LONZEAL LONGGANKANG Tenofovir Alafenamide Fumarate Tablets For Hepatitis 25mg*30

[Drug Name]
Generic Name: Tenofovir Alafenamide Fumarate Tablets
Trade Name: Longgankang
English Name: Tenofovir Alafenamide Fumarate Tablets
Chinese Pinyin: FuMaSuanBingFenTiNuoFuWeiPian

[Ingredients]
Tenofovir Alafenamide Fumarate.

[Properties]
This product is a film-coated tablet. It appears white or off-white after removal of the coating.

[Indications]
Tenofovir Alafenamide Fumarate Tablets are indicated for the treatment of chronic hepatitis B in adults and adolescents (aged 12 years and older, weighing at least 35 kg) (see [Pharmacology and Toxicology]).

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

[Adverse Reactions]
Summary of the Safety Profile in Overseas Patients: Adverse reaction assessments were based on pooled safety data from two controlled Phase 3 studies in which 866 HBV-infected patients received tenofovir alafenamide 25 mg once daily in a double-blind manner through Week 96 (median duration of blinded study drug exposure, 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 tablets. No other adverse reactions associated with tenofovir alafenamide tablets were observed in the subgroup of subjects receiving open-label tenofovir alafenamide tablets during the double-blind period from Weeks 96 to 120 (see [Pharmacology and Toxicology]).

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

[Precautions]
1. Hepatitis Exacerbation: Sudden onset after discontinuation of treatment. Warning: Acute exacerbations of hepatitis (usually associated with elevated plasma HBV DNA levels) have been reported in patients who discontinued hepatitis B treatment. Most cases are self-limited, but severe exacerbations, including fatal outcomes, may occur after discontinuation of hepatitis B treatment. Liver function should be monitored regularly with clinical and laboratory follow-up for at least 6 months after discontinuation of hepatitis B treatment. If appropriate, hepatitis B treatment may need to be resumed. Discontinuation of treatment is not recommended in patients with advanced liver disease or cirrhosis, as worsening hepatitis after treatment may lead to hepatic decompensation. In patients with decompensated liver disease, hepatitis flares are particularly severe and sometimes fatal. Spontaneous exacerbations of chronic hepatitis B are relatively common during treatment and are characterized by transient increases in serum alanine aminotransferase (ALT). After initiating antiviral therapy, some patients may experience increases in serum ALT. In patients with compensated liver disease, such increases in serum ALT are typically not accompanied by increases in serum bilirubin concentrations or liver decompensation. Patients with cirrhosis may be at increased risk of liver decompensation following an exacerbation and should therefore be closely monitored during treatment. 2. HBV Transmission: Patients must be informed that tenofovir alafenamide tablets do not protect against the risk of HBV transmission through sexual contact or blood contamination. Appropriate precautions must continue. 3. Patients with Decompensated Liver Disease: There are no safety and efficacy data for tenofovir alafenamide tablets in patients with decompensated liver disease and HBV infection with a Child Pugh Turcotte (CPT) score > 9 (i.e., Class C). These patients may be at increased risk for serious hepatic or renal adverse reactions. Therefore, hepatobiliary and renal indices and parameters in this patient population should be closely monitored (see [Pharmacology and Toxicology]). 4. Lactic Acidosis/Severe Hepatomegaly Lactic acidosis and severe hepatomegaly, including fatal cases, have been reported with the use of nucleoside analogs (including tenofovir disoproxil fumarate or other tenofovir prodrugs) alone or in combination with other antiretroviral drugs. Treatment with tenofovir alafenamide tablets should be suspended in any patient whose clinical or laboratory results suggest lactic acidosis or significant hepatotoxicity (which may include hepatomegaly and steatosis, even in the absence of significant transaminase elevations). 5. Renal Impairment: Patients with Creatinine Clearance < 30 mL/min. The use of once-daily tenofovir alafenamide tablets in patients with creatinine clearance ≥ 15 mL/min but < 30 mL/min, and patients with creatinine clearance < 15 mL/min undergoing hemodialysis, is based on very limited pharmacokinetic data and modeling and simulations. There are no safety data for the use of tenofovir alafenamide tablets in HBV-infected patients with creatinine clearance < 30 mL/min. Tenofovir alafenamide tablets are not recommended for patients with creatinine clearance < 15 mL/min who are not undergoing hemodialysis (see [Dosage and Administration]). 6. Nephrotoxicity: The potential risk of nephrotoxicity from long-term exposure to low levels of tenofovir with tenofovir alafenamide administration cannot be ruled out (see [Pharmacology and Toxicology]). 7. Patients Coinfected with HBV and Hepatitis C or Hepatitis D Virus: There are no data on the safety and efficacy of tenofovir alafenamide tablets in patients coinfected with hepatitis C or hepatitis D virus. Coadministration guidelines for hepatitis C treatment should be followed (see [Drug Interactions]). 8. Hepatitis B and HIV Coinfection: Due to the risk of HIV drug resistance, tenofovir alafenamide tablets are not recommended for the treatment of HIV-1 infection. The safety and efficacy of tenofovir alafenamide tablets in patients coinfected with HIV-1 and HBV have not been established. Before initiating treatment with tenofovir alafenamide tablets, all HBV-infected patients should undergo HIV antibody testing. If positive, they should receive the appropriate antiretroviral combination regimen recommended for patients coinfected with HIV-1. 9. Concomitant Use with Other Medications: Tenofovir alafenamide tablets should not be used concomitantly with products containing tenofovir alafenamide, tenofovir disoproxil fumarate, or adefovir dipivoxil. 10. Lactose Intolerance: Tenofovir alafenamide tablets contain alpha-lactose. Therefore, patients with rare genetic problems of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medication. 11. Effects on Ability to Drive and Use Machinery: Tenofovir alafenamide tablets have no or negligible effects on the ability to drive and use machinery. Patients should be informed that dizziness has been reported during treatment with tenofovir alafenamide tablets.

