2.1     Chronic Hepatitis B

The recommended dose of Adefovir Dipivoxil Tablets in chronic hepatitis B patients for patients 12 years of age and older with adequate renal function is 10 mg, once daily, taken orally, without regard to food. The optimal duration of treatment is unknown.

Adefovir Dipivoxil Tablets is not recommended for use in children less than 12 years of age.

2.2     Dose Adjustment in Renal Impairment

Significantly increased drug exposures were seen when Adefovir Dipivoxil Tablets was administered to adult patients with renal impairment [See Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)]. Therefore, the dosing interval of Adefovir Dipivoxil Tablets should be adjusted in adult patients with baseline creatinine clearance less than 50 mL per minute using the following suggested guidelines (See 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.

Table 1  Dosing Interval Adjustment of Adefovir Dipivoxil Tablets in Adult Patients with Renal Impairment

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 [See Warnings and Precautions (5.2)]

5.1      Exacerbation of Hepatitis after Discontinuation of Treatment

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.

5.2      Nephrotoxicity

Nephrotoxicity characterized by a delayed onset of gradual increases in serum creatinine and decreases in serum phosphorus was historically shown to be the treatment-limiting toxicity of adefovir dipivoxil therapy at substantially higher doses in HIV-infected patients (60 and 120 mg daily) and in chronic hepatitis B patients (30 mg daily). Chronic administration of Adefovir Dipivoxil Tablets (10 mg once daily) may result in delayed nephrotoxicity. The overall risk of nephrotoxicity in patients with adequate renal function is low. However, this is of special importance in patients at risk of or having underlying renal dysfunction and patients taking concomitant nephrotoxic agents such as cyclosporine, tacrolimus, aminoglycosides, vancomycin and non-steroidal anti-inflammatory drugs [See Adverse Reactions (6.2) and Clinical Pharmacology (12.3)] . It is recommended that creatinine clearance is calculated in all patients prior to initiating therapy with Adefovir Dipivoxil Tablets.

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 [See Dosage and Administration (2.2)] . The risks and benefits of Adefovir Dipivoxil Tablets treatment should be carefully evaluated prior to discontinuing Adefovir Dipivoxil Tablets in a patient with treatment-emergent nephrotoxicity.

5.3      HIV Resistance

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.

5.4      Lactic Acidosis/Severe Hepatomegaly with Steatosis

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).

5.5      Coadministration with Other Products

Adefovir Dipivoxil Tablets should not be used concurrently with products containing tenofovir disoproxil fumarate or tenofovir alafenamide.

5.6      Clinical Resistance

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.

6.1      Clinical Trials Experience

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.

The incidence of these adverse reactions in studies 437 and 438, where 522 patients with chronic hepatitis B and compensated liver disease received double-blind treatment with Adefovir Dipivoxil Tablets (N=294) or placebo (N=228) for 48 weeks is presented in Table 2. Patients who received open-label Adefovir Dipivoxil Tablets for up to 240 weeks in Study 438 reported adverse reactions similar in nature and severity to those reported in the first 48 weeks.

a In these studies, the overall incidence of adverse reactions with Adefovir Dipivoxil Tablets was similar to that reported with placebo. The incidence of adverse reactions is derived from treatment-related events as identified by the study investigators.

No patients treated with Adefovir Dipivoxil Tablets developed a confirmed serum creatinine increase greater than or equal to 0.5 mg/dL from baseline or confirmed phosphorus decrease to 2 mg/dL or less by Week 48. By Week 96, 2% of Adefovir Dipivoxil Tablets-treated patients, by Kaplan-Meier estimate, had increases in serum creatinine greater than or equal to 0.5 mg/dL from baseline (no placebo-controlled results were available for comparison beyond Week 48). For patients who chose to continue Adefovir Dipivoxil Tablets for up to 240 weeks in Study 438, 4 of 125 patients (3%) had a confirmed increase of 0.5 mg/dL from baseline. The creatinine elevation resolved in 1 patient who permanently discontinued treatment and remained stable in 3 patients who continued treatment. For 65 patients who chose to continue Adefovir Dipivoxil Tablets for up to 240 weeks in Study 437, 6 had a confirmed increase in serum creatinine of greater than or equal to 0.5 mg/dL from baseline with 2 patients discontinuing from the study due to the elevated serum creatinine concentration. See Adverse Reactions (6.2) for changes in serum creatinine in patients with underlying renal insufficiency at baseline.

6.2      Special Risk Patients

Pre- and Post-Liver Transplantation Patients

Additional adverse reactions observed from an open-label study (Study 435) in pre- and post- liver transplantation patients with chronic hepatitis B and lamivudine-resistant hepatitis B administered Adefovir Dipivoxil Tablets once daily for up to 203 weeks include: abnormal renal function, renal failure, vomiting, rash, and pruritus.

