Date of approval.
Date of revision.
Propofol Tenofovir Tablets Instructions
Please read the instructions carefully and use under the guidance of a doctor
Drug Name]
Generic name: Propofol Tenofovir Tablets
Trade name: Vemlidy®Velipid®
English name: Tenofovir alafenamide tablets
Hanyu Pinyin：Bingfentinuofuwei Pian
Ingredients
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: 534.5
【Properties】.
This product is a yellow, round film-coated tablet. After the coating is removed, it appears white or off-white. The diameter of the tablet is 8 mm, one side is engraved with “GSI” and the other side is engraved with “25”.
Indications
Propofol Tenofovir 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
This product contains tenofovir propofol fumarate, 25mg as propofol tenofovir.
Dosage]
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. Take orally. To be taken with food.
Missed Doses
If a dose of propofol tenofovir is missed and less than 18 hours after the usual dosing time, the patient should take a dose as soon as possible and resume the normal dosing schedule. If the usual dosing schedule has been exceeded by more than 18 hours, 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 tablet, the patient should take an additional tablet. If a patient vomits more than 1 hour after taking a propofol tenofovir tablet, the patient does not need to take another tablet.
Special Populations
Seniors
No dose adjustment of Propofol Tenofovir Tablets is required for patients 65 years of age and older (see [Pharmacology and Toxicology]).
Renal Impairment
No dose adjustment of propofol tenofovir tablets is necessary 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.
Propofol tenofovir tablets should be given on the day of hemodialysis, after completion of hemodialysis treatment (see [Pharmacology and Toxicology]).
There are no dosing recommendations for patients on CrCl < 15 mL/min who are not receiving hemodialysis (see [Pharmacology and Toxicology]).
Hepatic Impairment
No dose adjustment of propofol tenofovir tablets is required for patients with hepatic impairment (see [Precautions] and see [Pharmacology and Toxicology]).
Pediatric Population
The safety and efficacy of propofol tenofovir tablets have not been established in children under 12 years of age or weighing < 35 kg. No data are available.
[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 patients with HBV infection received propofol tenofovir 25 mg once daily until week 96 in a double-blind manner (median duration of drug exposure in blinded studies was 104 weeks). The most commonly reported adverse effects were headache (12%), nausea (6%), and fatigue (6%). After week 96, patients continued to receive their original blinded treatment or received open-label propofol tenofovir tablets. No other adverse reactions to propofol tenofovir tablets were identified in the subgroup of subjects treated with open-label propofol tenofovir 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 Dosing 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
The 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 in which 227 mainland Chinese patients with HBV infection received 25 mg of once-daily propofol tenofovir. The safety profile of mainland Chinese patients with HBV infection receiving propofol tenofovir was generally consistent with the safety profile observed in 2 phase 3 studies overseas.
None of the mainland Chinese patients discontinued cotinofovir treatment due to adverse events.
Reports 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 levels of HBV DNA) have been reported in patients who have 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 short-lived 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 associated with increased serum bilirubin concentrations or liver failure. Patients with cirrhosis may be at higher risk of liver failure after hepatitis has progressed and should therefore be monitored closely during treatment.
2. HBV transmission
Patients must be informed that propofol tenofovir 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 propofol tenofovir tablets in patients with decompensated liver disease and Child Pugh Turcotte (CPT) score > 9 (i.e., Grade C) HBV infection. 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 with nucleoside analogs (including tenofovir disoproxil fumarate or other tenofovir precursors) alone or in combination with other antiretroviral drugs. Treatment with propofol tenofovir 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 < 30 mL/min
The use of once-daily propofol tenofovir tablets in patients with CrCl ≥ 15 mL/min but < 30 mL/min and in patients with CrCl < 15 mL/min who are receiving hemodialysis is based on very limited pharmacokinetic data and modeling and simulation. Safety data are not available for the use of propofol tenofovir tablets in the treatment of HBV-infected patients with CrCl < 30 mL/min.
Propofol Tenofovir Tablets are not recommended for use in patients with CrCl < 15 mL/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 propofol tenofovir 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 tablets are not recommended for the treatment of HIV-1 infection because of the risk of developing HIV resistance. The safety and efficacy of propofol tenofovir tablets in patients co-infected with HIV-1 and HBV have not been established. All HBV-infected patients should be tested for HIV antibodies prior to initiating treatment with propofol tenofovir, and if positive, the appropriate combination antiretroviral regimen recommended for patients co-infected with HIV-1 should be used.
