Date of approval.
Date of revision.
Adefovir Capsules Instructions
Please read the instructions carefully and use under the guidance of a physician
Drug Name]
Generic name: Adefovir Capsules
Trade Name: Mingzheng®
English Name: Adefovir Dipivoxil Capsules
Hanyu Pinyin: Adefuweizhi Jiaonang
Ingredients
The main ingredient of this product is adefovir
Chemical name: [[2-(6-amino-9H-purin-9-yl)ethoxy]methyl]phosphonic acid bis(pivaloyloxymethyl) ester
Chemical structure formula.
Molecular formula: C20H32N5O8P
Molecular weight: 501.47
Excipients.
Pre-gelatinized starch, cross-linked sodium carboxymethyl cellulose, lactose, talc, magnesium stearate, hydroxypropyl methyl cellulose hollow capsule
Properties
The content of this product is white or off-white powder.
Indications
This product is indicated for the treatment of adult chronic hepatitis B patients with evidence of active hepatitis B virus replication with persistent elevation of serum aminotransferase (ALT or AST) or active hepatic histological lesions in compensated liver function.
Specification
10mg
Dosage]
Patients must be treated with this product under the supervision of a physician experienced in the treatment of chronic hepatitis B. Adults (18-65 years)
For patients with normal renal function, the recommended dose of this product is 10mg once daily, either orally before or after a meal.
This indication is based primarily on the results of a 48-week clinical trial. The optimal duration of treatment has not been determined. Do not use more than the recommended dose. The relationship between treatment efficacy and long-term clinical prognosis (e.g., hepatocellular carcinoma or decompensated cirrhosis) has not been established.
Patients should be monitored regularly for hepatitis B biochemical markers, virological markers, and serum markers at least every 6 months.
at least once every 6 months.
Discontinuation of the drug may be considered in the following situations
Based on experience with lamivudine, HBeAg-positive patients may be considered for discontinuation of therapy after HBeAg seroconversion has occurred with this product and treatment has continued for 6 months with testing confirming efficacy.
For HBeAg-negative patients, long-term treatment is recommended until at least HBsAg seroconversion or loss of efficacy is achieved and the drug is discontinued. The advantages and disadvantages of discontinuation must be weighed. Patients should be closely monitored by an experienced physician.
Discontinuation is not recommended in patients with decompensated liver disease or cirrhotic decompensation occurring during treatment. Patients with renal impairment
Adefovir is excreted by the kidneys, therefore patients with renal insufficiency require adjustment of the dosing interval. Creatinine clearance
Patients with creatinine clearance ≥ 50 mL/min do not require dosing interval adjustment. Detailed adjustment protocols for dosing intervals in patients with creatinine clearance < 50 mL/min are shown in Table 1, and the number of doses should not exceed the recommended number in the table (see [Precautions] – Renal Function). Although pharmacokinetic studies have included patients with renal impairment, these guidelines for dosing interval adjustments have not been evaluated for safety and efficacy in the clinical setting. Therefore, clinical outcomes in these patients should be closely monitored. Studies have not been conducted in patients with creatinine clearance below 10 mL/min. Therefore, there is no reference dosing regimen available.
Table 1: Recommended dosing regimens for patients with renal insufficiency
Creatinine clearance (mL/min) 30-4910-29 Patients on hemodialysis* Recommended dose
and dosing interval 10mg
1 dose every 48 hours 10mg
10mg every 72 hours after dialysis
Every 7 days *Recommended dosing regimen is derived from the results of a study of 3 high-flow dialysis sessions per week.
Patients with Hepatic Impairment
No dosing regimen adjustment is required in patients with hepatic impairment (see [Pharmacokinetics] – Patients with Hepatic Impairment).
Adverse Reactions
Domestic Clinical Studies
Study ADF30001 is a randomized, double-blind, placebo-controlled, 52-week study in 480 Chinese patients with HBeAg-positive compensated chronic hepatitis B to evaluate the efficacy and safety of adefovir 10 mg in Chinese patients. The following adverse events were reported in at least one case in the study population during the 52-week study period and were evaluated by the investigator as drug-related: fatigue, gastrointestinal reactions (abdominal discomfort, epigastric pain, diarrhea, nausea, gastric distress), nasopharyngitis, dizziness, rash, alopecia, hepatic pain, spontaneous abortion, insomnia, abnormal laboratory tests (elevated ALT, CPK and ALP, neutrophil and leukopenia), with an overall incidence of ≤2% for any single adverse event. The most common was fatigue. The only serious adverse event was one spontaneous miscarriage.
Adverse events of hepatitis exacerbation were reported in patients who discontinued treatment with adefovir according to the trial protocol, which is consistent with the results observed in the later international clinical studies.
International clinical studies
Adult patients with compensated liver disease
In Studies 437 and 438, patients received adefovir 10 mg (n=294) or placebo (n=228), respectively.
(n=228) for 48 weeks. In the follow-up study in 438, patients continued adefovir
In the follow-up study of 438, patients continued to take adefovir 10 mg and experienced a similar type and extent of adverse reactions after 48 weeks as in the first 48 weeks, with a slight increase in the incidence compared to the first 48 weeks.
The incidence of adverse reactions was similar in the adefovir 10 mg treatment group and the placebo treatment group. All treatment-related clinical adverse events with an incidence of ≥3% in patients in the treatment group are listed in Table 2 and compared with the placebo group.
