Adefovir Dipivoxil Prescribing Information
Severe acute exacerbation of hepatitis has been reported in patients who have discontinued anti-hepatitis B therapy, including therapy with Adefovir Dipivoxil Tablets. Hepatic function should be monitored at repeated intervals with both clinical and laboratory follow-up for at least several months in patients who discontinue Adefovir Dipivoxil Tablets. If appropriate, resumption of anti-hepatitis B therapy may be warranted.
In clinical trials of Adefovir Dipivoxil Tablets, exacerbations of hepatitis (ALT elevations 10 times the upper limit of normal or greater) occurred in up to 25% of patients after discontinuation of Adefovir Dipivoxil Tablets. These events were identified in studies GS-98-437 and GS-98-438 (N=492). Most of these events occurred within 12 weeks of drug discontinuation. These exacerbations generally occurred in the absence of HBeAg seroconversion, and presented as serum ALT elevations in addition to re-emergence of viral replication. 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.
Warnings and Precautions (5.2) and
Significantly increased drug exposures were seen when Adefovir Dipivoxil Tablets was administered to adult patients with renal impairment
Additionally, it is important to note that these guidelines were derived from data in patients with pre-existing renal impairment at baseline. They may not be appropriate for patients in whom renal insufficiency evolves during treatment with Adefovir Dipivoxil Tablets. Therefore, clinical response to treatment and renal function should be closely monitored in these patients.
Creatinine Clearance (mL/min)a | Hemodialysis Patients | |||
Greater than or equal to 50 | 30 - 49 | 10 - 29 | ||
| Recommended dose and dosing interval | 10 mg every 24 hours | 10 mg every 48 hours | 10 mg every 72 hours | 10 mg every 7 days following dialysis |
aCreatinine clearance calculated by Cockcroft-Gault method using lean or ideal body weight.
The pharmacokinetics of adefovir have not been evaluated in non-hemodialysis patients with creatinine clearance less than 10 mL per minute; therefore, no dosing recommendation is available for these patients.
No clinical data are available to make dosing recommendations in adolescent patients with renal insufficiency
Prior to initiating adefovir dipivoxil therapy, HIV antibody testing should be offered to all patients. Treatment with anti-hepatitis B therapies, such as Adefovir Dipivoxil Tablets, that have activity against HIV in a chronic hepatitis B patient with unrecognized or untreated HIV infection may result in emergence of HIV resistance. Adefovir Dipivoxil Tablets has not been shown to suppress HIV RNA in patients; however, there are limited data on the use of Adefovir Dipivoxil Tablets to treat patients with chronic hepatitis B co-infected with HIV.
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).
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).
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).
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).
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.
This indication is based on histological, virological, biochemical, and serological responses in adult patients with HBeAg+ and HBeAg- chronic hepatitis B with compensated liver function, and with clinical evidence of lamivudine-resistant hepatitis B virus with either compensated or decompensated liver function.
For patients 12 to less than 18 years of age, the indication is based on virological and biochemical responses in patients with HBeAg+ chronic hepatitis B virus infection with compensated liver function.
Significantly increased drug exposures were seen when Adefovir Dipivoxil Tablets was administered to adult patients with renal impairment
Warnings and Precautions (5.2) and
The pharmacokinetics of adefovir have been evaluated in healthy volunteers and patients with chronic hepatitis B. Adefovir pharmacokinetics are similar between these populations.
Absorption
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.
Effects of Food on Oral Absorption
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.
Distribution
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.
Metabolism and Elimination
Following oral administration, adefovir dipivoxil is rapidly converted to adefovir. Forty-five percent of the dose is recovered as adefovir in the urine over 24 hours at steady state following 10 mg oral doses of Adefovir Dipivoxil Tablets. Adefovir is renally excreted by a combination of glomerular filtration and active tubular secretion [
Adefovir dipivoxil is rapidly converted to adefovir in vivo. At concentrations substantially higher (greater than 4000-fold) than those observed in vivo, adefovir did not inhibit any of the common human CYP450 enzymes, CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Adefovir is not a substrate for these enzymes. However, the potential for adefovir to induce CYP450 enzymes is unknown. Based on the results of these in vitro experiments and the renal elimination pathway of adefovir, the potential for CYP450 mediated interactions involving adefovir as an inhibitor or substrate with other medicinal products is low.
The pharmacokinetics of adefovir have been evaluated in healthy adult volunteers following multiple dose administration of Adefovir Dipivoxil Tablets (10 mg once daily) in combination with lamivudine (100 mg once daily) (N=18), trimethoprim/sulfamethoxazole (160/800 mg twice daily) (N=18), acetaminophen (1000 mg four times daily) (N=20), ibuprofen (800 mg three times daily) (N=18), and enteric coated didanosine (400 mg) (N=21). The pharmacokinetics of adefovir have also been evaluated in post-liver transplantation patients following multiple dose administration of Adefovir Dipivoxil Tablets (10 mg once daily) in combination with tacrolimus (N=16). The pharmacokinetics of adefovir have been evaluated in healthy volunteers following single dose pegylated interferon α-2a (PEG-IFN) (180 mcg) (N=15).
Adefovir did not alter the pharmacokinetics of lamivudine, trimethoprim/sulfamethoxazole, acetaminophen, ibuprofen, enteric coated didanosine (didanosine EC), or tacrolimus. The evaluation of the effect of adefovir on the pharmacokinetics of pegylated interferon α-2a was inconclusive due to the high variability of pegylated interferon alpha-2a.