9. Combination with other drugs
Propofol tenofovir tablets should not be used in combination with products containing propofol tenofovir, tenofovir disoproxil fumarate or adefovir.
10. Lactose intolerance
Propofol tenofovir 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 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 propofol tenofovir tablets.
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 adverse effects (see [Pharmacologic Toxicology]).
If indicated, consider the use of propofol tenofovir tablets 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.
The risk to nursing children cannot be excluded. Therefore, propofol tenofovir tablets should not be used during breastfeeding.
Fertility
No data are available on the effect of propofol tenofovir tablets on human fertility. Animal studies have not shown adverse effects of propofol tenofovir on fertility.
Pediatric Dosage]
The safety and efficacy of Propofol Tenofovir Tablets have not been established in children under 12 years of age or weighing < 35 kg. No data are available.
Geriatric Use
No dose adjustment of Propofol Tenofovir Tablets is required for patients aged 65 years and older (see [Pharmacology and Toxicology]).
Drug Interactions]
Interaction studies have been conducted in adults only.
Propofol Tenofovir 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 reduce propofol tenofovir plasma concentrations, which may result in loss of efficacy of propofol tenofovir tablets (see Table 2).
The combination of propofol tenofovir 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 the activity of OATP1B1 and/or OATP1B3.
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.
Information on drug interactions between propofol tenofovir tablets and potentially co-administered drugs is summarized in Table 2 below (“↑” 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; “IV” indicates intravenous route). The drug interactions described are based on studies conducted using propofol tenofovir or the drug interactions that may occur when using propofol tenofovir tablets.
Table 2: Interactions between Vemlidy and other drugs
Effect of drugs on drug levels by therapeutic areaa,b.
Mean ratios (90% confidence interval) of AUC, Cmax, and Cmin for the proposed anticonvulsant carbamazepine in combination with propofol tenofovir tablets
(300 mg given orally, b.i.d.)
Propofol tenofovir c
(25 mg given orally, s.d.) Propofol tenofovir
↓ Cmax 0.43 (0.36, 0.51)
↓ AUC 0.45 (0.40, 0.51)
Tenofovir
↓ Cmax 0.70 (0.65, 0.74)
↔ AUC 0.77 (0.74, 0.81) 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
↔ Cmax 1.02 (0.92, 1.13)
↔ AUC 1.13 (1.04, 1.23) No dose adjustment for midazolam (given by mouth or intravenously) is required. Midazolam d
(1 mg IV, s.d.)
Propofol tenofovir c
(25 mg given orally, q.d.) Midazolam
↔ Cmax 0.99 (0.89, 1.11)
↔ AUC 1.08 (1.04, 1.14) Antidepressant sertraline
(50 mg given orally, s.d.)
Propofol tenofovir e
(10 mg given orally, q.d.) Propofol tenofovir
↔ Cmax 1.00 (0.86, 1.16)
↔ AUC 0.96 (0.89, 1.03)
Tenofovir.
Tenofovir ↔ Cmax 1.10 (1.00, 1.21)
Tenofovir ↔ AUC 1.02 (1.00, 1.04)
↔ Cmin 1.01 (0.99, 1.03) No dose adjustment for propofol tenofovir tablets or sertraline is required. Sertraline
(50 mg given orally, s.d.)
Propofol Tenofovir e
(10 mg given orally, q.d.) Sertraline
↔ Cmax 1.14 (0.94, 1.38)
↔ AUC 0.93 (0.77, 1.13) Antifungal Itraconazole
Ketoconazole has not been studied for interaction.
Expected.
↑ Propofol tenofovir is not recommended for co-administration. Anti-branched bacteriophage 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 for propofol tenofovir tablets or sofosbuvir is required. Ledipavir/sofosbuvir
(90 mg/400 mg given orally, q.d.)
Propofol Tenofovirf
(25 mg given orally, q.d.) Ledipavir
↔ Cmax 1.01 (0.97, 1.05)
↔ AUC 1.02 (0.97, 1.06)
Cmin 1.02 (0.98, 1.07) ↔ Cmin 1.02 (0.98, 1.07)
Sofosbuvir.