Table 2
Among all patients treated with adefovir in studies 437 and 438
Incidence ≥ 3% of treatment-related adverse events (Grade 1-4) (0-48 weeks) Adefovir 10 mg placebo (n=294) (n=228) Malaise 13% 14% Headache 9% 10% Abdominal pain 9% 11% Nausea 5% 8% Gastrointestinal distention 4% 4% Diarrhea 3% 4% Dyspepsia 3% 2%
The incidence of abnormal laboratory results observed in the adefovir 10 mg treatment group in these studies was similar to that in the placebo group. However, elevated liver transaminases occurred at a higher rate in the placebo group.
The incidence of ≥1% of all grade 3 and
abnormalities of grade 3 and 4 laboratory results in the adefovir 10 mg treatment group versus the placebo group.
Table 3
Incidence of ≥1% of all Grade 3 and 4 laboratory results in all patients treated with adefovir 10 mg in studies 437 and 438
rate of abnormal grade 3 and 4 laboratory results (0-48 weeks) Adefovir 10 mg
Placebo (n=294) (n=228) ALT (>5x upper limit of normal) 20% 41% Hematuria (≥3+) 11% 10% AST (>5x upper limit of normal) 8% 23% Creatine kinase (>4x upper limit of normal) 7% 7% Amylase (>2x upper limit of normal) 4% 4% Glycosuria (≥3+) 1% 3%
In studies 437 and 438, patients received adefovir 10 mg and placebo, respectively, for 48 weeks. Among patients with good renal function, increases in serum creatinine of ≥0.3 mg/dL from baseline values were observed in 4% and 2% of patients in the treatment and control groups, respectively, at week 48. no patient had an increase in serum creatinine of ≥0.5 mg/dL from baseline at week 48. at week 96, by Kaplan-Meier estimator analysis, 10% and 2% of patients on adefovir, respectively, had an increase in serum creatinine of ≥0.3 mg/dL from baseline. patients had increases in serum creatinine of ≥0.3 mg/dL and ≥0.5 mg/dL from baseline, respectively (no placebo control after week 48). Of the 492 patients, 29 experienced an increase in serum creatinine of ≥0.3 mg/dL from baseline, of which 20 experienced a decrease in serum creatinine values (≤0.2 mg/dL increase from baseline) after continuation of therapy, 8 remained unchanged, and 1 decreased after discontinuation of therapy.
Increases in serum creatinine values have been observed in two extended, open clinical trials.
Of the 125 HBeAg-negative patients (treated for up to 226 weeks), four patients developed confirmed serum creatinine increases of at least 0.5 mg/dL from baseline, and one of them withdrew from the trial due to elevated serum creatinine concentrations. No patient presented with a confirmed serum phosphorus level <2.0 mg/dL.
Of the 65 HBeAg-positive patients (treated for up to 234 weeks), 6 patients had confirmed serum creatinine increases of at least 0.5 mg/dL from baseline, 2 of whom withdrew from the trial due to elevated serum creatinine concentrations. 2 patients had confirmed serum phosphorus levels <2.0 mg/dL and did not withdraw from the trial as a result.
Clinical and laboratory evidence of hepatitis exacerbation was observed after discontinuation of adefovir 10 mg treatment. When patients were followed for 6 months after discontinuation, the incidence of post-discontinuation ALT elevations was higher in the adefovir 10 mg treatment group than in the placebo group. These ALT rebound after discontinuation was usually self-limiting and there was no evidence of an association with clinically or laboratory confirmed decompensated liver disease.
Patients at special risk
In an open study, patients with chronic hepatitis B before (n=226) and after (n=241) liver transplantation with clinical evidence of lamivudine resistance were treated with adefovir for up to 203 weeks, with a median duration of 51 and 99 weeks, respectively. Most of these patients had some degree of underlying renal insufficiency or had other risk factors for renal insufficiency during the treatment period. By Kaplan-Meier estimator analysis, serum creatinine increased by ≥0.3 and ≥0.5 mg/dL from baseline in 26% and 16% of patients at 48 weeks of treatment, respectively, and by Kaplan-Meier estimator analysis, a decrease in serum phosphorus was observed in 4% and 6% of patients at 48 and 96 weeks of treatment, respectively. However, the extent of the effect of adefovir on alterations in serum creatinine and serum phosphorus is difficult to assess because of the coexistence of multiple risk factors for renal insufficiency in these patients.
Alterations in serum creatinine were observed in patients before and after liver transplantation with risk factors for abnormal renal function, including combined cyclosporine and tacrolimus, underlying renal insufficiency, hypertension, diabetes mellitus, and in transplantation. Adefovir was discontinued in 4% (19/467) of pre- and post-transplant liver transplant patients due to renal events.
Common adverse events (incidence >1% of) in pre- and post-transplant liver transplant patients treated with adefovir include
Systemic: malaise
Neurologic: headache
Digestive system: nausea, abdominal pain, vomiting, diarrhea Metabolism and nutrition: hypophosphatemia
Skin and subcutaneous tissue: pruritus, rash
Genitourinary system: creatinine elevation (very common: incidence > 10%), renal function abnormalities, renal failure post-marketing data
In addition to the adverse reactions reported in clinical trials, the following possible adverse reactions have been reported after the launch of adefovir. The frequency of such adverse events has not been evaluated because they are voluntarily reported and originate from an unknown number of people.
Metabolic and nutritional abnormalities: hypophosphatemia
Muscle and connective tissue abnormalities: osteochondrosis (manifested by bone pain and occasional fractures) and myopathy, both associated with proximal tubular lesions.