Changes in renal function occurred in pre-and post-liver transplantation patients with risk factors for renal dysfunction, including concomitant use of cyclosporine and tacrolimus, renal insufficiency at baseline, hypertension, diabetes, and on-study transplantation. Therefore, the contributory role of Adefovir Dipivoxil Tablets to these changes in renal function is difficult to assess.

Increases in serum creatinine greater than or equal to 0.3 mg/dL from baseline were observed in 37% and 53% of pre-liver transplantation patients by Weeks 48 and 96, respectively, by Kaplan-Meier estimates. Increases in serum creatinine greater than or equal to 0.3 mg/dL from baseline were observed in 32% and 51% of post-liver transplantation patients by Weeks 48 and 96, respectively, by Kaplan-Meier estimates. Serum phosphorus values less than 2 mg/dL were observed in 3/226 (1.3%) of pre-liver transplantation patients and in 6/241 (2.5%) of post-liver transplantation patients by last study visit. Four percent (19 of 467) of patients discontinued treatment with Adefovir Dipivoxil Tablets due to renal adverse events.

6.3      Pediatric Patients

Assessment of adverse reactions is based on a placebo-controlled study (Study 518) in which 173 pediatric patients aged 2 to less than 18 years with chronic hepatitis B and compensated liver disease received double-blind treatment with Adefovir Dipivoxil Tablets (N=115), or placebo (N=58) for 48 weeks [See Clinical Studies (14.4) and Use In Specific Populations (8.4)] .

The safety profile of Adefovir Dipivoxil Tablets in patients 12 to less than 18 years of age (N=56) was similar to that observed in adults. No pediatric patients treated with Adefovir Dipivoxil Tablets developed a confirmed serum creatinine increase greater than or equal to 0.5 mg/dL from baseline or a confirmed phosphorus decrease to less than 2 mg/dL by Week 48.

6.4      Post-Marketing Experience

In addition to adverse reaction reports from clinical trials, the following possible adverse reactions have also been identified during post-approval use of adefovir dipivoxil. Because these events have been reported voluntarily from a population of unknown size, estimates of frequency cannot be made.

Metabolism and Nutrition Disorders: hypophosphatemia

Gastrointestinal Disorders: pancreatitis

Musculoskeletal System and Connective Tissue Disorders: myopathy, osteomalacia (manifested as bone pain and may contribute to fractures), both associated with proximal renal tubulopathy

Renal and Urinary Disorders: renal failure, Fanconi syndrome, proximal renal tubulopathy

8.1      Pregnancy

Pregnancy Exposure Registry
There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to Adefovir Dipivoxil Tablets during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.

8.2      Lactation

Risk Summary

It is not known whether adefovir is present in human breast milk, affects human milk production, or has effects on the breastfed infant. 

The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Adefovir Dipivoxil Tablets and any potential adverse effects on the breastfed infant from Adefovir Dipivoxil Tablets or from the underlying maternal condition. 

8.4      Pediatric Use

8.5      Geriatric Use

Clinical studies of Adefovir Dipivoxil Tablets did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. In general, caution should be exercised when prescribing to elderly patients since they have greater frequency of decreased renal or cardiac function due to concomitant disease or other drug therapy.

8.6      Patients with Impaired Renal Function

It is recommended that the dosing interval for Adefovir Dipivoxil Tablets be modified in adult patients with baseline creatinine clearance less than 50 mL per minute. The pharmacokinetics of adefovir have not been evaluated in non-hemodialysis patients with creatinine clearance less than 10 mL per minute or in adolescent patients with renal insufficiency; therefore, no dosing recommendations are available for these patients  [See Dosage and Administration (2.2) and Warning and Precautions (5.2)].

12.1      Mechanism of Action

Adefovir is an antiviral drug  [See Microbiology (12.4)].

12.3      Pharmacokinetics

12.4      Microbiology

13.1      Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term oral carcinogenicity studies of adefovir dipivoxil in mice and rats were carried out at exposures up to approximately 10 times (mice) and 4 times (rats) those observed in humans at the therapeutic dose for HBV infection. In both mouse and rat studies, adefovir dipivoxil was negative for carcinogenic findings. Adefovir dipivoxil was mutagenic in the in vitro mouse lymphoma cell assay (with or without metabolic activation). Adefovir induced chromosomal aberrations in the in vitro human peripheral blood lymphocyte assay without metabolic activation. Adefovir dipivoxil was not clastogenic in the in vivo mouse micronucleus assay and adefovir was not mutagenic in the Ames bacterial reverse mutation assay using S. typhimurium and E. coli strains in the presence or absence of metabolic activation. In reproductive toxicology studies, no evidence of impaired fertility was seen in male or female rats at systemic exposure approximately 19 times that achieved in humans at the therapeutic dose.