Sofosbuvir ↔ Cmax 0.96 (0.89, 1.04)
Sofosbuvir ↔ AUC 1.05 (1.01, 1.09)
GS331007g
GS331007g ↔ Cmax 1.08 (1.05, 1.11)
GS331007g ↔ AUC 1.08 (1.06, 1.10)
↔ Cmin 1.10 (1.07, 1.12)
Propofol tenofovir
Cmin 1.03 (0.94, 1.14) ↔ Cmax 1.03 (0.94, 1.14)
AUC 1.32 (1.25, 1.40) ↔ AUC 1.32 (1.25, 1.40)
Tenofovir
↑ Cmax 1.62 (1.56, 1.68)
↑ AUC 1.75 (1.69, 1.81)
↑ Cmin 1.85 (1.78, 1.92) No dose adjustment for propofol tenofovir tablets or ledipavir/sofosbuvir is required. Sofosbuvir/vipatasvir
(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 tablets or sofosbuvir/vipatasvir. Sofosbuvir/vipatasvir/vociclib (400 mg/100 mg/100 mg + 100 mgi orally, q.d.)
Propofol tenofovirf
(25 mg orally, q.d.) Sofosbuvir
↔ Cmax 0.95 (0.86, 1.05)
↔ AUC 1.01 (0.97, 1.06)
GS331007g
Cmax ↔ Cmax 1.02 (0.98, 1.06)
GS331007g ↔ AUC 1.04 (1.01, 1.06)
Vipatavir.
Cmax 1.05 (0.96, 1.16) ↔ Cmax 1.05 (0.96, 1.16)
Vipatavir ↔ AUC 1.01 (0.94, 1.07)
Vipatavir ↔ Cmin 1.01 (0.95, 1.09)
Voxilivir.
Fusilivir ↔ Cmax 0.96 (0.84, 1.11)
Voxilivir ↔ AUC 0.94 (0.84, 1.05)
Fosfomycin ↔ Cmin 1.02 (0.92, 1.12)
Fospropatentinovir
↑ Cmax 1.32 (1.17, 1.48)
↑ AUC 1.52 (1.43, 1.61) No dose adjustment for propofol tenofovir tablets or sofosbuvir/velpatasvir/vosiravir was required. Interactions have not been studied with the herbal supplement St. John’s wort (Hypericum perforatum).
Expected.
↓ Propofol tenofovir is not recommended for co-administration. Oral contraceptive norgestimate
(0.180 mg/0.215 mg/0.250 mg given orally, q.d.)
Ethinylestradiol
(0.025 mg given orally, q.d.)
Propofol Tenofovir c
(25 mg given orally, q.d.) Norethindrone
↔ Cmax 1.17 (1.07, 1.26)
↔ AUC 1.12 (1.07, 1.17)
Cmin 1.16 (1.08, 1.24) ↔ Cmin 1.16 (1.08, 1.24)
Methylnortriptyline
↔ Cmax 1.10 (1.02, 1.18)
AUC 1.09 (1.01, 1.18) ↔ AUC 1.09 (1.01, 1.18)
Cmin 1.11 (1.03, 1.20) ↔ Cmin 1.11 (1.03, 1.20)
Ethinylestradiol
Cmax 1.22 (1.15, 1.29) ↔ Cmax 1.22 (1.15, 1.29)
AUC 1.11 (1.07, 1.16) ↔ AUC 1.11 (1.07, 1.16)
↔ Cmin 1.02 (0.93, 1.12) No dose adjustment for propofol tenofovir tablets or norethindrone/ethinyl estradiol is 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 emtricitabine/propofol tenofovir fixed-dose combination tablets
d. One sensitive CYP3A4 substrate
e. Studies with emivrevir/cobicistat/emtricitabine/propofol tenofovir fixed-dose combination tablets
f. Studies with emtricitabine/ribivirine/propofol tenofovir fixed-dose combination tablets
g. Major circulating nucleoside metabolites of sofosbuvir
h. Studies with propofol tenofovir 40 mg and emtricitabine 200 mg
i. Additional studies with fosamprenavir 100 mg to achieve the expected fosamprenavir exposure in HCV-infected patients.
Overdose]
If an overdose occurs, the patient must be monitored for signs of toxicity (see not [ADVERSE REACTIONS]).
Treatment of propofol tenofovir tablet overdose 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.
Clinical Trials]
The efficacy and safety of Vemlidy in patients with chronic hepatitis B is based on 48 and 96 weeks of data from two randomized, double-blind, active-controlled studies, GSUS3200108 (“Study 108”) and GSUS3200110 (“Study 110”), conducted overseas and in mainland China. The safety of Vemlidy was also supported by pooled data from overseas patients who continued to receive blinded treatment from Week 96 to Week 120 in Studies 108 and 110 and from overseas patients who participated in the open-label period in Studies 108 and 110 from Week 96 to Week 120 (N = 361 continued to receive Vemlidy; N = 180 switched from tenofovir disoproxil fumarate to Vemlidy at Week 96).