Digestive system abnormalities: pancreatitis
Renal and urinary system abnormalities.
Renal failure, proximal tubular lesions, Fanconi syndrome
Contraindications
This product is contraindicated in patients with known hypersensitivity to adefovir, adefovir, or any of the excipients in adefovir capsules.
[Precautions].
Warnings
1. Worsening of hepatitis after cessation of treatment. Acute exacerbation of hepatitis has been reported in patients who discontinued hepatitis B treatment (including treatment with adefovir). Therefore, patients who discontinue adefovir therapy must be monitored closely for several months for liver function, including clinical manifestations and laboratory indices. Treatment for hepatitis B should be resumed if needed.
2. Nephrotoxicity. Nephrotoxicity is a dose-limiting toxicity of adefovir treatment, particularly in patients with HIV infection
(60 and 120 mg daily) and at higher doses in patients with chronic hepatitis B (30 mg daily), where nephrotoxicity is characterized by a delayed progressive increase in serum creatinine and a decrease in serum phosphorus. Long-term administration of adefovir (10 mg daily) may result in delayed nephrotoxicity. However, it is particularly likely to cause renal impairment in patients who have risk factors for renal impairment themselves, have underlying renal insufficiency, or are using drugs that have an impact on renal function (e.g., cyclosporine, tacrolimus, aminoglycosides, vancomycin, and nonsteroidal anti-inflammatory drugs).
Monitoring of renal function and blood phosphorus is required in all patients on adefovir therapy, especially those with pre-existing renal insufficiency or other risk factors. Dose adjustments may be required in patients who develop renal insufficiency on a basal or therapeutic basis (see [DOSAGE]). The risks and benefits of adefovir therapy should be carefully evaluated before discontinuing adefovir in patients who develop nephrotoxicity on therapy.
3. HIV drug resistance. All patients should be monitored for HIV antibodies prior to initiating adefovir therapy. The use of anti-hepatitis B therapy with anti-HIV activity, such as adefovir, in patients with chronic hepatitis B co-infection (HIV infection that is undiagnosed or untreated) may cause HIV to become resistant. There is no information that adefovir has the ability to inhibit HIV RNA in patients. However, there is limited information on the use of adefovir in the treatment of chronic hepatitis B patients with co-infection with HIV.
4. Lactic acidosis/severe hepatomegaly with steatosis. Severe hepatomegaly with lactic acidosis and hepatic steatosis, including deaths, have been reported with nucleoside analogs alone or in combination with antiretroviral therapy.
The majority of these cases were in women. Obesity and chronic nucleoside exposure may be risk factors. Nucleoside analogs should be used with particular caution in patients with liver disease with known risk factors; however, cases have been reported in patients without known risk factors. Adefovir therapy should be withheld when patients develop lactic acidosis or significant hepatotoxicity (which may include hepatomegaly and steatosis, even without significant transaminase elevation).
Precautions
The dose used should not be allowed to exceed the recommended dose. Duration of therapy
The optimal course of therapy has not been determined. Renal function
Long-term treatment with 10 mg adefovir has a low overall risk of renal impairment following dosing in patients with good renal function; it may cause renal impairment in patients who have their own risk factors for renal impairment, have underlying renal insufficiency, or are using drugs that have an effect on renal function (e.g., cyclosporine, tacrolimus, aminoglycosides, vancomycin, and nonsteroidal anti-inflammatory drugs). It is recommended that all patients should have their creatinine clearance tested prior to taking adefovir.
It is important that all patients have their renal function and blood phosphorus monitored during adefovir therapy. It is recommended that monitoring be done every four weeks for the first year of drug administration and may be done every three months thereafter. For patients with risk factors for developing renal insufficiency or a history of renal insufficiency, more frequent monitoring is recommended.
Because adefovir is excreted renally, adjust the dosing regimen for patients with creatinine clearance <50 mL/min (see [Dosage]). Patients with end-stage renal disease (ESRD) treated with forms of dialysis other than hemodialysis (e.g., ambulatory peritoneal dialysis) have not been studied.
Clinical studies have found elevated serum creatinine and/or decreased serum phosphorus in patients treated with adefovir for chronic hepatitis B at doses 3-12 times higher than the recommended 10 mg dose.
Alterations in serum creatinine have also been found in patients following liver transplantation. These alterations are generally mild or moderate and have been seen in patients with multiple risk factors for altered renal function (see [Adverse Reactions]).
Clinical evaluation of adefovir has not been performed in patients receiving concomitant nephrotoxic drugs or drugs secreted via the same renal transport protein (human organic anion transport protein 1 [hOAT1]).
Caution must be exercised in the combination of 10 mg adefovir with drugs actively secreted via the renal tubules because such combinations may cause increased serum concentrations of adefovir or the combined drug due to competition for the same elimination pathway (see [Drug Interactions]).
Liver function
Acute exacerbations of hepatitis have been reported in patients who discontinued treatment for hepatitis B, including treatment with adefovir. Therefore, patients who discontinue treatment with adefovir must have their liver function monitored regularly for at least several months. Treatment for hepatitis B should be resumed when needed.
In foreign clinical trials, hepatitis exacerbations occurred in approximately 25% of patients after discontinuation of adefovir therapy
(ALT ≥ 10 times the upper limit of normal). Most of these events occurred within 12 weeks of stopping treatment. These patients who developed hepatitis exacerbations usually had no seroconversion of HBeAg and showed elevated ALT and reappearance of viral replication. In studies conducted in HBeAg-positive and HBeAg-negative patients with compensated liver function, hepatitis exacerbations were usually not accompanied by the onset of hepatic decompensation. However, patients with advanced liver disease or cirrhosis may be at increased risk of hepatic failure. Although most events appear to be self-limiting or remit after restarting treatment, severe cases of hepatitis exacerbation have been reported, including isolated deaths. Therefore, it is important that patients be closely monitored after discontinuation of therapy.
