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ENGLISH NAME: Adefovir Dipivoxil Tablets
LICENSE NUMBER: 10 mg  H20080034
PRODUCT PACKAGING: plastic bottle with Silica Gel Desiccant;
7 tablets/box, 14 tablets/box,  28 tablets/box
STORAGE CONDITION: Shading, Closed, Preservation of the Shade
SHELF LIFE: 24 Months
Description: Adefovir Dipivoxil is a diester prodrug of adefovir. Adefovir is an acyclic nucleotide analog with activity against human hepatitis B virus (HBV). The chemical name of Adefovir Dipivoxil is 9-[2-[[bis[(pivaloyloxy)methoxy]-phosphinyl]-methoxy]ethyl]adenine. Adefovir Dipivoxil is a white to off-white powder with an aqueous solubility of 19 mg/mL at pH 2.0 and 0.4 mg/mL at pH 7.2. It has an octanol/aqueous phosphate buffer (pH 7) partition coefficient (log p) of 1.91. Adefovir Dipivoxil tablets are for oral administration. Each tablet contains 10 mg of Adefovir Dipivoxil and the following inactive ingredients: copovidone, anhydrous lactose, microcrystalline cellulose, silicon dioxide, crospovidone and magnesium stearate.

Pharmacological effects: Adefovir is an acyclic nucleotide analog of adenosine monophosphate which is phosphorylated to the active metabolite adefovir diphosphate by cellularkinases. Adefovir diphosphate inhibits HBV DNA polymerase (reverse transcriptase) by competing with the natural substrate deoxyadenosine triphosphate and by causing DNA chain termination after its incorporation into viral DNA. The inhibition constant (Ki) for adefovir diphosphate for HBV DNA polymerase was 0.1 µM. Adefovir diphosphate is a weak inhibitor of human DNA polymerases α and β with Ki values of 1.18 µM and 0.97 µM, respectively. The concentration of adefovir that inhibited 50% of viral DNA synthesis (EC50) in HBV transfected human hepatoma cell lines ranged from 0.2 to 2.5 µM. The combination of adefovir with lamivudine showed additive anti-HBV activity.

Pharmacokinetics: The pharmacokinetics of adefovir have been evaluated in healthy volunteers and patients with chronic hepatitis B. Adefovir pharmacokinetics are similar between these populations. Adefovir Dipivoxil is a diester prodrug of the active moiety adefovir. Based on a cross study comparison, the approximate oral bioavailability of adefovir from Adefovir Dipivoxil Tablets is 59%. Following oral administration of a 10 mg single dose of Adefovir Dipivoxil Tablets to chronic hepatitis B patients (N=14), the peak adefovir plasma concentration (Cmax) was 18.4 ± 6.26 ng/mL (mean ± SD) and occurred between 0.58 and 4.00 hours (median=1.75 hours) post dose. The adefovir area under the plasma concentration-time curve (AUC0–∞) was 220 ± 70.0 ng·h/mL. Plasma adefovir concentrations declined in a biexponential manner with a terminal elimination half-life of 7.48 ± 1.65 hours. The pharmacokinetics of adefovir in subjects with adequate renal function were not affected by once daily dosing of 10 mg Adefovir Dipivoxil Tablets over seven days. The impact of long-term once daily administration of 10 mg Adefovir Dipivoxil Tablets on adefovir pharmacokinetics has not been evaluated. Adefovir exposure was unaffected when a 10 mg single dose of Adefovir Dipivoxil Tablets was administered with food (an approximately 1000 kcal high-fat meal). Adefovir Dipivoxil Tablets may be taken without regard to food. In vitro binding of adefovir to human plasma or human serum proteins is less than or equal to 4% over the adefovir concentration range of 0.1 to 25 µg/mL. The volume of distribution at steady-state following intravenous administration of 1.0 or 3.0 mg/kg/day is 392 ± 75 and 352 ± 9 mL/kg, respectively.

Indications: Adefovir Dipivoxil Tablets are indicated for the treatment of chronic hepatitis B in patients 12 years of age and older with evidence of active viral replication and either evidence of persistent elevations in serum aminotransferases (ALT or AST) or histologically active disease.

Precautions: In the HBeAg-positive and HBeAg-negative studies in patients with compensated liver function, the exacerbations were not generally accompanied by hepatic decompensation. However, patients with advanced liver disease or cirrhosis may be at higher risk for hepatic decompensation. Although most events appear to have been self-limited or resolved with re-initiation of treatment, severe hepatitis exacerbations, including fatalities, have been reported. Therefore, patients should be closely monitored after stopping treatment. It is important to monitor renal function for all patients during treatment with Adefovir Dipivoxil Tablets, particularly for those with pre-existing or other risks for renal impairment. Patients with renal insufficiency at baseline or during treatment may require dose adjustment The efficacy and safety of Adefovir Dipivoxil Tablets have not been studied in patients less than 18 years of age with different degrees of renal impairment and no data are available to make dosage recommendations in these patients. Caution should be exercised when prescribing Adefovir Dipivoxil Tablets to adolescents with underlying renal dysfunction, and renal function in these patients should be closely monitored. Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs alone or in combination with antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Particular caution should be exercised when administering nucleoside analogs to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with Adefovir Dipivoxil Tablets therapy should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations)
Adverse reaction: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Clinical and laboratory evidence of exacerbations of hepatitis have occurred after discontinuation of treatment with Adefovir Dipivoxil Tablets. Adverse reactions to Adefovir Dipivoxil Tablets identified from placebo-controlled and open label studies include the following: asthenia, headache, abdominal pain, diarrhea, nausea, dyspepsia, flatulence, increased creatinine, and hypophosphatemia.
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