The primary efficacy endpoint in both trials was the proportion of patients with plasma HBV DNA levels below 29 IU/mL at week 48. Vemlidy met the criteria for non-inferiority in achieving HBV DNA below 29 IU/mL compared to tenofovir disoproxil fumarate in the overseas study.
Clinical data from overseas patients
In Study 108, untreated and treated HBeAg-negative overseas patients with compensated liver function were randomized in a 2:1 ratio to receive either Vemlidy (25 mg; N = 285) once daily or tenofovir disoproxil fumarate (300 mg; N = 140) once daily. The mean age of these patients was 46 years, 61% were male, 72% were Asian, 25% were white, and 2% (8 subjects) were black; 24%, 38%, and 31% were HBV genotypes B, C, and D, respectively. 21% of patients were treated (previously with oral antivirals, including entecavir (N = 41), lamivudine (N = 42), tenofovir disoproxil fumarate (N = 40), and tenofovir disoproxil (N = 40). Tenofovir (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 history of cirrhosis.
In study 110, untreated and treated HBeAg-positive overseas patients with compensated liver function were randomized in a 2:1 ratio to receive either Vemlidy (25 mg; N = 581) once daily or tenofovir disoproxil fumarate (300 mg; N = 292) once daily. The mean age of these patients was 38 years, 64% were male, 82% were Asian, 17% were white, < 1% (5 subjects) were black. 17%, 52%, and 23% of patients had HBV genotypes B, C, and D, respectively. 26% of patients were treated (previously 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.
Treatment outcomes for overseas patients at study 108 and study 110 through week 48 are shown in Tables 3 and 4. Additional outcomes for overseas patients through week 96 are shown in Table 5.
Table 3: HBV DNA efficacy parameters for overseas patients at week 48a
Study 108 (HBeAg negative) Study 110 (HBeAg positive) Vemlidy (N = 285) TDF (N = 140) Vemlidy (N = 581) TDF (N = 292) HBV DNA < 29 IU/mL94%93%64%67% Treatment differenceb1.8% (95% CI = -3.6% to 7.2%) 3.6% (95% CI = -9.8% to 2.6%) HBV DNA ≥ 29 IU/mL2%3%31%30% Baseline HBV DNA
< 7 log10 IU/mL
≥ 7 log10 IU/mL
96% (221/230)
85% (47/55)
92% (107/116)
96% (23/24) N/AN/A baseline HBV DNA
< 8 log10 IU/mL
≥ 8 log10 IU/mLN/AN/A
82% (254/309)
43% (117/272)
82% (123/150)
51% (72/142) Not treated with nucleosidec
Received nucleoside therapy 94% (212/225)
93% (56/60) 93% (102/110)
93% (28/30)68% (302/444)
50% (69/137) 70% (156/223)
57% (39/69) No virologic data at week 48 4% 4% 5% 3% Discontinued study drug due to lack of efficacy 00< 1%0 Discontinued study drug due to AE or death 1% 1% 1% 1% 1% Discontinued study drug due to other reasons d2% 3% 3% 2% Missing data during window but still receiving study drug < 1% 1% < 1% 0 N/A = not Applicable
TDF = tenofovir disoproxil fumarate
a. Missing = Failure to analyze.
b. Adjusted for stratification by baseline plasma HBV DNA class and oral antiviral drug treatment status.
c. Treatment-naive subjects include those who received < 12 weeks of oral antiviral therapy with any nucleoside or nucleotide analogue (including tenofovir disoproxil fumarate or tenofovir propofol).
d. Includes patients who discontinued treatment for reasons other than AE, death, or lack or loss of efficacy (e.g., withdrawal of consent, missed visits, etc.).