Patients have been treated with nucleoside analogs with lactic acidosis (without hypoxemia) usually associated with hepatic steatosis and severe hepatomegaly, including isolated cases of fatalities. Treatment with nucleoside analogs should be discontinued when there is a rapid increase in transaminase levels, progressive hepatomegaly, or unexplained metabolic lactic acidosis. Caution should be taken in the use of nucleoside analogs in any patient with hepatomegaly or other known risk factors for liver disease (especially in obese women). These patients should be followed closely.
Co-infection with HIV
In patients with chronic hepatitis B co-infection (undiagnosed or untreated HIV infection), the use of anti-hepatitis B therapy with anti-HIV activity, such as adefovir (10 mg is the recommended dose for hepatitis B, higher doses may have anti-HIV activity
), which may make HIV resistant. Patients co-infected with HIV should have their HIV RNA levels controlled with effective antiviral therapy (< 400 copies/mL) before starting treatment of HBV infection with adefovir 10mg. Adefovir 10 mg has not been shown to suppress HIV RNA in patients; however, limited information is available on the use of adefovir in the treatment of chronic hepatitis B patients with co-infection with HIV.
Other
The safety and efficacy of this product in children and adolescents under 18 years of age and in older adults over 65 years of age are not known.
Patients should be advised that adefovir treatment does not reduce the risk of transmission of hepatitis B virus to others and that appropriate protective measures are still needed.
Nivalic acid, a product of adefovir metabolism to adefovir in the body, is excreted from the kidneys in combination with free carnosine. Adefovir should therefore be used with caution in patients with known congenital carnitine deficiency. The clinical significance of binding to carnitine is not known. The effects of combining adefovir with drugs that lower carnosine levels such as valproic acid or other pivalic acid releasing drugs have not been studied. This product 10 mg once daily for the treatment of chronic
In clinical studies of HBV infection, changes in serum carnitine levels were similar in patients in the treatment and placebo groups. Therefore, patients do not require routine supplementation with levocarnitine or monitoring of serum carnitine levels during treatment with adefovir 10 mg once daily.
Adefovir should not be used in combination with tenofovir disoproxil fumarate or products containing tenofovir disoproxil fumarate, including Truvada (emtricitabine/tenofovir disoproxil fumarate combination tablets) and Atripla (efavirenz/emtricitabine/tenofovir disoproxil fumarate combination tablets).
Effects on the ability to drive and operate machinery
The effect of adefovir on the ability to drive and operate machinery has not been studied. Adverse effects of adefovir on such activities cannot be speculated based on pharmacological properties.
[For pregnant and lactating women].
Fertility
Animal studies have shown that adefovir has no effect on fertility in males and females (see [Pharmacology and Toxicology] – Preclinical Safety Data).
Pregnancy
Pregnancy Classification C
There is insufficient information on the use of adefovir in pregnant women.
Animal studies of intravenous administration of adefovir have demonstrated reproductive toxicity (see [Pharmacology and Toxicology] – Preclinical Safety Data). Animal studies of oral administration of adefovir have not shown teratogenic or embryotoxic effects.
Adefovir should not be used in pregnant women if possible, and if it is necessary, the benefits should be weighed against the disadvantages. Adefovir should be considered for use during pregnancy only if the potential benefit is definitely greater than the risk to the fetus.
No information is available on the effect of adefovir on mother-to-child transmission of HBV. Therefore, the standard recommended regimen for immunization of infants to prevent HBV infection in newborns should be followed.
Because the potential risk to the developing human embryo is not known, effective contraception is recommended for women of childbearing age treated with adefovir.
Lactation
It is not known whether adefovir is secreted into human breast milk. Therefore, mothers who are taking adefovir should be cautioned not to breastfeed their infants.
[Pediatric Use].
The efficacy and safety of this product in patients under 18 years of age are not known (see
Precautions]
-Other). Adefovir should not be used in children and adolescents.
Geriatric Use
The efficacy and safety of this product in elderly patients over 65 years of age are not known (see [Precautions] – Miscellaneous).
Precautions] – Other).
Caution should be taken in elderly patients receiving this product because of reduced cardiac and renal function and the frequency of co-morbidities and
The frequency of co-morbidities and concomitant use of other drugs is higher in elderly patients.
Drug Interactions]
Adefovir is rapidly converted to adefovir in vivo. At concentrations significantly higher than those observed in vivo
(>4000-fold), adefovir does not inhibit any of the following common human CYP450 enzymes.
CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Adefovir is not an active substrate for these enzymes. However, it is not clear whether adefovir is able to induce CYP450 enzymes. Based on the results of in vitro experiments and the renal elimination pathway of adefovir, it is unlikely that adefovir acts as an inhibitor or substrate for CYP450-mediated interactions with other drugs.
Adefovir is excreted via the kidney by glomerular filtration and active tubular secretion (see [
Pharmacokinetics]
-Elimination). With the exception of ibuprofen, lamivudine, acetaminophen, meperidine/sulfamethoxazole, and tenofovir DF, the effects of adefovir have not been evaluated.
