Date of approval.
Date of revision.
Propofol Tenofovir Fumarate Tablets Instructions
Please read the instructions carefully and use under the guidance of a doctor
Drug Name]
Generic name: Tenofovir alafenamide Fumarate Tablets
English name: Tenofovir alafenamide Fumarate Tablets
Hanyu Pinyin: Fumasuan Bingfentinuofuwei Pian
Ingredients
The main ingredient of this product is tenofovir propofol fumarate.
Chemical name: Prop-2-yl N-[(S)-({[(2R)-1-(6-amino-9H-purin-9-yl)propan-2-yl]-oxo}methyl)(phenoxy)phosphoryl]-l-alanine ester, (2E)-but-2-enoic acid (2:1)
Chemical structure formula.
Molecular formula: C21H29O5N6P-½(C4H4O4)
Molecular weight: 534.50
【Properties】.
This product is a yellow round film coated tablet, after removing the coating, it appears white or off-white.
Indications
Propofol Tenofovir Fumarate Tablets are indicated for the treatment of chronic hepatitis B in adults and adolescents (age 12 years and older, weight at least 35 kg) (see [Pharmacology and Toxicology]).
Specification
25mg (as propofol tenofovir)
Dosage]
Treatment should be initiated by a physician with experience 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. Take orally. To be taken with food.
Missed Doses
If a dose of tenofovir propofol fumarate is missed and the usual dosing time has been exceeded by less than 18 hours, the patient should take a dose as soon as possible and resume the normal dosing schedule. If more than 18 hours have elapsed since the usual dosing time, the patient should not take the missed dose and should only resume the normal dosing schedule.
If a patient vomits within 1 hour of taking a propofol tenofovir fumarate tablet, that patient should take an additional tablet. If a patient vomits more than 1 hour after taking tenofovir disoproxil fumarate, the patient should not take another tablet.
Special Populations
Elderly people
No dose adjustment of tenofovir disoproxil fumarate tablets is required for patients aged 65 years and older (see [Pharmacology and Toxicology]).
Renal impairment
No dose adjustment of tenofovir disoproxil fumarate is required for adults or adolescents (age at least 12 years and weight at least 35 kg) with estimated creatinine clearance (CrCl) ≥ 15 mL/min or CrCl<15 mL/min who are receiving hemodialysis.
On the day of hemodialysis, propofol tenofovir fumarate tablets should be given after completion of hemodialysis treatment (see [Pharmacology and Toxicology]).
There are no dosing recommendations for patients with CrCl<15mL/min who are not receiving hemodialysis (see [Pharmacology and Toxicology]).
Hepatic Impairment
No dose adjustment of tenofovir propofol fumarate tablets is required for patients with hepatic impairment (see [Precautions] and see [Pharmacology and Toxicology]).
Pediatric Population
The safety and efficacy of Tenofovir Propofol Fumarate Tablets have not been established in children younger than 12 years of age or weighing <35 kg. There are no available data.
[Adverse Reactions].
Summary of safety profile in overseas patients
Adverse reactions were evaluated based on pooled safety data from 2 controlled phase 3 studies overseas in which 866 HBV-infected patients received propofol tenofovir 25 mg once daily in a double-blind manner until week 96 (median duration of drug exposure in blinded studies was 104 weeks). The most frequently reported adverse reactions were headache (12%), nausea (6%), and fatigue (6%). After week 96, patients continued treatment with their original blinded state or received open-label propofol tenofovir fumarate tablets. No other adverse reactions were identified in the subgroup of subjects treated with open-label tenofovir disoproxil fumarate tablets from week 96 to week 120 of the double-blind period (see [Pharmacology and Toxicology]).