The pharmacokinetics of adefovir were unchanged when Adefovir Dipivoxil Tablets was coadministered with lamivudine, trimethoprim/sulfamethoxazole, acetaminophen, didanosine EC, tacrolimus (based on cross study comparison), and pegylated interferon α-2a. When Adefovir Dipivoxil Tablets was coadministered with ibuprofen (800 mg three times daily) increases in adefovir Cmax(33%), AUC (23%) and urinary recovery were observed. This increase appears to be due to higher oral bioavailability, not a reduction in renal clearance of adefovir.
Apart from lamivudine, trimethoprim/sulfamethoxazole, and acetaminophen, the effects of coadministration of Adefovir Dipivoxil Tablets with drugs that are excreted renally, or other drugs known to affect renal function have not been evaluated.
The effect of adefovir on cyclosporine concentrations is not known.
No drug interaction studies have been performed in adolescent patients 12 to less than 18 years of age.
Gender
The pharmacokinetics of adefovir were similar in male and female patients.
Race
The pharmacokinetics of adefovir have been shown to be comparable in Caucasians and Asians. Pharmacokinetic data are not available for other racial groups.
Geriatric Patients
Pharmacokinetic studies have not been conducted in the elderly.
Pediatric Patients
The pharmacokinetics of adefovir were assessed from drug plasma concentrations in 53 HBeAg positive hepatitis B pediatric patients with compensated liver disease. The exposure of adefovir following a 48 week daily treatment with adefovir dipivoxil 10 mg tablet in pediatric patients 12 to less than 18 years of age(Cmax= 23.3 ng/ml and AUC 0–24 = 248.8 ng·h/ml) was comparable to that observed in adult patients.
Renal Impairment
In adults with moderately or severely impaired renal function or with end-stage renal disease (ESRD) requiring hemodialysis, C max, AUC, and half-life (T1/2) were increased compared to adults with normal renal function. It is recommended that the dosing interval of Adefovir Dipivoxil Tablets be modified in these patients [See
The pharmacokinetics of adefovir in non-chronic hepatitis B patients with varying degrees of renal impairment are described in Table 3. In this study, subjects received a 10 mg single dose of Adefovir Dipivoxil Tablets.
| Renal Function Group | Unimpaired | Mild | Moderate | Severe |
|---|---|---|---|---|
| Baseline creatinine clearance (mL/min) | >80 | 50–80 | 30–49 | 10–29 |
| (N=7) | (N=8) | (N=7) | (N=10) | |
| Cmax(ng/mL) | 17.8 ± 3.22 | 22.4 ± 4.04 | 28.5 ± 8.57 | 51.6 ± 10.3 |
| AUC0–∞(ng∙h/mL) | 201 ± 40.8 | 266 ± 55.7 | 455 ± 176 | 1240 ± 629 |
| CL/F (mL/min) | 469 ± 99.0 | 356 ± 85.6 | 237 ± 118 | 91.7 ± 51.3 |
| CLrenal(mL/min) | 231 ± 48.9 | 148 ± 39.3 | 83.9 ± 27.5 | 37.0 ± 18.4 |
A four-hour period of hemodialysis removed approximately 35% of the adefovir dose. The effect of peritoneal dialysis on adefovir removal has not been evaluated.
The pharmacokinetics of adefovir have not been studied in adolescent patients with renal dysfunction
Hepatic Impairment
The pharmacokinetics of adefovir following a 10 mg single dose of Adefovir Dipivoxil Tablets have been studied in non-chronic hepatitis B patients with hepatic impairment. There were no substantial alterations in adefovir pharmacokinetics in patients with moderate and severe hepatic impairment compared to unimpaired patients. No change in Adefovir Dipivoxil Tablets dosing is required in patients with hepatic impairment.
Table 1). The safety and effectiveness of these dosing interval adjustment guidelines have not been clinically evaluated.
Additionally, it is important to note that these guidelines were derived from data in patients with pre-existing renal impairment at baseline. They may not be appropriate for patients in whom renal insufficiency evolves during treatment with Adefovir Dipivoxil Tablets. Therefore, clinical response to treatment and renal function should be closely monitored in these patients.
Creatinine Clearance (mL/min) a | Hemodialysis Patients | |||
Greater than or equal to 50 | 30 - 49 | 10 - 29 | ||
| Recommended dose and dosing interval | 10 mg every 24 hours | 10 mg every 48 hours | 10 mg every 72 hours | 10 mg every 7 days following dialysis |
a Creatinine clearance calculated by Cockcroft-Gault method using lean or ideal body weight.
The pharmacokinetics of adefovir have not been evaluated in non-hemodialysis patients with creatinine clearance less than 10 mL per minute; therefore, no dosing recommendation is available for these patients.
No clinical data are available to make dosing recommendations in adolescent patients with renal insufficiency
Warnings and Precautions (5.2)]
Adefovir Dipivoxil is available as tablets. Each tablet contains 10 mg of adefovir dipivoxil. The tablets are white, round, flat faced beveled edged tablets, debossed Σ 3 on one side and plain on the other side.
Adefovir Dipivoxil Tablets are contraindicated in patients with previously demonstrated hypersensitivity to any of the components of the product.
Resistance to adefovir dipivoxil can result in viral load rebound which may result in exacerbation of hepatitis B and, in the setting of diminished hepatic function, lead to liver decompensation and possible fatal outcome.
In order to reduce the risk of resistance in patients with lamivudine resistant HBV, adefovir dipivoxil should be used in combination with lamivudine and not as adefovir dipivoxil monotherapy.
In order to reduce the risk of resistance in all patients receiving adefovir dipivoxil monotherapy, a modification of treatment should be considered if serum HBV DNA remains above 1000 copies/mL with continued treatment.
Long-term (144 week) data from Study 438 (N=124) show that patients with HBV DNA levels greater than 1000 copies/mL at Week 48 of treatment with adefovir dipivoxil were at greater risk of developing resistance than patients with serum HBV DNA levels below 1000 copies/mL at Week 48 of therapy.