With the exception of ibuprofen, lamivudine, acetaminophen, meperidine/sulfamethoxazole, and tenofovir DF, drug interactions between 10 mg adefovir and other drugs that are secreted via the kidney or are known to affect renal function have not been evaluated.
Combination of 10 mg adefovir with other drugs secreted via the renal tubules or drugs that alter renal tubular secretion may increase serum concentrations of adefovir or the combination drug (see [PRECAUTIONS] – Renal Function). 10 mg adefovir should be used with caution in combination with drugs actively secreted via the renal tubules because the two drugs compete for the same elimination pathway and may cause increased serum concentrations of adefovir or the combination drug. serum concentrations. When adefovir is co-administered with renal excretory drugs or other drugs known to affect renal function, patients should be closely monitored for adverse events.
Adefovir does not alter the pharmacokinetics of lamivudine, methotrexate/sulfamethoxazole, acetaminophen, and ibuprofen. When adefovir 10 mg was combined with lamivudine 100 mg, the pharmacokinetics of both were not altered.
When 10 mg of adefovir was administered concomitantly with ibuprofen (800 mg, 3 times a day), adefovir
Cmax (33%), AUC (23%), and urinary recovery increased. This increase appeared to be due to increased oral bioavailability rather than decreased renal clearance.
[Drug overdose].
Signs and Symptoms
Mild to moderate gastrointestinal reactions have been observed after high doses of this product (250 mg and 500 mg once daily, 25-50 times higher than the recommended dose for the treatment of chronic HBV infection) for 14 consecutive days in HIV-positive patients.
Treatment
If an overdose occurs, the patient must be monitored for evidence of toxicity and standard supportive therapy must be instituted if necessary.
Adefovir can be cleared by hemodialysis, and the median weight-corrected hemodialysis clearance of adefovir is 104 mL/min. peritoneal dialysis clearance of adefovir has not been studied.
[Clinical Trials].
HBeAg-positive chronic hepatitis B
Study 437 was a randomized, double-blind, placebo-controlled study of adefovir in HBeAg-positive patients with chronic hepatitis B. The efficacy and safety of adefovir 10 mg was evaluated in three groups: adefovir 10 mg, 30 mg, and placebo. The median age of the patients was 33 years. 74% of the patients were male, 59% were Asian, 36% were white, and 24% had a history of prior interferon therapy. At baseline
patients had a median total Knodell Histological Activity Index (HAI) score of 10 and a median serum HBV DNA level of 8.36 log10 as measured by the polymorphic enzyme chain reaction.
copies/mL, and the median ALT level was 2.3 times the upper limit of normal.
HBeAg-negative (anti-HBe positive / HBV DNA positive) chronic hepatitis B
Study 438 was a randomized, double-blind, placebo-controlled study of adefovir in HBeAg-negative, anti-HBe positive patients that evaluated the efficacy and safety of adefovir 10 mg. The median age of the patients was 46 years. 83% were male patients, 66% were Caucasian, 30% were Asian, and 41% had a history of prior interferon therapy. At baseline, patients had a Knodell Histological Activity Index
(HAI) score at baseline was a median total score of 10, and the median serum HBV DNA level measured by the multiplex enzyme chain reaction assay was 7.08 log10
copies/mL, and a median ALT of 2.3 times the upper limit of normal.
The primary efficacy endpoint for both studies was histological improvement at 48 weeks; the results are shown in Tables 4 and 5.
Table 4
Histologic response at 48 weeks* Study 437 Study 438 Adefovir
10 mg placebo Adefovir
10 mg placebo (n=168) (n=161) (n=121) (n=57) Improvement** 53%25%64%35% No improvement 37%67%29%63% Data missing/unable to assess 10%7%7%2%* Intent-to-treat population (patients with ≥1 dose of study drug) with assessable baseline biopsy data.
**Histologic improvement defined as ≥2-point decrease in Knodell necrosis-inflammation score and no worsening of Knodell fibrosis score.
Table 5
Change in Ishak fibrosis score at 48 weeks
Number of cases with adequate control biopsy information Study 437 Study 438 Adefovir
10 mg placebo Adefovir
10 mg placebo (n=150) (n=146) (n=112) (n=55) Ishak fibrosis score improvement* 34%19%34%14% no change 55%60%62%50% deterioration11%21%4%36%* Change in Ishak fibrosis score ≥1 point
At week 48, improvements were observed in patients treated with adefovir in the following indicators compared to placebo treatment: mean serum HBV DNA changes (log10 copies/mL), ALT normalization and HBeAg seroconversion (Table 6).
Table 6
Serum HBV DNA alterations, ALT normalization and HBeAg seroconversion at 48 weeks Study 437 Study 438 Adefovir
10 mg placebo Adefovir
10 mg placebo (n=167) (n=171) (n=123) (n=61) Serum HBV DNA
Mean ± standard deviation of change from baseline
(log10 copies/mL) -3.57±1.64-0.98±1.32-3.65±1.14-1.32±1.25ALT normalization 48%16%72%29%HBeAg seroconversion 12%6%-*-**HBeAg seroconversion does not occur in HBeAg negative patients.
In studies 437 and 438, HBeAg-positive patients continued treatment with adefovir up to 72 weeks.
HBeAg-negative patients continued treatment with adefovir until 144 weeks, resulting in a continued decrease in the mean serum HBV DNA of the patients. An increase in the proportion of patients with negative HBV DNA and normalized ALT was found in both studies. In Study 437, the rate of HBeAg conversion and HBeAg seroconversion was also increased in patients treated with adefovir for up to 72 weeks (Tables 7 and 8).