Summary Table of Adverse Reactions
The following adverse reactions have been identified with the use of propofol tenofovir in patients with chronic hepatitis B (Table 1). Adverse reactions are listed below by body system organ classification and frequency of occurrence based on analysis at week 96 of the overseas study. The frequencies are defined as follows: very common (≥1/10), common (≥1/100 to <1/10), rare (≥1/1,000 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 with propofol tenofovir
Systemic Organ Classification Frequency Adverse Reactions Gastrointestinal Disorders Common Diarrhea, Vomiting, Nausea, Abdominal Pain, Bloating, Flatulence Systemic Disorders and Drug Site Conditions Common Fatigue Neurologic Disorders Very Common Headache Common Dizziness Skin and Subcutaneous Tissue Disorders Common Rash, Pruritus Hepatobiliary Disorders Common Increased Alanine Aminotransferase Musculoskeletal and Connective Tissue Disorders Common Arthralgia Safety in Mainland China Patients Summary of Characteristics
Assessment of adverse reactions in mainland Chinese patients was based on safety data analyzed through week 96 from 2 phase 3 studies in mainland China (227 mainland Chinese patients with HBV infection in the study received 25 mg of once-daily propofol tenofovir treatment). The safety profile of mainland Chinese patients with HBV infection receiving propofol tenofovir was generally consistent with the safety profile observed in the 2 phase 3 overseas studies.
None of the patients in mainland China discontinued propofol tenofovir treatment due to adverse events.
Report of suspected adverse reactions
The reporting of suspected adverse reactions after drug approval is important. This allows continuous monitoring of the benefit/risk balance of the use of the drug. In China, healthcare professionals are required to report any suspected adverse reactions through the national reporting system.
Contraindications
Hypersensitivity to the active ingredient or any of the excipients listed below: alpha lactose, microcrystalline cellulose, cross-linked sodium carboxymethylcellulose, magnesium stearate, polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc and iron oxide yellow.
Precautions]
1.Worsening of hepatitis
Sudden onset after stopping treatment
Warning: Acute exacerbations of hepatitis (usually associated with elevated plasma HBVDNA levels) have been reported in patients who discontinued hepatitis B treatment. Most cases are self-limiting, but severe exacerbations (including fatal outcomes) may occur after discontinuation of hepatitis B treatment. Liver function monitoring should be performed regularly through clinical and laboratory follow-up for at least 6 months after discontinuation of hepatitis B treatment. If appropriate, resumption of hepatitis B therapy may be required.
In patients with progressive liver disease or cirrhosis, discontinuation of therapy is not recommended because exacerbation of hepatitis after treatment may lead to hepatic decompensation. In patients with decompensated liver disease, hepatitis flare-ups are particularly serious and sometimes fatal.
Outbreaks during treatment
Spontaneous exacerbations of chronic hepatitis B are relatively common and are characterized by a transient increase in serum alanine aminotransferase (ALT). Serum ALT may increase in some patients after initiation of antiviral therapy. In patients with compensated liver disease, such increases in serum ALT are usually not accompanied by increased serum bilirubin concentrations or hepatic decompensation. Patients with cirrhosis may be at higher risk of developing hepatic decompensation after hepatitis has worsened and should therefore be monitored closely during treatment.
2. HBV transmission
Patients must be informed that propofol tenofovir fumarate tablets do not prevent the risk of HBV transmission by means of sexual contact or blood contamination. Appropriate prophylactic measures must continue to be taken.
3.Patients with decompensated liver disease
There are no data on the safety and efficacy of tenofovir disoproxil fumarate tablets in patients with decompensated liver disease and HBV infection with a ChildPughTurcotte (CPT) score>9 (i.e., grade C). These patients may be at higher risk for serious hepatic or renal adverse reactions. Therefore, hepatobiliary and renal indicators and parameters should be closely monitored in this patient population (see [Pharmacology and Toxicology]).
4. Lactic acidosis/severe fatty hepatomegaly
Lactic acidosis and severe fatty hepatomegaly, including fatal cases, have been reported when treated with nucleoside analogs (including tenofovir disoproxil fumarate or other tenofovir precursors) alone or in combination with other antiretroviral drugs. Treatment with propofol tenofovir fumarate tablets should be suspended in any patient whose clinical or laboratory findings suggest lactic acidosis or significant hepatotoxicity (which may include hepatomegaly and steatosis, even if transaminases are not significantly elevated).