Table 4: Other efficacy parameters for overseas patients at week 48a
Study 108 (HBeAg negative) Study 110 (HBeAg positive) Vemlidy (N = 285) TDF (N = 140) Vemlidy (N = 581) TDF (N = 292) ALT
ALT normalized (central lab)b83%75%72%67% ALT normalized (AASLD)c50%32%45%36% Serology
HBeAg conversion / serologic conversion dN/AN/A14% / 10%12% / 8% HBsAg conversion / serologic conversion 0 / 00 / 01% / 1%< 1% / 0N/A = not applicable
TDF = Tenofovir disoproxil fumarate
a. Missing = Failure to analyze.
b. The population for ALT normalization analysis includes only patients whose ALT exceeds the upper limit of normal (ULN) of the central laboratory range at baseline. central laboratory ULNs for ALT are as follows: ≤ 43 U/L and ≤ 35 U/L for males aged 18 to < 69 years and ≥ 69 years, respectively; ≤ 34 U/L and ≤ 32 U/L for females aged 18 to < 69 years and ≥ 69 years, respectively.
c. The population for ALT normalization analysis includes only patients whose ALT at baseline exceeds the American Association for the Study of Liver Diseases (AASLD) standard ULN (> 30 U/L and > 19 U/L for men and women, respectively, according to the 2016 AASLD guidelines).
d. The population used for serologic analysis included only patients who were antigen (HBeAg) positive and antibody (HBeAb) negative or absent at baseline.
Overseas patient experience after 48 weeks in Studies 108 and 110
At Week 96, viral suppression and biochemical and serologic responses were maintained with continued propofol tenofovir treatment (see Table 5).
Table 5: HBV DNA and other efficacy parameters in overseas patients at week 96a
Study 108 (HBeAg negative) Study 110 (HBeAg positive) Vemlidy (N = 285) TDF (N = 140) Vemlidy (N = 581) TDF (N = 292) HBV DNA < 29 IU/mL90%91%73%75% Baseline HBV DNA
< 7 log10 IU/mL
≥ 7 log10 IU/mL
90% 207/230)
91% (50/55)
91% 105/116)
92% (22/24) N/AN/A baseline HBV DNA
< 8 log10 IU/mL
≥ 8 log10 IU/mLN/AN/A
84% 260/309)
60% 163/272)
81% (121/150)
68% (97/142) Not treated with nucleoside therapyb
Received nucleoside therapy 90% 203/225)
90% (54/60) 92% 101/110)
87% (26/30)75% 331/444)
67% (92/137)75% (168/223)
72% (50/69) ALT
ALT normalized (central lab)c
ALT normalized (AASLD)d
81%
50%
71%
40%
75%
52%
68%
42% Serology
HBeAg conversion/seroconversione
HBsAg conversion/seroconversion
N/A
<1%/<1%
N/A
0/0
22%/18%
1%/1%
18%/12%
1%/0 N/A = Not applicable
TDF = Tenofovir disoproxil fumarate
a. Missing = Failure to Analyze
b. Treatment-naive subjects include those who received < 12 weeks of oral antiviral therapy with any nucleoside or nucleotide analogue (including tenofovir disoproxil fumarate or tenofovir propofol).
c. The population for ALT normalization analysis includes only patients whose ALT at baseline exceeds the central laboratory range ULN of ≤ 43 U/L and ≤ 35 U/L for males aged 18 to < 69 years and ≥ 69 years, respectively, and ≤ 34 U/L and ≤ 32 U/L for females aged 18 to < 69 years and ≥ 69 years, respectively.
d. The population for ALT normalization analysis includes only patients with ALT above the AASLD standard ULN at baseline (> 30 U/L for men and > 19 U/L for women according to the 2016 AASLD guidelines).
e. The population used for serologic analysis includes only patients who are antigen (HBeAg) positive and antibody (HBeAb) negative or absent at baseline.
Change in Bone Mineral Density Measurements
In both studies, the mean percentage decrease in bone mineral density (BMD; measured by dual-energy X-ray absorptiometry [DXA] analysis of the hip and lumbar spine) due to propofol tenofovir was smaller after 96 weeks of treatment compared with tenofovir disoproxil fumarate.
In overseas patients who continued blinded treatment after week 96, the mean percentage change in BMD in each group at week 120 was similar to that at week 96. During the open-label period for both studies, the mean percentage change in lumbar and total hip BMD from week 96 to week 120 in overseas patients continuing on Vemlidy was +0.6% and 0%, respectively, compared to +1.7% and +0.6% in patients switching from tenofovir disoproxil fumarate to Vemlidy at week 96. 0.6%.
Changes in renal function measures
In both studies, changes in renal safety parameters due to tenofovir disoproxil were smaller after 96 weeks of treatment compared with tenofovir disoproxil fumarate (smaller median decreases in CrCl estimates by using the Cockcroft-Gault method and smaller median percentage increases in urinary retinol-binding protein to creatinine and urinary β-2 microglobulin to creatinine ratios) (see [Caution ]).
