Adefovir Dipivoxil

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. ( 1 )

2 DOSAGE AND ADMINISTRATION One tablet containing 10 mg adefovir dipivoxil once daily orally with or without food. ( 2.1 ) Dose adjustment in renal impairment for adults ( 2.2 ) Creatinine Clearance (mL/min) Creatinine clearance calculated by Cockcroft-Gault method using lean or ideal body weight. Greater than or equal to 50 30 to 49 10 to 29 Hemodialysis Patients 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 No dose recommendations for ( 2.1 ): Non-hemodialysis patients with creatinine clearance less than 10 mL per minute. Adolescent patients with renal impairment. 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 are 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 were 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 Creatinine Clearance (mL/min) Creatinine clearance calculated by Cockcroft-Gault method using lean or ideal body weight. Greater than or equal to 50 30 to 49 10 to 29 Hemodialysis Patients 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 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) ].

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

12.3 Pharmacokinetics Adult Subjects 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 is 59%. Following oral administration of a 10 mg single dose of adefovir dipivoxil to chronic hepatitis B patients (N=14), the peak adefovir plasma concentration (C max ) 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 (AUC 0–∞ ) 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 over seven days. The impact of long-term once daily administration of 10 mg adefovir dipivoxil 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 was administered with food (an approximately 1000 kcal high-fat meal). Adefovir dipivoxil 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 microg/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. Adefovir is renally excreted by a combination of glomerular filtration and active tubular secretion [See Drug Interactions ( 7) and Clinical Pharmacology ( 12.3) ]. Assessment of Drug Interactions 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 (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 (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 microg) (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 was coadministered with lamivudine, trimethoprim/sulfamethoxazole, acetaminophen, didanosine EC, tacrolimus (based on cross study comparison), and pegylated interferon α-2a. When adefovir dipivoxil was coadministered with ibuprofen (800 mg three times daily) increases in adefovir C max (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 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. Special Populations 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 (C max = 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 (T 1/2 ) were increased compared to adults with normal renal function. It is recommended that the dosing interval of adefovir dipivoxil be modified in these patients [See Dosage and Administration ( 2.2) ]. 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. Table 3 Pharmacokinetic Parameters (Mean ± SD) of Adefovir in Patients with Varying Degrees of Renal Function Renal Function Group Unimpaired Mild Moderate Severe Baseline creatinine clearance (mL/min) >80 (N=7) 50 to 80 (N=8) 30 to 49 (N=7) 10 to 29 (N=10) C max (ng/mL) 17.8 ± 3.22 22.4 ± 4.04 28.5 ± 8.57 51.6 ± 10.3 AUC 0–∞ (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 CL renal (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 [See Use in Specific Populations ( 8.4) ]. Hepatic Impairment The pharmacokinetics of adefovir following a 10 mg single dose of adefovir dipivoxil 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 dosing is required in patients with hepatic impairment.