5. Renal impairment
Patients with creatinine clearance <30mL/min
The use of once-daily propofol tenofovir fumarate tablets in patients with CrCl ≥ 15 mL/min but <30 mL/min and in patients with CrCl <15 mL/min who are on hemodialysis is based on extremely limited pharmacokinetic data and modeling and simulation. No safety data are available for the use of propofol tenofovir fumarate tablets in the treatment of HBV-infected patients with CrCl<30mL/min.
Propofol tenofovir fumarate tablets are not recommended for use in patients with CrCl<15mL/min who are not receiving hemodialysis (see [Dosage]).
6.Nephrotoxicity
The potential risk of nephrotoxicity due to prolonged exposure to low levels of tenofovir as a result of propofol tenofovir administration cannot be excluded (see [Pharmacology and Toxicology]).
7. Patients co-infected with HBV and hepatitis C or hepatitis D virus
No data are available on the safety and efficacy of tenofovir propofol fumarate tablets in patients co-infected with hepatitis C or hepatitis D virus. Combination medication guidelines for the treatment of hepatitis C should be followed (see [Drug Interactions]).
8. Hepatitis B and HIV co-infection
Propofol tenofovir fumarate tablets are not recommended for the treatment of HIV-1 infection because of the risk of developing HIV resistance. The safety and efficacy of tenofovir propofol fumarate tablets in patients co-infected with HIV-1 and HBV have not been established. Prior to initiating treatment with tenofovir disoproxil fumarate, all HBV-infected patients should be tested for HIV antibodies and, if positive, the appropriate combination antiretroviral regimen recommended for patients co-infected with HIV-1 should be used.
9. Combination with other drugs
Tenofovir propofol fumarate tablets should not be used in combination with products containing tenofovir propofol, tenofovir disoproxil fumarate or adefovir.
10.Lactose intolerance
Tenofovir propofol fumarate tablets contain alpha lactose. Therefore, patients suffering from galactose intolerance, Lapp lactase deficiency or a rare genetic problem of glucose-galactose malabsorption should not take this drug.
11. Effects on the ability to drive and operate machinery
Propofol tenofovir fumarate tablets have no or negligible effect on the ability to drive and operate machinery. Patients should be informed that dizziness has been reported during treatment with tenofovir disoproxil fumarate.
For Pregnant and Lactating Women]
Pregnancy
There are no or very limited data on the use of propofol tenofovir in pregnant women (less than 300 pregnancy outcomes). However, a large body of data on pregnant women (over 1000 exposure outcomes) suggests no malformations or fetal/neonatal toxicity associated with tenofovir disoproxil fumarate.
With regard to reproductive toxicity, animal studies have not demonstrated direct or indirect harmful effects (see [Pharmacologic Toxicology]).
If indicated, tenofovir disoproxil fumarate tablets may be considered for use during pregnancy.
Lactation
It is not known whether propofol tenofovir is secreted into human breast milk. However, results from animal studies have shown that tenofovir can be secreted into breast milk. There is insufficient information on the effects of tenofovir in newborns/infants.
Risks to nursing children cannot be excluded. Therefore, tenofovir propofol fumarate tablets should not be used during breast-feeding.
Fertility
No data are available on the effect of propofol tenofovir disoproxil fumarate tablets on human fertility. Animal studies have not shown that propofol tenofovir has a deleterious effect on fertility.
Pediatric Dosage]
The safety and efficacy of Tenofovir Propofol Fumarate Tablets have not been established in children younger than 12 years of age or weighing <35 kg. There are no available data.
Geriatric Use]
No dose adjustment of Tenofovir Propofol Fumarate Tablets is required for patients aged 65 years and older (see [Pharmacology and Toxicology]).
Drug Interactions]
Interaction studies have been conducted in adults only.
Tenofovir propofol fumarate tablets should not be used in combination with drugs containing tenofovir disoproxil fumarate, propofol tenofovir, or adefovir.
Drugs that may affect propofol tenofovir
Propofol tenofovir is transported by Pgp and breast cancer resistance protein (BCRP). P-gp inducer drugs are expected to decrease propofol tenofovir plasma concentrations, which may result in loss of efficacy of propofol tenofovir fumarate tablets (see Table 2).
Combination of propofol tenofovir fumarate tablets with drugs that inhibit Pgp and/or BCRP may increase propofol tenofovir plasma concentrations.