[Special Use]
Precautions for Use in Children:
The safety and efficacy of tenofovir alafenamide tablets in children under 12 years of age or weighing less than 35 kg have not been established. No data are available.

Pregnancy and Lactation Precautions:
Pregnancy: There are no data on the use of tenofovir alafenamide in pregnant women, or such data are very limited (fewer than 300 pregnancies). However, extensive data on pregnant women (over 1000 exposures) indicate no teratogenicity or fetal/neonatal toxicity associated with tenofovir disoproxil fumarate. Regarding reproductive toxicity, animal studies have not demonstrated direct or indirect adverse effects (see [Pharmacology and Toxicology]). If necessary, use of tenofovir alafenamide tablets during pregnancy may be considered. Lactation: It is unknown whether tenofovir alafenamide is excreted in human milk. However, results from animal studies have shown that tenofovir is excreted in breast milk. There is insufficient information on the effects of tenofovir in neonates/infants. A risk to breastfeeding children cannot be excluded. Therefore, tenofovir alafenamide tablets should not be used during breastfeeding. Fertility: There are no data regarding the effects of tenofovir alafenamide tablets on human fertility. Animal studies have not shown that tenofovir alafenamide adversely affects fertility.

Elderly Precautions:
No dose adjustment of tenofovir alafenamide tablets is required for patients aged 65 years and older (see [Pharmacology and Toxicology]).

[Drug Interactions]
Interaction studies have been conducted only in adults. Tenofovir alafenamide tablets should not be coadministered 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 decrease tenofovir alafenamide plasma concentrations, which may result in loss of efficacy of tenofovir alafenamide tablets (see Table 2). Coadministration of tenofovir alafenamide fumarate tablets with medicinal products that inhibit P-gp and/or BCRP may increase tenofovir alafenamide plasma concentrations. 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 medicinal products: 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 unknown whether tenofovir alafenamide is an inhibitor of other UGT enzymes. Table 2 below summarizes drug interaction information between tenofovir alafenamide fumarate tablets and potential concomitant medicinal products ("↑" indicates an increase, "↓" indicates a decrease, "←→" indicates no change, "b.i.d." indicates twice daily, "s.d." indicates single dose, "q.d." indicates once daily, and "IV" indicates intravenous administration). These drug interactions are based on studies conducted with tenofovir alafenamide or are potential drug interactions with the use of tenofovir alafenamide fumarate tablets. See the package insert for details.

