Adefovir Dipivoxil (Page 7 of 9)

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

Adefovir dipivoxil was 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 log10 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 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
Efficacy Parameter * Pre-Liver Transplantation(N=226) Post-Liver Transplantation(N=241)
*
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.
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.
Denominator is patients with abnormal values at baseline and non-missing value at Week 48.
Mean change ± SD in HBV DNA from baseline (log10 copies/mL) –3.7 ± 1.6(N=117) –4.0 ± 1.6(N=164)
Proportion with undetectable HBV DNA (< 1000 copies/mL) 77/109 (71%) 64/159 (40%)
Stable or improved Child-Pugh-Turcotte score 86/90 (96%) 107/115 (93%)
Normalization of:
ALT 61/82 (74%) 56/110 (51%)
Albumin 43/54 (80%) 21/26 (81%)
Bilirubin 38/68 (58%) 29/38 (76%)
Prothrombin time 39/46 (85%) 5/9 (56%)

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 monotherapy or adefovir dipivoxil 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 log10 copies/mL for patients treated with adefovir dipivoxil and 3.46 ± 1.10 log10 copies/mL for patients treated with adefovir dipivoxil in combination with lamivudine. There was a mean decrease in serum HBV DNA of 0.31 ± 0.93 log10 copies/mL in patients receiving lamivudine alone. ALT normalized in 47% of patients treated with adefovir dipivoxil, in 53% of patients treated with adefovir dipivoxil 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 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 Specific Populations (8.4) and Clinical Pharmacology (12.3, 12.4)].

16 HOW SUPPLIED / STORAGE AND HANDLING

Adefovir Dipivoxil Tablets are white to off-white, round, flat-faced bevelled edge tablets, engraved “APO” on one side, “A10” on the other side. They are supplied as follows:

Bottles of 30s (NDC-60505-3947-3)

Store in original container at 20°C to 25°C (68°F to 77°F); excursions permitted from 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

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

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Patient Information).

  • Inform patients of the potential risks and benefits of adefovir dipivoxil tablets and of alternative modes of therapy.
  • Instruct patients to:
    • Follow a regular dosing schedule to avoid missing doses.
    • Immediately report any severe abdominal pain, muscle pain, yellowing of the eyes, dark urine, pale stools, and/or loss in appetite.
    • Inform their doctor or pharmacist if they develop any unusual symptom(s), or if any known symptom persists or worsens.
  • Advise patients that:
    • The optimal duration of adefovir dipivoxil tablets treatment and the relationship between treatment response and long-term outcomes such as hepatocellular carcinoma or decompensated cirrhosis are not known.
    • Patients should not discontinue adefovir dipivoxil tablets without first informing their physician [See Warnings and Precautions (5.1)].
    • Routine laboratory monitoring and follow-up with a physician is important during adefovir dipivoxil therapy.
    • Obtaining HIV antibody testing prior to starting adefovir dipivoxil tablets is important [See Warnings and Precautions (5.3)].
    • Adefovir dipivoxil tablets should not be administered concurrently with ATRIPLA or COMPLERA or STRIBILD or TRUVADA or VIREAD [See Warnings and Precautions (5.5)].
    • Lamivudine-resistant patients should use adefovir dipivoxil tablets in combination with lamivudine and not as adefovir dipivoxil tablets monotherapy [See Warnings and Precautions. (5.6)].
  • Inform patients that there is an antiretroviral pregnancy registry to monitor fetal outcomes of pregnant women exposed to adefovir dipivoxil [see Use in Specific Populations (8.1)].

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