In vitro, propofol tenofovir is a substrate for OATP1B1 and OATP1B3. The in vivo distribution of propofol tenofovir may be affected by OATP1B1 and/or OATP1B3 activity.
Effect of Propofol Tenofovir on Other Drugs
In vitro, propofol tenofovir is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6. In vivo, it is also not an inhibitor or inducer of CYP3A.
In vitro, propofol tenofovir is not an inhibitor of human uridine diphosphate glucuronosyltransferase (UGT) 1A1. It is not clear whether propofol tenofovir is an inhibitor of other UGT enzymes.
Drug interaction information between propofol tenofovir fumarate tablets and drugs that may be combined is summarized in Table 2 below (“↑” indicates an increase, “↓” indicates a decrease, and “↔” indicates no change; “b.i.d.” indicates twice-daily, “s.d.” indicates single dose, and “q.d.” indicates once daily; “IV” indicates intravenous route). The drug interactions described are based on studies conducted using propofol tenofovir or drug interactions that may occur with the use of propofol tenofovir fumarate tablets.
Table 2: Interactions between propofol tenofovir and other drugs
Effect of drugs on drug levels by therapeutic areaa,b.
Mean ratio (90% confidence interval) of AUC, Cmax, Cmin on the proposed anticonvulsant carbamazepine in combination with propofol tenofovir fumarate tablets
(300 mg given orally, b.i.d.)
Propofol tenofovir c
(25 mg given orally, s.d.) Propofol tenofovir
↓Cmax0.43(0.36,0.51)
↓AUC0.45(0.40,0.51)
tenofovir
↓Cmax0.70(0.65,0.74)
↔AUC0.77(0.74,0.81) Combination is not recommended. Oxcarbazepine.
Interactions have not been studied with phenobarbital.
Expected.
↓ Propofol tenofovir is not recommended for combination. Phenytoin Interactions have not been studied.
Expected.
↓ Propofol tenofovir is not recommended for co-administration. Midazolam d
(2.5 mg given orally, s.d.)
Propofol tenofovirc
(25 mg given orally, q.d.) Midazolam
↔Cmax1.02(0.92,1.13)
↔ AUC1.13(1.04,1.23) No dose adjustment for midazolam (given orally or intravenously) is required. Midazolam d
(1 mg IV,s.d.)
Propofol tenofovir c
(25 mg given orally, q.d.) Midazolam
↔Cmax0.99(0.89,1.11)
↔ AUC1.08(1.04,1.14) antidepressant sertraline
(50 mg given orally, s.d.)
Propofol tenofovir e
(10 mg given orally, q.d.) Propofol tenofovir
↔Cmax1.00(0.86,1.16)
↔ AUC0.96(0.89,1.03)
Tenofovir.
Tenofovir ↔ Cmax1.10(1.00,1.21)
Tenofovir ↔ AUC1.02(1.00,1.04)
↔Cmin1.01(0.99,1.03) No dose adjustment for tenofovir propofol fumarate tablets or sertraline is required. Sertraline.
(50 mg given orally, s.d.)
Propofol Tenofovir e
(10 mg given orally, q.d.) Sertraline
↔Cmax1.14(0.94,1.38)
↔ AUC0.93(0.77,1.13) antifungal Itraconazole
Ketoconazole has not been studied for interaction.
Expected.
↑ Propofol tenofovir is not recommended for combination. Anti-branched bacillus drug rifampicin
Rifapentine
Interactions have not been studied.
Expected.
↓ Propofol tenofovir is not recommended for combination. Rifabutin Interactions have not been studied.
Expected.
↓ Propofol tenofovir is not recommended for co-administration. HCV antiviral sofosbuvir (400 mg given orally, q.d.) has not been studied for interaction.
Expected.
↔ Sofosbuvir.
↔ GS331007 No dose adjustment of tenofovir propofol fumarate tablets or sofosbuvir is required. Ledipavir/sofosbuvir
(90 mg/400 mg given orally, q.d.)