13.2      Animal Toxicology and/or Pharmacology

Renal tubular nephropathy characterized by histological alterations and/or increases in BUN and serum creatinine was the primary dose-limiting toxicity associated with administration of adefovir dipivoxil in animals. Nephrotoxicity was observed in animals at systemic exposures approximately 3 - 10 times higher than those in humans at the recommended therapeutic dose of 10 mg/day.

14.1      Studies 437 and 438 (Pivotal Studies)

HBeAg-Positive Chronic Hepatitis B

Study 437 was a randomized, double-blind, placebo-controlled, three-arm-study in patients with HBeAg-positive chronic hepatitis B that allowed for a comparison between placebo and Adefovir Dipivoxil Tablets. The median age of patients was 33 years. Seventy-four percent were male, 59% were Asian, 36% were Caucasian, and 24% had prior interferon-α treatment. At baseline, patients had a median total Knodell Histology Activity Index (HAI) score of 10, a median serum HBV DNA level as measured by the Roche Amplicor Monitor polymerase chain reaction (PCR) assay (LLOQ = 1000 copies/mL) of 8.36 log 10 copies/mL and a median ALT level of 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 in patients who were HBeAg-negative at screening, and anti-HBe positive. The median age of patients was 46 years. Eighty-three percent were male, 66% were Caucasian, 30% were Asian and 41% had prior interferon-α treatment. At baseline, the median total Knodell HAI score was 10, the median serum HBV DNA level as measured by the Roche Amplicor Monitor PCR assay (LLOQ = 1000 copies/mL) was 7.08 log 10 copies/mL, and the median ALT was 2.3 times the upper limit of normal.

The primary efficacy endpoint in both studies was histological improvement at Week 48; results of which are shown in Table 4.

a Intent-to-Treat population (patients with ≥1 dose of study drug) with assessable baseline biopsies. 

b Histological improvement defined as ≥2 point decrease in the Knodell necro-inflammatory score with no worsening of the Knodell fibrosis score.

Table 5 illustrates the changes in Ishak Fibrosis Score by treatment group.

Table 5 Changes in Ishak Fibrosis Score at Week 48

a Change of 1 point or more in Ishak Fibrosis Score. 

At Week 48, improvement was seen with respect to mean change in serum HBV DNA (log 10 copies/mL), normalization of ALT, and HBeAg seroconversion as compared to placebo in patients receiving Adefovir Dipivoxil Tablets (Table 6).

Table 6 Change in Serum HBV DNA, ALT Normalization, and HBeAg Seroconversion at Week 48

a Patients with HBeAg-negative disease cannot undergo HBeAg seroconversion. 

Treatment Beyond 48 Weeks

In Study 437, continued treatment with Adefovir Dipivoxil Tablets to 72 weeks resulted in continued maintenance of mean reductions in serum HBV DNA observed at Week 48. An increase in the proportion of patients with ALT normalization was also observed in Study 437. The effect of continued treatment with Adefovir Dipivoxil Tablets on seroconversion is unknown.

In Study 438, patients who received Adefovir Dipivoxil Tablets during the first 48 weeks were re-randomized in a blinded manner to continue on Adefovir Dipivoxil Tablets or receive placebo for an additional 48 weeks. At Week 96, 50 of 70 (71%) of patients who continued treatment with Adefovir Dipivoxil Tablets had undetectable HBV DNA levels (less than 1000 copies/mL), and 47 of 64 (73%) of patients had ALT normalization. HBV DNA and ALT levels returned towards baseline in most patients who stopped treatment with Adefovir Dipivoxil Tablets.

From 141 eligible patients, there were 125 (89%) patients in Study 438 who chose to continue Adefovir Dipivoxil Tablets for up to 192 weeks or 240 weeks (4 years or 5 years). As these patients had already received Adefovir Dipivoxil Tablets for at least 48 weeks and appeared to be experiencing a benefit, they are not necessarily representative of patients initiating Adefovir Dipivoxil Tablets. Of these patients, 89/125 (71%) and 47/70 (67%) had an undetectable HBV DNA level (less than 1000 copies/mL) at Week 192 and Week 240, respectively. Of the patients who had an elevated ALT at baseline, 77/104 (74%) and 42/64 (66%) had a normal ALT at Week 192 and Week 240, respectively. Six (5%) patients experienced HBsAg loss.