In overseas patients in Studies 108 and 110 who continued on blinded therapy after Week 96, changes in renal laboratory test parameters relative to baseline were similar in each group at Week 120 as at Week 96. The mean (±SD) change in serum creatinine from week 96 to week 120 during the open-label period in studies 108 and 110 was -0.002 (0.10) mg/dL in patients who continued on Vemlidy, compared with a corresponding value of 0.008 (0.09) mg/dL in patients who switched from tenofovir disoproxil fumarate to Vemlidy at week 96. During the open-label period, the median change in eGFR from Week 96 to Week 120 in overseas patients continuing Vemlidy treatment was -0.6 mL/min, compared to +1.8 mL/min in patients switching from tenofovir disoproxil fumarate to Vemlidy at Week 96.
Clinical Data from Mainland China Patients
In the mainland China cohort of Study 108, primary and treated HBeAg-negative mainland China patients with compensated liver function were randomized in a 2:1 ratio to receive either Vemlidy (25 mg) once daily or tenofovir disoproxil fumarate (300 mg) once daily. 104 subjects received Vemlidy and 50 subjects received tenofovir disoproxil fumarate. 104 subjects received Vemlidy and 50 subjects received tenofovir disoproxil fumarate. The mean age was 43 years and 73% were male; 45%, 1%, 51%, and 1% of patients had HBV genotype B, B/C, C, and D, respectively.
In the mainland China cohort of Study 110, primary and treated HBeAg-positive mainland China patients with compensated liver function were randomized in a 2:1 ratio to receive either Vemlidy (25 mg) once daily or tenofovir disoproxil fumarate (300 mg) once daily. 123 subjects received Vemlidy and 57 subjects received tenofovir disoproxil fumarate. Vemlidy was administered to 123 subjects and tenofovir disoproxil fumarate to 57 subjects. The mean age was 34 years and 73% were male; 29% and 70% of patients had HBV genotype B and C, respectively.
Treatment outcomes for patients in mainland China at study 108 and study 110 through week 48 and week 96 are shown in Tables 6 and 7.
Table 6: HBV DNA efficacy parameters for patients in mainland China at week 48 and week 96a
Study 108 (HBeAg negative) Study 110 (HBeAg positive) Vemlidy (N = 104) TDF (N = 50) Vemlidy (N = 123) TDF (N = 57) Week 48 Week 96 Week 48 Week 96 Week 48 Week 96 Week 48 Week 96 HBV DNA < 29 IU/mL 89%92% 98%92%61%79%68%75%95% CI82% to 95%85% to 97%89% to
100%81% to 98%52% to
70%71% to 86%55% to
80%62% to 86% HBV DNA ≥ 29 IU/mL8%3%02%37%18%28%19% No virologic data at Week 48 and Week 96 Discontinuation of study drug due to lack of efficacy00000000 Discontinuation of study drug due to AE or death002%2%0000 Discontinuation of study drug for other reasonsb2%4%04%2%3%4%5% Missing data during window but still receiving study drug 1%1%000000N/A = Not applicable
TDF = tenofovir disoproxil fumarate
a.Missing = Failure to analyze.
b. Includes patients who discontinued treatment for reasons other than AE, death, or lack or loss of efficacy (e.g., withdrawal of consent, missed visits, etc.).
Table 7: Other efficacy parameters for patients in mainland China at week 48 and week 96a
Study 108 (HBeAg negative) Study 110 (HBeAg positive) Vemlidy (N = 104) TDF (N = 50) Vemlidy (N = 123) TDF (N = 57) Week 48 Week 96 Week 48 Week 96 Week 48 Week 96 Week 48 Week 96 ALT
ALT normalized (central lab)b83%85%86%72%75%85%67%72% Standardized ALT (AASLD)c65%65%48%48%59%70%47%53% Serology
HBeAg Conversion/Serology Conversion dN/AN/A15%/11%
19%/14%
11%/9%18%/12% HBsAg conversion/serological conversion 1%/02%/00/00/00/02%/1%0/00/0N/A = Not applicable
TDF = Tenofovir disoproxil fumarate
a. Missing = Failure to analyze.
b. The population for ALT normalization analysis includes only patients whose ALT exceeds the upper limit of normal (ULN) of the central laboratory range at baseline. central laboratory ULNs for ALT are as follows: ≤ 43 U/L and ≤ 35 U/L for men aged 18 to < 69 years and ≥ 69 years, respectively; and ≤ 34 U/L and ≤ 32 U/L for women aged 18 to < 69 years and ≥ 69 years, respectively.
c. The population for ALT normalization analysis includes only patients whose ALT at baseline exceeds the American Association for the Study of Liver Diseases (AASLD) criteria ULN, which are as follows: >30 U/L and >19 U/L for men and women at baseline, respectively, according to the 2016 AASLD guidelines.
d. The population for serological analysis includes only patients who are antigen positive (HBeAg) and antibody negative (HBeAb) or deficient at baseline.