Propofol Tenofovir f
(25 mg given orally, q.d.) Ledipavir
↔Cmax1.01(0.97,1.05)
↔ AUC1.02(0.97,1.06)
Cmin1.02(0.98,1.07) ↔ Cmin1.02(0.98,1.07)
Sofosbuvir.
Sofosbuvir ↔ Cmax0.96(0.89,1.04)
Sofosbuvir ↔ AUC1.05(1.01,1.09)
GS331007g
↔ Cmax1.08(1.05,1.11)
GS331007g ↔ AUC1.08(1.06,1.10)
Cmin1.10(1.07,1.12) ↔ Cmin1.10(1.07,1.12)
Propofol tenofovir
Cmax1.03(0.94,1.14) ↔ Cmax1.03(0.94,1.14)
AUC1.32(1.25,1.40) ↔ AUC1.32(1.25,1.40)
Tenofovir
↑Cmax1.62(1.56,1.68)
↑AUC1.75(1.69,1.81)
↑Cmin1.85(1.78,1.92) No dose adjustment of tenofovir propofol fumarate tablets or ledipavir/sofosbuvir is required. Sofosbuvir/vipatavir
(400 mg/100 mg given orally, q.d.) Interactions have not been studied.
Expected.
↔ Sofosbuvir.
↔ GS331007
↔ Vipatavir
↑ Propofol tenofovir does not require dose adjustment for propofol tenofovir fumarate tablets or sofosbuvir/vipatasvir. Sofosbuvir/vipatasvir/vociclib (400mg/100mg/100mg+100mgi orally, q.d.)
Propofol tenofovir f
(25mg orally, q.d.) Sofosbuvir
↔Cmax0.95(0.86,1.05)
AUC1.01(0.97,1.06) ↔ AUC1.01(0.97,1.06)
GS331007g
GS331007g ↔ Cmax1.02(0.98,1.06)
AUC1.04(1.01,1.06) ↔ AUC1.04(1.01,1.06)
Vipatavir.
Cmax1.05(0.96,1.16) ↔ Cmax1.05(0.96,1.16)
AUC1.01(0.94,1.07) ↔ AUC1.01(0.94,1.07)
Vipatavir ↔ Cmin1.01(0.95,1.09)
Voxilivir.
Voxilivir ↔ Cmax0.96(0.84,1.11)
Voxilivir ↔ AUC0.94(0.84,1.05)
Cmin1.02(0.92,1.12) ↔ Cmin1.02(0.92,1.12)
Propofol tenofovir fumarate
↑Cmax1.32(1.17,1.48)
↑AUC1.52(1.43,1.61) No dose adjustment for propofol tenofovir fumarate tablets or sofosbuvir/velpatasvir/vosiravir was required. The herbal supplement St. John’s wort (Hypericumperforatum) has not been studied for interactions.
Expected.
↓ Propofol tenofovir is not recommended for co-administration. Oral contraceptive Norgestrel
(0.180 mg/0.215 mg/0.250 mg given orally, q.d.)
Ethinylestradiol
(0.025mg given orally, q.d.)
Propofol tenofovir c
(25 mg given orally, q.d.) Norgestromin
↔Cmax1.17(1.07,1.26)
↔ AUC1.12(1.07,1.17)
Cmin1.16(1.08,1.24) ↔ Cmin1.16(1.08,1.24)
Methylnortriptyline
↔ Cmax1.10(1.02,1.18)
AUC1.09(1.01,1.18) ↔ AUC1.09(1.01,1.18)
Cmin1.11(1.03,1.20) ↔ Cmin1.11(1.03,1.20)
Ethinylestradiol
Cmax1.22(1.15,1.29) ↔ Cmax1.22(1.15,1.29)
AUC1.11(1.07,1.16) ↔ AUC1.11(1.07,1.16)
↔Cmin1.02(0.93,1.12) No dose adjustment for propofol tenofovir fumarate tablets or norgestimate/ethinyl estradiol was required. a. All interaction studies were conducted in healthy volunteers
b. All no-action cut-offs range from 70%143%
c. Studies were conducted using a fixed-dose combination tablet of emtricitabine/propofol tenofovir
d. A sensitive CYP3A4 substrate
e. Studies with a fixed-dose combination tablet of everolimus/cobicistat/emtricitabine/propofol tenofovir
f. Study using an emtricitabine/ribivirine/propofol tenofovir fixed-dose combination tablet
g. Major circulating nucleoside metabolites of sofosbuvir
h. Studies with propofol tenofovir 40 mg and emtricitabine 200 mg
i. Additional studies with fosamprenavir 100mg to achieve the expected fosamprenavir exposure in HCV-infected patients.