Table 7
Rates of HBV DNA regression, ALT normalization, and HBeAg seroconversion at weeks 24, 48, and 72 – Study 437
(All patients in the 10 mg treatment group of this product, n=309)* Serum HBV DNA negative by PCR at week 24 48 72
(<400 copies/mL)14%26%46%ALT normalized 41%67%75%HBeAg seroconverted 13%23%44%HBeAg seroconverted 8%14%23%*Kaplan-Meier estimation method
Table 8
Change in serum HBV DNA and ALT at weeks 96 and 144 and the percentage of patients with negative HBV DNA and normalized ALT – Study 438
(Patients in the 10 mg treatment group) Median serum HBV DNA alterations at week 96 (n=79) Week 144 (n=67)
(log10 copies/ml)-3.47
(n=70)-3.63
(n=67) Negative HBV DNA by PCR
(< 1000 copies/mL) 71%
(50/70)79%
(53/67) Median of ALT changes
(IU/L)-59
(n=71)-54
(n=67) Percentage of ALT normalization 73% (47/64) 69% (43/62)
Patients before and after liver transplantation
Study 435 was an open, uncontrolled study that included 324 patients with chronic hepatitis B with clinical evidence of lamivudine resistance, 128 of whom were pre-liver transplant and 196 of whom were post-liver transplant. In patients before and after liver transplantation, the median baseline serum HBV DNA levels measured by the multiplex enzyme chain reaction assay were 7.4 and 8.2 log10
The median baseline ALT levels were 1.8 and 2.1 times the upper limit of normal, respectively. The results of this study are presented in Table 9. Serum HBV DNA decreased similarly in lamivudine-resistant patients on adefovir, regardless of the patient’s HBV DNA polymutase variability at baseline.
The clinical significance of these results and their relationship to histologic improvement is unclear.
Table 9
Efficacy of pre- and post-transplant patients at 48 weeks Efficacy parameters Pre-liver transplant Post-liver transplant (n=128) (n=196) Change in serum HBV DNA from baseline
Mean ± standard deviation (log10
copies/ml)
-3.8±1.4
-4.1±1.6Child-Pugh-Turcotte score
Stabilization or improvement 92% * 96% conversion to normal for the following indicators:** ALT 76% 49% albumin 81% 76% bilirubin 50% 75% prothrombin time 83% 20% * 24 weeks information
** Patients whose denominator was an abnormal value at baseline.
Patients with evidence of clinical resistance to lamivudine
In a double-blind, controlled study in 59 patients with chronic hepatitis B resistant to lamivudine, 48 weeks of lamivudine monotherapy, adefovir monotherapy, or adefovir combined with lamivudine showed reductions in serum HBV DNA levels (mean ± standard deviation) from baseline of 0.31 ± 0.93, 4.00 ± 1.41, and 3.46 ± 1.10 log10 copies/ml. The results were similar for adefovir monotherapy or adefovir combined with lamivudine treatment. The clinical significance of these HBV DNA changes has not been determined.
Forty patients with HBeAg-positive or negative lamivudine-resistant decompensated chronic hepatitis B being treated with lamivudine 100 mg plus 10 mg of this product for 52 weeks showed a median decrease in serum HBV DNA of 4.6 log10
copies/ml. Liver function also improved after one year of treatment.
Drug resistance.
Clinical study data.
Adefovir-resistant HBV monotherapy that emerged from clinical studies.
In a placebo-controlled phase 3 clinical study of 271 HBeAg-positive or pre-C region variants receiving 48 weeks of
10 mg adefovir treatment of chronic hepatitis B patients with HBV isolates were genotyped and phenotyped. No HBV DNA polymutase mutant strains associated with adefovir resistance were detected in patients at baseline and at 48 weeks when genetic analysis was performed.
The cumulative probability of adefovir resistance-associated mutations in HBAeAg-negative patients at 96, 144, 192, and 240 weeks was 3%, 11%, 18%, and 29%, respectively.
The median incidence of adefovir resistance-associated mutations in HBAeAg-positive patients after 135, 189, and 235 weeks of therapy was
The incidence was 3%, 17% and 20%, respectively.
Study of adefovir plus lamivudine in lamivudine-resistant patients.
In an open study of pre- and post-transplant liver patients with clinical evidence of lamivudine resistance, no adefovir resistance-associated variants were observed at 48 weeks.
After up to 3 years of exposure, no patients treated with adefovir and lamivudine were resistant to adefovir
drug. However, four patients who discontinued lamivudine developed rtN236T mutations during adefovir monotherapy, and all developed serum HBV rebound.
Pharmacology and Toxicology]
Pharmacodynamic characteristics
Mechanism of action
Adefovir is an acyclic phosphorylated nucleoside analogue of adenosine monophosphate. It is phosphorylated into an active metabolite, adefovir diphosphate, by the action of cellular kinase. Adefovir diphosphate inhibits HBV DNA polymutase (reverse transcriptase) in two ways: by competing with the natural substrate deoxyadenosine triphosphate, and by causing DNA strand lengthening and termination upon integration into viral DNA. The inhibition constant (Ki) of adefovir diphosphate against HBV DNA polymutase is 0.1 µM, but the inhibition of human DNA polymutase a and γ is weaker with Ki values of 1.18 µM and 0.97 µM, respectively.