Changes in bone mineral density measurements in mainland Chinese patients
Based on pooled data from both studies, after 96 weeks of treatment, propofol tenofovir was associated with a small mean percentage increase in spine BMD relative to baseline and a small mean percentage decrease in hip BMD relative to baseline in mainland Chinese patients, compared with a mean percentage decrease in spine BMD compared with baseline and a larger mean percentage decrease in hip BMD in the tenofovir disoproxil fumarate group.
Changes in Renal Function Measurements in Mainland China Patients
Based on pooled data from both studies, after 96 weeks of treatment, changes in renal safety parameters were smaller in mainland Chinese patients due to tenofovir propofol compared to tenofovir fumarate (mean increase in serum creatinine was smaller in the tenofovir propofol group compared to the tenofovir fumarate group, median decrease in eGFR was smaller in the tenofovir propofol group compared to the tenofovir fumarate group, and urinary retinol binding protein and creatinine were smaller in the tenofovir propofol group compared to the tenofovir fumarate group. The median increase in the percentage of urinary retinol-binding protein to creatinine ratio was smaller in the propofol tenofovir group, and the median percentage of urinary β2-microglobulin to creatinine ratio was lower in the propofol tenofovir group, compared with an increase in the median percentage in the tenofovir fumarate group) (attend [Precautions]).
Pharmacology and Toxicology
Pharmacological effects
Mechanism of action
Propofol tenofovir is a phosphoramidite drug precursor (2′-deoxyadenosine monophosphate analogue) of tenofovir. Propofol tenofovir enters primary hepatocytes via passive diffusion and the hepatic uptake transporters OATP1B1 and OATP1B3. In primary hepatocytes, propofol tenofovir is hydrolyzed primarily by carboxylesterase 1 to form tenofovir. Intracellular tenofovir then undergoes phosphorylation to form the pharmacologically active metabolite tenofovir diphosphate. Tenofovir diphosphate is integrated into viral DNA by HBV reverse transcriptase, which leads to DNA chain termination, thereby inhibiting HBV replication.
Tenofovir has specific activity against hepatitis B virus and human immunodeficiency virus (HIV1 and HIV2). Tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerases, including mitochondrial DNA polymerase γ, based on multiple assays including mitochondrial DNA analysis, and shows no signs of mitochondrial toxicity in vitro.
Antiviral activity
The antiviral activity of propofol tenofovir was evaluated in HepG2 cells against a panel of clinical isolates of HBV representing genotypes A-H. The EC50 (50% effective concentration) values for propofol tenofovir ranged from 34.7 to 134.4 nM, with an overall mean EC50 of 86.6 nM. The CC50 (50% cytotoxic concentration) in HepG2 cells> 44,400 nM.
Drug resistance
In a pooled analysis of overseas patients treated with Vemlidy, patients with virologic breakthrough (HBV DNA < 69 IU/mL followed by 2 consecutive follow-up visits with HBV DNA ≥ 69 IU/mL, or an increase of 1.0 log10 or more relative to the nadir HBV DNA), patients with HBV DNA ≥ 69 IU/mL (week 96 only), or patients with HBV DNA ≥ 69 IU/mL at week 24 (week 24 only). Sequence analysis of paired baseline and treatment-phase HBV isolates was performed for patients with HBV DNA ≥ 69 IU/mL at Week 96 or early discontinuation at or after Week 24. No amino acid substitutions associated with Vemlidy resistance were identified in these isolates (genotypic and phenotypic analyses) in overseas patient analyses at week 48 (N = 20) and week 96 (N = 72).