Drug Overdose]
If an overdose occurs, patients must be monitored for signs of toxicity (see [Adverse Reactions]).
Treatment of tenofovir tablet overdose with propofol fumarate requires general supportive measures, including monitoring of vital signs and observation of the patient’s clinical status.
Tenofovir can be effectively cleared by hemodialysis with an extraction factor of approximately 54%. It is not known whether peritoneal dialysis can remove tenofovir.
Pharmacology and Toxicology
Pharmacological effects
Tenofovir propofol fumarate is an anti-hepatitis B virus drug.
Mechanism of action
Tenofovir propofol fumarate is a prodrug for the phosphoramidation of tenofovir (2′-deoxyadenosine monophosphate analogue). Tenofovir propofol fumarate enters primary hepatocytes as a lipophilic cell-permeable compound via passive diffusion and hepatic uptake of the transport proteins OATP1B1 and OATP1B3, which are hydrolyzed by carboxylesterase 1 to tenofovir and subsequently phosphorylated by intracellular cellular kinases to form the pharmacologically active metabolite tenofovir diphosphate. Tenofovir diphosphate inhibits HBV replication by integrating into viral DNA via HBV reverse transcriptase and terminating the DNA strand.
Tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerases, including mitochondrial DNA polymerase γ, and has not been shown to be toxic to mitochondria in cell culture.
Antiviral activity
The antiviral activity of tenofovir propofol fumarate was assessed in a transient transfection assay in HepG2 cells against a clinical isolate of HBV representing genotype A-H. The EC50 (half effective concentration) of tenofovir propofol fumarate ranged from 34.7 to 134.4 nM, with an overall mean value of 86.6 nM and a CC50 (half cytotoxic concentration) above 44,400 nM. No antagonistic effects were seen in cellular assays of tenofovir in combination with HBV nucleoside reverse transcriptase inhibitors (entecavir, lamivudine, and telbivudine).
Drug resistance
In a pooled analysis of trials 108 and trials 110 in first-time or previously treated subjects treated with tenofovir propofol fumarate, for virologic breakthrough at week 48 (HBV DNA ≥ 69 IU/mL [400 copies/mL] at 2 consecutive visits after HBV DNA had < 69 IU/mL, or HBV DNA increased from nadir) or subjects with HBV DNA ≥ 69 IU/mL at Week 24 or early discontinuation thereafter, genotypic resistance analysis was performed for baseline paired and on-treatment HBV isolates. On-treatment HBV reverse transcriptase structural domain amino acid substitutions (all occurring at polymorphic positions) were seen in some HBV isolates (5/20); however, no specific substitutions with a sufficiently high incidence associated with tenofovir resistance to propofol fumarate were seen.
Cross-resistance
The antiviral activity of tenofovir propofol fumarate was measured in a HepG2 cell transient transfection assay for a group of isolates with HBV nucleoside reverse transcriptase inhibitor resistance-associated mutations. HBV isolates with the lamivudine resistance-associated mutation rtM204V/I (±rtL180M±rtV173L) and the entecavir resistance-associated mutations rtT184G, rtS202G, or rtM250V (in the case of rtL180M and rtM204V mutations) showed a less than 2-fold decrease in susceptibility to tenofovir with propofol fumarate. HBV isolates with adefovir resistance-associated mutations in either rtA181T, rtA181V, or rtN236T also had less than a 2-fold reduction in EC50 values for tenofovir with propofol fumarate, but the double mutation in rtA181V and rtN236T had a 3.7-fold reduction in sensitivity to tenofovir with propofol fumarate. The clinical relevance of these mutations is not clear.
Toxicological studies
Genotoxicity
No genotoxicity was seen with tenofovir propofol fumarate in the Ames test, mouse lymphoma test, or rat micronucleus test.
