been established. No data are available. Precautions for pregnancy and lactation: There is no data on the use of tenofovir alafenamide in pregnant women or such data are very limited (less than 300 pregnancy outcomes). However, a large amount of data on pregnant women (more than 1000 exposure outcomes) shows that there is no morphological or fetal/neonatal toxicity associated with tenofovir disoproxil fumarate. Regarding reproductive toxicity, animal studies have not shown direct or indirect adverse effects (see [Pharmacology and Toxicology]), and if necessary, tenofovir alafenamide fumarate tablets can be considered for use during pregnancy. It is not clear whether tenofovir alafenamide is secreted into human milk. However, animal study results have shown that tenofovir can be secreted into breast milk. There is insufficient information on the effects of tenofovir in neonates/infants. Risks to breastfeeding children cannot be ruled out. Therefore, tenofovir alafenamide fumarate tablets should not be used during breastfeeding. There is no data on the effect of tenofovir alafenamide fumarate tablets on human fertility. Animal studies have not shown that tenofovir alafenamide has a harmful effect on fertility. Elderly precautions: No dose adjustment of tenofovir alafenamide fumarate tablets is required for patients aged 65 years and above (see [Pharmacology and Toxicology]).

Interaction studies have been conducted only in adults. Tenofovir alafenamide fumarate tablets should not be co-administered with medicinal products containing tenofovir disoproxil fumarate, tenofovir alafenamide, or adefovir dipivoxil. Medications that may affect tenofovir alafenamide Tenofovir alafenamide is transported by P-gp and breast cancer resistance protein (BCRP). P-gp inducers are expected to reduce plasma concentrations of tenofovir alafenamide, which may result in loss of efficacy of tenofovir alafenamide tablets (see Table 2). Co-administration of tenofovir alafenamide tablets with medicinal products that inhibit P-gp and/or BCRP may increase plasma concentrations of tenofovir alafenamide. In vitro, tenofovir alafenamide is a substrate of OATP1B1 and OATP1B3. The in vivo distribution of tenofovir alafenamide may be affected by the activity of OATP1B1 and/or OATP1B3. Effects of tenofovir alafenamide on other drugs In vitro, tenofovir alafenamide is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 or CYP2D6. In vivo, it is not an inhibitor or inducer of CYP3A. In vitro, tenofovir alafenamide is not an inhibitor of human uridine diphosphate glucuronosyltransferase (UGT) 1A1. It is not clear whether tenofovir alafenamide is an inhibitor of other UGT enzymes. The following Table 2 summarizes the drug interaction information between tenofovir alafenamide fumarate tablets and possible co-administered drugs ("↑" indicates increase, "↓" indicates decrease, "←→" indicates no change, "b.i.d." means twice daily, "s.d." means single dose, "q.d." means once daily; "IV" means intravenous route). The drug interactions are based on studies conducted with tenofovir alafenamide or are drug interactions that may occur when using tenofovir alafenamide fumarate tablets.

Store below 30°C.

25mg*30 tablets

24 months

Chengdu Easton Bio Pharmaceuticals Co., Ltd.

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  2009-06-01

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