1 INDICATIONS AND USAGE 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.

Adefovir dipivoxil tablets are a nucleotide analogue indicated for the treatment of chronic hepatitis B in patients 12 years of age and older.

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6 ADVERSE REACTIONS The following adverse reactions are discussed in other sections of the labeling: Severe acute exacerbations of Hepatitis [ S ee Boxed Warning , Warnings and Precautions (5.1) ] Nephrotoxicity [See Boxed Warning , Warnings and Precautions (5.2) ] Most common adverse reaction (incidence greater than 5%) in compensated liver disease patients were asthenia, headache, abdominal pain and nausea.

( 6.1 ) The most common adverse reaction in pre- and post- transplantation lamivudine-resistant liver disease patients was increased creatinine.

( 6.2 ) To report SUSPECTED ADVERSE REACTIONS, contact Apotex Corp.

at 1-800-706-5575or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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.

Adverse reactions to adefovir dipivoxil 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 (N=294) or placebo (N=228) for 48 weeks is presented in Table 2.

Patients who received open-label adefovir dipivoxil for up to 240 weeks in Study 438 reported adverse reactions similar in nature and severity to those reported in the first 48 weeks.

Table 2 Adverse Reactions (Grades 1 to 4) Reported in ≥3% of All Adefovir Dipivoxil-Treated Patients in Pooled Studies 437 to 438 Studies (0 to 48 Weeks) In these studies, the overall incidence of adverse reactions with adefovir dipivoxil was similar to that reported with placebo.

The incidence of adverse reactions is derived from treatment-related events as identified by the study investigators.

Adverse Reaction Adefovir Dipivoxil 10 mg (N=294) Placebo (N=228) Asthenia 13% 14% Headache 9% 10% Abdominal Pain 9% 11% Nausea 5% 8% Flatulence 4% 4% Diarrhea 3% 4% Dyspepsia 3% 2% No patients treated with adefovir dipivoxil developed a confirmed serum creatinine increase greater than or equal to 0.5 mg/dL from baseline or a confirmed phosphorus decrease to 2 mg/dL or less by Week 48.

By Week 96, 2% of adefovir dipivoxil-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 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 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 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 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 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 (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 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 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