14.2      Study 435 (Pre- and Post-Liver Transplantation Patients)

Adefovir Dipivoxil Tablets were also evaluated in an open-label, uncontrolled study of 467 chronic hepatitis B patients pre- (N=226) and post- (N=241) liver transplantation with clinical evidence of lamivudine-resistant hepatitis B virus (Study 435). At baseline, 60% of pre-liver transplantation patients were classified as Child-Pugh-Turcotte score of Class B or C. The median baseline HBV DNA as measured by the Roche Amplicor Monitor PCR assay (LLOQ = 1000 copies/mL) was 7.4 and 8.2 log 10 copies/mL, and the median baseline ALT was 1.8 and 2.0 times the upper limit of normal in pre- and post-liver transplantation patients, respectively. Results of this study are displayed in Table 7. Treatment with Adefovir Dipivoxil Tablets resulted in a similar reduction in serum HBV DNA regardless of the patterns of lamivudine-resistant HBV DNA polymerase mutations at baseline. The significance of the efficacy results listed in Table 7 as they relate to clinical outcomes is not known.

Table 7 Efficacy in Pre- and Post-Liver Transplantation Patients at Week 48

a Data are missing for 29% (HBV DNA) and 37% to 45% (CPT Score, Normalization of ALT, Albumin, Bilirubin, and PT) of total patients enrolled in the study.

b Denominator is the number of patients with serum HBV DNA ≥1000 copies/mL at baseline using the Roche Amplicor Monitor PCR Assay (LLOQ = 1000 copies/mL) and non-missing value at Week 48. 

c Denominator is patients with abnormal values at baseline and non-missing value at Week 48. 

14.3      Study 461 (Clinical Evidence of Lamivudine Resistance)

In Study 461, a double-blind, active controlled study in 59 chronic hepatitis B patients with clinical evidence of lamivudine-resistant hepatitis B virus, patients were randomized to receive either Adefovir Dipivoxil Tablets monotherapy or Adefovir Dipivoxil Tablets in combination with lamivudine 100 mg or lamivudine 100 mg alone. At Week 48, the mean ± SD decrease in serum HBV DNA as measured by the Roche Amplicor Monitor PCR assay (LLOQ = 1000 copies/mL) was 4.00 ± 1.41 log 10 copies/mL for patients treated with Adefovir Dipivoxil Tablets and 3.46 ± 1.10 log 10 copies/mL for patients treated with Adefovir Dipivoxil Tablets in combination with lamivudine. There was a mean decrease in serum HBV DNA of 0.31 ± 0.93 log 10 copies/mL in patients receiving lamivudine alone. ALT normalized in 47% of patients treated with Adefovir Dipivoxil Tablets, in 53% of patients treated with Adefovir Dipivoxil Tablets in combination with lamivudine, and 5% of patients treated with lamivudine alone. The significance of these findings as they relate to clinical outcomes is not known.

14.4      Study 518 (Pediatric Study)

Study 518 was a double-blind, placebo-controlled, study in which 173 pediatric patients (ages 2 to less than 18 years) with chronic hepatitis B (CHB) infection and elevated ALT were randomized 2:1 (115 receiving adefovir dipivoxil and 58 receiving placebo). Randomization was stratified by prior treatment and age 2 to less than 7 years old (cohort 1), 7 to less than 12 years old (cohort 2), and 12 to less than 18 years old (cohort 3). All patients in cohort 3 received 10 mg tablet formulation; all patients in cohorts 1 and 2 received an investigational suspension formulation (0.3 mg/kg/day cohort 1, 0.25 mg/kg/day cohort 2) once daily. The primary efficacy endpoint was HBV DNA less than 1000 copies/mL plus normalization of ALT at the end of Week 48.

In cohort 3 (N=83), significantly more patients treated with Adefovir Dipivoxil Tablets achieved the primary efficacy endpoint at the end of 48 weeks of blinded treatment (23%) when compared to placebo-treated patients (0%). The proportion of patients from cohorts 1 and 2 who responded to treatment with adefovir dipivoxil was not statistically significant when compared to the placebo arm, although the adefovir plasma concentrations in these patients were comparable to those observed in older patients. Overall, 22 of 115 (19%) of pediatric patients who received adefovir dipivoxil versus 1 of 58 (2%) of placebo treated patients responded to treatment by Week 48 [See Adverse Reactions (6.3), Use In Special Populations (8.4) and Clinical Pharmacology (12.3,12.4)].

Store in original container at 25 °C (77 °F), excursions permitted to 15° - 30 °C (59° - 86 °F) (See USP Controlled Room Temperature).

Do not use if seal over bottle opening is broken or missing.