Antiviral activity
The in vitro concentration (IC50) of adefovir that inhibited 50% of viral DNA replication as determined by transfection of human hepatocellular tumor cell lines with HBV was 0.2-2.5 µM. adefovir in combination with lamivudine exhibited additional anti-HBV activity in vitro.
Drug resistance
Long-term (96-144 weeks) genotypic analysis of resistance in patients treated with adefovir but still with detectable serum HBV DNA identified rtN236T and rtA181V variants associated with adefovir resistance. In vitro studies found that the rtN236T variant resulted in a 4- to 14-fold reduction in HBV susceptibility to adefovir, and that the variants that produced this
Serum HBV DNA levels rebounded in all 6 patients. rtA181V variant resulted in a 2.5-3 fold reduction in its sensitivity to adefovir in vitro, and serum HBV DNA levels rebounded in 2 of the 3 patients who developed this variant.
Cross-resistance
Recombinant HBV variants containing lamivudine resistance-associated mutations (rtL_180M, rtM204I, rtM204V, rtL180M+rtM204V, rtV173L) in the HBV DNA polymutase gene are sensitive to adefovir in vitro. Adefovir also showed anti-HBV effects in patients with lamivudine-resistant-associated mutant HBV, with a median decrease in serum HBV DNA of 4.3 log10 copies/ml. HBV variants containing DNA polymutations (rtT128N and rtR153Q or rtW153Q, associated with hepatitis B immunoglobulin resistance) were sensitive to adefovir in vitro. HBV strains expressing the rtN236T variant associated with adefovir resistance were 2-3-fold less sensitive to lamivudine in vitro, but remained sensitive to lamivudine in vivo. Preliminary in vitro and patient data suggest that the rtA181V variant HBV strain expressed as adefovir-resistant-associated is 3-fold less susceptible to lamivudine in vitro.
Adefovir resistance leads to a rebound in viral load, which exacerbates hepatitis B, declines liver function, leads to hepatic failure, and is potentially fatal.
In patients with evidence of lamivudine resistance (rtL180M, rtA181T, and/or rtM2041/V)
or patients with prior lamivudine exposure, to reduce the risk of resistance, adefovir should be coadministered with lamivudine and not used alone.
For patients receiving adefovir monotherapy, to reduce the risk of resistance, a change in treatment regimen should be considered if serum HBV DNA levels are consistently above 1000 copies/mL.
Toxicology studies
Chronic toxicity: In animal (mice, rats and monkeys) studies, tubular nephropathy characterized by histological changes and/or elevated urea nitrogen and serum creatinine was the primary dose-limiting toxic response to adefovir. Nephrotoxicity was observed in animal studies occurring at exposures at least 3-10 times greater than those at the recommended human therapeutic dose (10 mg/day).
Genotoxicity: Adefovir was mutagenic in in vitro murine lymphocytoma cellular assays (with and without metabolic activation), but had no chromosomal disruptor effects in in vivo mouse micronucleus assays at doses of up to 2,000 mg/day.
Adefovir induced chromosomal aberrations in human peripheral blood lymphocytes in vitro without metabolic activation. Adefovir was not mutagenic in Ames bacterial reversion mutation assays using Salmonella typhimurium and Escherichia coli strains (with or without metabolic activation).
Reproductive toxicity:Adefovir had no effect on fertility or reproduction when given orally to male and female rats. No embryotoxicity or embryonic malformations were observed in rats or rabbits given adefovir orally.
In pregnant rats given adefovir intravenously, an increase in embryotoxicity and incidence of fetal malformations (generalized edema, eye vesicle depression, umbilical hernia and tail kink) was observed at doses that produced significant maternal toxicity (20 mg/kg/day equivalent to 38 times the exposure at the recommended therapeutic dose for humans). No adverse effects were observed at an intravenous dose of 2.5 mg/kg/day equivalent to 12 times the human exposure.
Carcinogenicity: In long-term carcinogenicity studies in mice and rats, oral administration of adefovir at doses of 10 mg/kg/day and 5 mg/kg/day equivalent to 10 and 4 times the human therapeutic dose (10 mg/day), respectively, did not show carcinogenic effects.
Pharmacokinetics
Absorption
Adefovir, or adefovir dipivaloyl methyl ester, is the precursor drug of the active ingredient adefovir. The bioavailability of adefovir after oral administration of 10 mg of this product is 59 %. The median time to reach peak blood concentration (Cmax) after a single oral dose of 10 mg was 1.75 hours (range: 0.58-4.0 hours) in patients with chronic hepatitis B. The median time to reach peak blood concentration (Cmax) after a single oral dose of 10 mg was 1.75 hours (range: 0.58-4.0 hours).
The median Cmax was the geometric mean of 16.70 (9.66-30.56) ng/mL and the median AUC0-∞ was 204.40 (109.75-356.05) ngh/mL (see Table 10-3 for the corresponding mean values). The pharmacokinetic parameters for the oral administration of 10 mg of this product in Chinese are shown in Table 10-1.
Effect of food on oral absorption
The systemic exposure of adefovir is not affected when adefovir 10 mg is taken with food. Distribution
Preclinical studies have shown that adefovir is distributed in most tissues following oral administration of adefovir, with the highest concentrations of distribution including renal, hepatic, and intestinal tissues. Adefovir concentrations in in vitro studies ranged from 0.1 to
25 μg/mL when
Binding to human plasma or human serum proteins was ≤ 4 %. Intravenous administration 1.0 or
The steady-state volume of distribution after intravenous administration of 1.0 or 3.0 mg/kg/day was 392±75 and 352±9 mL/kg, respectively.