Cross-resistance
The antiviral activity of propofol tenofovir was evaluated in HepG2 cells against a group of isolates containing nucleoside (acid) reverse transcriptase inhibitor mutations. HBV isolates expressing rtV173L, rtL180M and rtM204V/I substitutions associated with lamivudine resistance remained susceptible to propofol tenofovir (EC50 fold change < 2). HBV isolates expressing rtL180M, rtM204V + rtT184G, rtS202G or rtM250V substitutions associated with entecavir resistance remained susceptible to corticosteroid tenofovir. HBV isolates expressing single mutations in rtA181T, rtA181V or rtN236T associated with adefovir resistance remained sensitive to cotinofovir; however, HBV isolates expressing rtA181V + rtN236T showed reduced sensitivity to cotinofovir (EC50 fold change of 3.7). The clinical relevance of these substitutions is not clear.
Non-clinical toxicology
Non-clinical studies in rats and dogs have shown that bone and kidney are the primary target organs for toxicity. This skeletal toxicity was observed to be reduced by BMD in rats and dogs when tenofovir exposure was at least four times the expected exposure following propofol tenofovir administration. Very mild histiocytic infiltration was observed in the canine eye at exposures of approximately 4 and 17 times the expected post-administration exposure of propofol tenofovir and tenofovir, respectively.
Propofol tenofovir was not mutagenic or chromosome-breaking in routine genotoxicity analyses.
Tenofovir exposure was lower in rats and mice following propofol tenofovir administration compared to tenofovir disoproxil fumarate, so only tenofovir disoproxil fumarate was used for carcinogenicity studies and perinatal-postnatal studies in rats. Routine studies of carcinogenic potential using tenofovir (in the fumarate form) versus routine studies of reproduction and development using tenofovir (in the fumarate form) or propofol tenofovir showed no specific hazard to humans. Reproductive toxicity studies in rats and rabbits showed no effects on mating, fertility, pregnancy, or fetal litter parameters. However, in a perinatal-postnatal toxicity study at maternal toxicity doses, tenofovir disoproxil fumarate reduced the viability index and body weight of the pups. Long-term oral administration carcinogenicity studies in mice showed a lower incidence of duodenal tumors, which is thought to be possibly related to higher local concentrations of the drug in the gastrointestinal tract at high doses of 600 mg/kg/day. The mechanism of tumor formation in mice and its potential relevance to humans have not been determined.
Pharmacokinetics]
Pharmacotherapeutic group: systemic antivirals, nucleoside and nucleotide reverse transcriptase inhibitors; ATC code: J05AF13.
Absorption
Following oral administration of Vemlidy to adult patients with chronic hepatitis B in the fasting state, peak plasma concentrations of propofol tenofovir were observed at approximately 0.48 hours post-dose. 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, based on a phase 3 overseas CHB subject population pharmacokinetic analysis. A single dose of Vemlidy given with a high-fat meal increased propofol tenofovir exposure by 65% relative to fasting conditions.
Based on a phase 3 population pharmacokinetic analysis of CHB subjects in mainland China, the mean steady-state AUC0-24 was 0.17 µg-hr/mL and 0.26 µg-hr/mL for propofol tenofovir (N = 180) and tenofovir (N = 225), respectively. steady-state Cmax was 0.18 µg-hr/mL for propofol tenofovir and tenofovir, respectively. Cmax was 0.18 and 0.02 µg/mL for tenofovir and tenofovir, respectively.
Distribution
The binding rate 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 0.01-25 µg/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 doses < 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/Nonlinearity
Propofol tenofovir exposure is dose proportional over a dose range of 8 to 125 mg.
Pharmacokinetics in Special Populations
Age, Sex, and Ethnic Group
No clinically relevant differences in pharmacokinetics by age or ethnicity 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) administered as 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
Store at 30°C or below.
Packaging
High-density polyethylene (HDPE) bottles are sealed with a polypropylene continuous threaded child-resistant cap with an induction-activated aluminum foil liner. Each bottle contains silica gel desiccant and polyester cotton stopper.
Available in the following package sizes: 1 bottle per box, each bottle contains 30 film-coated tablets.
Expiration date
24 months
Execution Standard
Import registration standard: JX20180150
Approval number
Imported drug registration certificate no.
【Manufacturer
Company Name: Patheon Inc.
Production Address: 2100 Syntex Court, Mississauga, Ontario, L5N 7K9 Canada
Phone Number: 001 815-484-8900
Fax Number: 001 815-484-8901
Report adverse drug reactions
Domestic Contact Name: Gilead (Shanghai) Pharmaceutical Technology Co.
Domestic contact address: 31F, No. 1198, Century Avenue, China (Shanghai) Pilot Free Trade Zone
Domestic contact telephone number: 4008201135
CN-MAY18-EU-MAY18