[Pharmacological Actions]
Pharmacological Actions Mechanism of Action: Tenofovir alafenamide is a phosphoramidite prodrug of tenofovir (a 2'-deoxyadenosine monophosphate analog). Tenofovir alafenamide enters primary hepatocytes via passive diffusion and the hepatic uptake transporters OATP1B1 and OATP1B3. Within primary hepatocytes, tenofovir alafenamide is primarily hydrolyzed by carboxylesterase 1 to form tenofovir. Tenofovir is subsequently phosphorylated within the cell to form the pharmacologically active metabolite, tenofovir diphosphate. Tenofovir diphosphate inhibits HBV replication by incorporating it into viral DNA via HBV reverse transcriptase, leading to DNA chain termination. Tenofovir has specific activity against hepatitis B virus and human immunodeficiency virus (HIV-1 and HIV-2). Based on multiple studies, including mitochondrial DNA analysis, tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerases, including mitochondrial DNA polymerase γ, and exhibits no evidence of mitochondrial toxicity in vitro. Antiviral activity: The antiviral activity of tenofovir alafenamide was evaluated 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. CC50 (50% cytotoxic concentration) > 44,400 nM in HepG2 cells. Resistance: In a pooled analysis of overseas patients treated with tenofovir alafenamide, matched baseline and treatment comparisons were performed for patients who experienced virologic breakthrough (HBV DNA ≥ 69 IU/mL for two consecutive visits after HBV DNA < 69 IU/mL, or an increase of 1.0 log10 or greater from the nadir HBV DNA), patients with HBV DNA ≥ 69 IU/mL (week 96 only), or patients with HBV DNA ≥ 69 IU/mL at premature discontinuation at week 24 or later. Cross-resistance: The antiviral activity of tenofovir alafenamide against a panel of isolates harboring nucleos(t)ide reverse transcriptase inhibitor mutations was evaluated in HepG2 cells. HBV isolates expressing the rtV173L, rtL180M, and rtM204V/I substitutions associated with lamivudine resistance remained susceptible to tenofovir alafenamide (EC50 fold change < 2). HBV isolates expressing the rtL180M, rtM204V, rtT184G, rtS202G, or rtM250V substitutions associated with entecavir resistance remained susceptible to tenofovir alafenamide. HBV isolates expressing the rtA181T, rtA181V, or rtN236T single mutations associated with adefovir resistance remained susceptible to tenofovir alafenamide; however, HBV isolates expressing rtA181V or rtN236T showed reduced susceptibility to tenofovir alafenamide (EC50 fold change of 3.7). The clinical relevance of these substitutions is unknown. Nonclinical Toxicology: Nonclinical studies in rats and dogs revealed that bones and kidneys were the primary target organs of toxicity. Bone toxicity, including decreased bone mass density, was observed in rats and dogs at tenofovir exposures at least four times the expected exposure following administration of tenofovir alafenamide. Minimal histiocytic infiltration of the eyes was observed in dogs at exposures approximately four times and 17 times the expected exposure following administration of tenofovir alafenamide, respectively. Tenofovir alafenamide was not mutagenic or clastogenic in conventional genotoxicity analyses. Tenofovir alafenamide exposures in rats and mice were lower than those following administration of tenofovir disoproxil fumarate, so only carcinogenicity studies and perinatal-postnatal studies in rats were conducted using tenofovir disoproxil fumarate. Conventional studies of carcinogenic potential using tenofovir disoproxil fumarate and conventional reproductive and developmental studies using tenofovir disoproxil fumarate or tenofovir alafenamide showed no specific hazard to humans. Reproductive toxicity studies in rats and rabbits showed no effects on mating, fertility, pregnancy, or fetal parameters. However, in perinatal and postnatal toxicity studies at maternally toxic doses, tenofovir disoproxil fumarate reduced pup vitality and body weight. Long-term oral carcinogenicity studies in mice showed a low incidence of duodenal tumors, which is believed to be related to higher local gastrointestinal drug concentrations at the high dose of 600 mg/kg/day. The mechanism of tumor formation in mice and its potential relevance to humans have not been determined.

Storage: Store below 30°C

Specifications: 25 mg x 30 tablets per bottle

Packaging: Oral solid high-density polyethylene bottle, 30 tablets/bottle/box.

Expiration Date: 18 months

Approval Number: National Medicine Standard H20213310

Manufacturer: Shijiazhuang Longze Pharmaceutical Co., Ltd.