Metabolism
Following oral administration, adefovir is rapidly converted to adefovir. Adefovir does not inhibit any of the following human CYP450 isozymes: CYP1A2, CYP2D6, CYP2C9, CYP2C19, CYP3A4 at concentrations much higher than in vivo concentrations (>4,000-fold), and is not a substrate for these enzymes. Based on the results of in vitro experiments and the known elimination pathways of adefovir, adefovir is less likely to interact with other drugs through CYP450-mediated interactions.
Elimination
Adefovir is excreted via glomerular filtration and active tubular secretion via the kidneys. Adefovir 10 mg can be recovered in the urine up to 45 % of the administered dose after 24 hours following multiple doses. Plasma adefovir concentrations were reduced in a biexponential manner with a median terminal elimination half-life of 7.22 hours (4.72-10.70 hours).
The pharmacokinetic parameters of this product were similar in the three populations of healthy Chinese subjects, healthy US subjects, and US HBV patients. (See Tables 10-1, 10-2, 10-3)
Table 10-1. Pharmacokinetic parameters of this product in Chinese healthy subjects (geometric mean)
Pharmacokinetic
Parameters AUC0-
(ngh/mL)Cmax
(ng/mL)tmax
(h)t1/2z
(h)CL renal
(L/h)a single dose
(Study 489) 18920.80.637.0612.1 steady state
(Study 489) 22020.40.638.7914.5
Table 10-2 Pharmacokinetic parameters of this product in healthy subjects in the United States (geometric mean)
Pharmacokinetic
Parameters AUC0-
(ngh/mL)Cmax
(ng/mL)tmax
(h)t1/2z
(h)CL renal
(L/h)a single dose
(Study 476) 19220.4 0.76 6.42 – steady state
(Study 475) 207*21.7 1.02 7.03 10.6
Table 10-3 Pharmacokinetic parameters of this product in US HBV patients (geometric mean)
Pharmacokinetic
Parameters AUC0-
(ngh/mL) Cmax
(ng/mL)tmax
(h)t1/2z
(h)CL renal
(L/h)a single dose
(Study 472) 21017.51.757.229.78a steady-state
(Study 472) 204*18.31.007.149.24 Note: AUC and Cmax are geometric means, tmax, t1/2z(h) and CL kidney
are median values
*: AUC0-tau
a : Converted from estimated body weight 60 kg, e.g. 163(mL/h/kg) = 163/1000(L/h/kg)
163/1000(L/h/kg) x 60kg = 9.78(L/h)
Linear/non-linear:
The pharmacokinetic parameters of adefovir at doses in the range of 10-60 mg are proportional to the dose administered and are not affected by multiple dosing.
Special Populations
Gender
The pharmacokinetics of adefovir are similar in male and female patients.
Elderly
There is a lack of information on the pharmacokinetics of adefovir in the elderly.
Children
There is a lack of information on the pharmacokinetics of adefovir in children.
Race
The available data do not suggest that the pharmacokinetic properties of adefovir differ between races.
Patients with renal impairment
The Cmax, AUC0-∞ and t1/2 of adefovir are increased in patients with moderate to severe renal impairment or end-stage renal disease (ESRD) requiring dialysis. Therefore, it is recommended that patients with creatinine clearance < 50 mL/min (mL/min) or patients who already have ESRD and require dialysis need to adjust the dosing interval when treating with adefovir 10 mg
(see [Dosage]).
The pharmacokinetic parameters of adefovir in patients with non-chronic hepatitis B with varying degrees of renal insufficiency are shown in Table 11. In this study, subjects received adefovir 10 mg as a single dose.
Table 11
Adefovir pharmacokinetic parameters in patients with varying degrees of renal function
(Mean ± standard deviation)
Renal function index Normal Mild Moderate Severe Baseline creatinine clearance
(mL/min)>80
(n=7)50 – 80
(n=8)30 – 49
(n=7)10 – 29
(n=10)Cmax
(ng/mL)17.8±3.2222.4±4.0428.5±8.5751.6±10.3AUC 0-
(ngh/mL)201±40.8266±55.7455±1761240±629CL/F
(mL/min)469±99.0356±85.6237±11891.7±51.3CL kidney
(mL/min)231±48.9148±39.383.9±27.537.0±18.4
Four hours of hemodialysis cleared approximately 35% of the adefovir dose. The effect of peritoneal dialysis on clearance of adefovir has not been evaluated.
Patients with hepatic impairment
The pharmacokinetic profile in patients with moderate to severe hepatic impairment is similar to that of healthy subjects. Therefore, no dose adjustment is required in patients with hepatic impairment.
Storage
Seal and store in a dry place below 25℃.
Packaging
High-density polyethylene bottle: 14 capsules/bottle, 1 bottle/box, each bottle contains 1 bag of silica gel desiccant; 30 capsules/bottle, 1 bottle/box, each bottle contains 1 bag of silica gel desiccant.
【Expiration date】.
24 months.
【Execution standard
【Approval number】
State Drug Quasi-Zi H20060666
【Marketing License Holder】
Company Name: Zhengda Tianqing Pharmaceutical Group Co.
Registered Address: No. 369, Yuzhou South Road, Lianyungang City, Jiangsu Province
Manufacturer
Company Name: Zhengda Tianqing Pharmaceutical Group Co.
Address: No. 369, Yuzhou South Road, Lianyungang City, Jiangsu Province
Postal Code: 222062
Telephone number: 0518-85804002
Fax number: 0518-85806524
Website: http://www.cttq.com