Reproductive toxicity
No effects on fertility, mating behavior, or early embryonic development were observed in male rats given the equivalent of 155 times the human dose (in terms of body surface area) of tenofovir propofol fumarate from 28 days prior to mating to the mating period and in female rats from 14 days prior to mating to day 7 of gestation.
In the embryo-fetal development toxicity test, no fertility impairment or embryo-fetal toxicity was observed in pregnant rats and rabbits given orally 25, 100, 250 mg/kg/day and 10, 30, 100 mg/kg/day of tenofovir propofol fumarate during the organogenesis period (days 6-17 of gestation in rats and days 7-20 of gestation in rabbits), and the NOAEL for embryo-fetal toxicity in rats and rabbits was (no adverse effect dose seen) at exposures to tenofovir propofol fumarate equivalent to 1 and 51 times the human recommended daily dose, respectively. Propofol tenofovir fumarate was rapidly converted to tenofovir; exposure to tenofovir measured in rats and rabbits was 54 and 85 times greater than the recommended daily dose of tenofovir in humans, respectively.
Because of the rapid conversion of propofol tenofovir fumarate to tenofovir and the lower tenofovir exposure measured in rats and mice given propofol tenofovir fumarate compared with tenofovir disoproxil (TDF), only the rat perinatal toxicity test with TDF was performed. Doses up to 600 mg/kg/day were administered during lactation; no adverse effects were seen in offspring on day 7 of gestation and day 20 of lactation when tenofovir exposure was approximately 12 and 18 times the recommended daily dose of tenofovir at human propofol fumarate, respectively.
Tests in rats and monkeys have shown that tenofovir can be secreted into breast milk. On day 11 after oral administration of TDF (maximum dose 600 mg/kg/day) to lactating rats, milk concentrations peaked at approximately 24% of the median plasma concentration in the high-dose group of animals. After a single subcutaneous injection of tenofovir 30 mg/kg in lactating monkeys, the concentration in milk was approximately 4% of the plasma concentration and the exposure (AUC) was approximately 20% of the plasma exposure.
Carcinogenicity
Propofol tenofovir fumarate was rapidly converted to tenofovir in rats and mice after administration, and the exposure of the latter was lower than the exposure of tenofovir after TDF administration, so only TDF was used for the carcinogenicity test. In the long-term oral administration carcinogenicity test, tenofovir exposure was up to approximately 10 times (mice) and 4 times (rats) the exposure of tenofovir at a therapeutic dose (300 mg) for human chronic hepatitis B infection with tenofovir disoproxil fumarate, and this exposure was approximately 151 times (mice) and 50 times (rats) the exposure of tenofovir at a therapeutic dose for human tenofovir disoproxil propofol fumarate. The incidence of hepatic adenomas was increased in female mice at high doses (approximately 151 times the human therapeutic dose of tenofovir at propofol fumarate). Results of the carcinogenicity test in rats were negative.
Other
Slight to mild infiltration of posterior uveal mononuclear cells of similar severity was seen in dogs given tenofovir propofol fumarate for 3 and 9 consecutive months; reversible after a three-month recovery period. At the NOAEL for ocular toxicity, the systemic exposure of canine propofol tenofovir and tenofovir fumarate was 5 and 14 times greater than the exposure of propofol tenofovir and tenofovir fumarate at the recommended daily dose of propofol tenofovir fumarate in humans, respectively.
Pharmacokinetics]
Drug treatment group: systemic antiviral drugs, nucleoside and nucleotide reverse transcriptase inhibitors; ATC code: J05AF13.
Absorption
After oral administration of propofol tenofovir fumarate tablets to adult patients with chronic hepatitis B in the fasting state, peak propofol tenofovir plasma concentrations were observed at approximately 0.48 hours after administration. Based on a phase 3 population pharmacokinetic analysis of overseas CHB subjects, the mean steady-state AUC0-24 for propofol tenofovir (N=698) and tenofovir (N=856) were 0.22 µg-hr/mL and 0.32 µg-hr/mL, respectively. steady-state Cmax for propofol tenofovir and tenofovir A single dose of propofol tenofovir fumarate tablets given with a high-fat meal increased propofol tenofovir exposure by 65% relative to the fasting condition.
