Adefovir Dipivoxil (Page 3 of 9)

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

7 DRUG INTERACTIONS

Since adefovir is eliminated by the kidney, coadministration of adefovir dipivoxil with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of either adefovir and/or these coadministered drugs [See Clinical Pharmacology (12.3)].

Patients should be monitored closely for adverse events when adefovir dipivoxil is coadministered with drugs that are excreted renally or with other drugs known to affect renal function [ See Warnings and Precautions (5.2)].

Adefovir dipivoxil should not be administered in combination with VIREAD [ See Warnings and Precautions (5.5)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Exposure Registry

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

Risk Summary

Prospective pregnancy data from the APR are not sufficient to adequately assess the risk of birth defects, miscarriage or adverse maternal or fetal outcomes. Adefovir disoproxil (ADV) use during pregnancy has been evaluated in a limited number of individuals reported to the APR and the number of exposures to adefovir is insufficient to make a risk assessment compared to a reference population. The estimated background rate for major birth defects is 2.7% in the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP). The estimated rate of miscarriage is not reported in the APR. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The estimated background rate of miscarriage in the U.S. general population is 15–20%.

In animal reproduction studies with oral ADV, no adverse developmental effects were observed at exposures (Cmax ) 23 times higher in rats and 40 times higher in rabbits than those at the recommended human dose (RHD) of adefovir dipivoxil (see Data).

Data

Animal Data

In an embryo-fetal development study, ADV was administered orally to pregnant rabbits (at 1, 5, or 20 mg/kg/day) during organogenesis (on gestation day 6 through 18). No adverse developmental effects were observed at up to the highest dose tested, at systemic exposure (Cmax ) 40 times that in humans at the RHD of adefovir dipivoxil.

In a pre/post-natal development study, ADV was administered orally to pregnant rats (at 2.5, 10, or 40 mg/kg/day) from organogenesis, through late gestation, delivery, and lactation (gestation day 7 to lactation/postpartum day 20). Reduced body weight of the offspring due to maternal toxicity was observed at systemic exposure 23 times that in humans at the RHD of adefovir dipivoxil.

In an embryo-fetal development study, ADV was administered intravenously to pregnant rats (at 2.5, 10, and 20 mg/kg/day) during organogenesis (gestation day 6 through 15). Embryo-fetal toxicity including malformations (anasarca, depressed eye bulge, umbilical hernia and kinked tail) and skeletal variations (reduction of ossified metacarpal bones, increases in thoracic vertebrae and decreases in lumbar vertebrae) occurred at systemic exposure (Cmax) 38 times that in humans at the RHD of adefovir dipivoxil. No adverse developmental effects were observed at an exposure (Cmax) 12 times that in humans at the RHD of adefovir dipivoxil.

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 and any potential adverse effects on the breastfed infant from adefovir dipivoxil or from the underlying maternal condition.

8.4 Pediatric Use

Pediatric patients 12 to less than 18 years: The safety, efficacy, and pharmacokinetics of adefovir dipivoxil in pediatric patients (aged 12 to less than 18 years) were evaluated in a double-blind, randomized, placebo-controlled study (GS-US-103-518, Study 518) in 83 pediatric patients with chronic hepatitis B and compensated liver disease. The proportion of patients treated with adefovir dipivoxil who achieved the primary efficacy endpoint of serum HBV DNA less than 1,000 copies/mL and normal ALT levels at the end of 48 weeks blinded treatment was significantly greater (23%) when compared to placebo-treated patients (0%) [S ee Clinical Studies (14.4), Dosage and Administration (2) and Adverse Reactions (6.3)].

Pediatric patients 2 to less than 12 years: Patients 2 to less than 12 years of age were also evaluated in Study 518. The efficacy of adefovir dipivoxil was not significantly different from placebo in patients less than 12 years of age.

Adefovir dipivoxil tablets are not recommended for use in children below 12 years of age.

8.5 Geriatric Use

Clinical studies of adefovir dipivoxil 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 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 Warnings and Precautions (5.2)].

10 OVERDOSAGE

Doses of adefovir dipivoxil 500 mg daily for 2 weeks and 250 mg daily for 12 weeks have been associated with gastrointestinal side effects. If overdose occurs the patient must be monitored for evidence of toxicity, and standard supportive treatment applied as necessary.

Following a 10 mg single dose of adefovir dipivoxil, a four-hour hemodialysis session removed approximately 35% of the adefovir dose.

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