Based on a phase 3 population pharmacokinetic analysis of CHB subjects in mainland China, the mean steady-state AUC0-24 for propofol tenofovir (N=180) and tenofovir (N=225) were 0.17µg-hr/mL and 0.26µg-hr/mL, respectively. the steady-state Cmax were 0.18 and 0.02µg/mL, respectively.
Distribution
The binding of propofol tenofovir to human plasma proteins was approximately 80% in samples collected during the clinical trial. Binding of tenofovir to human plasma proteins was less than 0.7% and was concentration independent in the range of 0.01-25µg/mL.
Biotransformation
Metabolism is the major route of elimination of propofol tenofovir in humans, accounting for >80% of the oral dose. In vitro studies have shown that propofol tenofovir is metabolized to tenofovir (the major metabolite) via carboxylesterase-1 in hepatocytes and histone A in PBMCs and macrophages. In vivo, propofol tenofovir is hydrolyzed intracellularly to form tenofovir (the major metabolite), which is phosphorylated to form the active metabolite tenofovir diphosphate.
In vitro, propofol tenofovir is not metabolized by CYP1A2, CYP2C8, CYP2C9, CYP2C19, or CYP2D6. Very small amounts of propofol tenofovir are metabolized by CYP3A4.
Elimination
Renal excretion of intact propofol tenofovir is the secondary route, with elimination in the urine at a dose of <1%. Propofol tenofovir is eliminated primarily after metabolism to tenofovir. The median plasma half-lives of propofol tenofovir and tenofovir are 0.51 and 32.37 hours, respectively. Tenofovir is eliminated from the body by the kidneys through glomerular filtration and active tubular secretion.
Linearity/non-linearity
Propofol tenofovir exposure is dose proportional over the dose range of 8 to 125 mg.
Pharmacokinetics in Special Populations
Age, Sex, and Ethnic Group
No clinically relevant differences in pharmacokinetics listed by age or ethnic group were identified. Pharmacokinetic differences based on gender were not considered clinically relevant.
Hepatic Impairment
In patients with severe hepatic impairment, total plasma concentrations of propofol tenofovir and tenofovir were lower than the corresponding values observed in subjects with normal liver function. After adjustment for protein binding, unbound (free) propofol tenofovir plasma concentrations in patients with severe hepatic impairment were similar to those in patients with normal hepatic function.
Renal Impairment
In the propofol tenofovir study, no clinically relevant differences in propofol tenofovir or tenofovir pharmacokinetics were observed between healthy subjects and patients with severe renal impairment (CrCl estimates >15 but <30 mL/min).
Pediatric population
The pharmacokinetics of propofol tenofovir and tenofovir were evaluated in treatment-naive HIV1-infected adolescents receiving propofol tenofovir (10 mg) administration (receiving a fixed-dose combination tablet of everolimus, cobicistat, and emtricitabine (E/C/F/TAF; Genvoya)). No clinically relevant differences in the pharmacokinetics of propofol tenofovir or tenofovir were observed between HIV1-infected adolescents and adult subjects.
Storage】Storage below 30℃.
Package】Polyvinyl chloride solid pharmaceutical hard tablets and pharmaceutical aluminum foil, plus polyester/aluminum/polyethylene pharmaceutical composite bag and solid pharmaceutical paper bag with silica gel desiccant, 10 tablets/plate, 3 plates/bag, 1 bag/box.
【Validity】24 months
【Execution standard
【Approval number】
【Marketing license holder
Company Name: Chengdu BITE Pharmaceutical Co.
Address: No.15 Gaopeng Avenue, High-tech Zone, Chengdu
Phone number: 400-800-6276
Manufacturer
Company Name: Chengdu Bite Pharmaceutical Co.
Production Address: No. 1166, Airport Road 4, Southwest Airport Economic Development Zone, Shuangliu, Chengdu, China
Postal Code: 610207
Telephone number: 400-800-6276
Fax number: 028-85913399
Website: http://www.btyy.com