Adefovir Dipivoxil

Name: Adefovir Dipivoxil

Dosing & Uses

Dosage Forms & Strengths

tablet

  • 10mg

Chronic Hepatitis B

10 mg PO qDay

Renal Impairment

CrCl ≥ 50 mL/min: Dose adjustment not necessary

CrCl 30-49 mL/min: 10 mg PO q48hr

CrCl 10-29 mL/min: 10 mg PO q72hr

Hemodialysis: 10 mg qWeek following dialysis

Dosage Forms & Strengths

tablet

  • 10mg

Chronic Hepatitis B

<12 years old: Not recommended

≥12 years old: Administer as in adults, 10 mg PO qDay

Renal Impairment

CrCl ≥ 50 mL/min: Dose adjustment not necessary

CrCl 30-49 mL/min: 10 mg PO q48hr

CrCl 10-29 mL/min: 10 mg PO q72hr

Hemodialysis: 10 mg qWeek following dialysis

Indications

HEPSERA is 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.

How supplied

Dosage Forms And Strengths

HEPSERA is available as tablets. Each tablet contains 10 mg of adefovir dipivoxil. The tablets are white and debossed with “10” and “GILEAD” on one side and the stylized figure of a liver on the other side.

Storage And Handling

HEPSERA is available as tablets. Each tablet contains 10 mg of adefovir dipivoxil. The tablets are white and debossed with “10” and “GILEAD” on one side and the stylized figure of a liver on the other side. They are packaged as follows: Bottles of 30 tablets (NDC 61958-0501-1) containing desiccant (silica gel) and closed with a child-resistant closure.

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.

Manufactured for: Gilead Sciences, Inc. Foster City, CA 94404. November 2012

Warnings

Included as part of the PRECAUTIONS section.

Overdose

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 HEPSERA, a four-hour hemodialysis session removed approximately 35% of the adefovir dose.

Clinical pharmacology

Mechanism of Action

Adefovir is an antiviral drug.

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 HEPSERA is 59%.

Following oral administration of a 10 mg single dose of HEPSERA to chronic hepatitis B patients (N=14), the peak adefovir plasma concentration (Cmax) 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 (AUC0-∞) 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 HEPSERA over seven days. The impact of long-term once daily administration of 10 mg HEPSERA on adefovir pharmacokinetics has not been evaluated.

Effects of Food on Oral Absorption

Adefovir exposure was unaffected when a 10 mg single dose of HEPSERA was administered with food (an approximately 1000 kcal high-fat meal). HEPSERA 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 μg/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 HEPSERA. Adefovir is renally excreted by a combination of glomerular filtration and active tubular secretion [See DRUG INTERACTIONS].

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 HEPSERA (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 HEPSERA (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 (PEGIFN) (180 μg) (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 HEPSERA was coadministered with lamivudine, trimethoprim/sulfamethoxazole, acetaminophen, didanosine EC, tacrolimus (based on cross study comparison), and pegylated interferon α-2a. When HEPSERA was coadministered with ibuprofen (800 mg three times daily) increases in adefovir Cmax (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 HEPSERA 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 (Cmax = 23.3 ng/mL and AUC024 = 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, Cmax, AUC, and half-life (T½) were increased compared to adults with normal renal function. It is recommended that the dosing interval of HEPSERA be modified in these patients [See DOSAGE AND ADMINISTRATION].

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 HEPSERA.

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) 50–80 (N=8) 30–49 (N=7) 10–29 (N=10)
Cmax (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
CLrenal (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].

Hepatic Impairment

The pharmacokinetics of adefovir following a 10 mg single dose of HEPSERA 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 HEPSERA dosing is required in patients with hepatic impairment.

Microbiology

Mechanism of Action

Adefovir is an acyclic nucleotide analog of adenosine monophosphate which is phosphorylated to the active metabolite adefovir diphosphate by cellular kinases. Adefovir diphosphate inhibits HBV DNA polymerase (reverse transcriptase) by competing with the natural substrate deoxyadenosine triphosphate and by causing DNA chain termination after its incorporation into viral DNA. The inhibition constant (Ki) for adefovir diphosphate for HBV DNA polymerase was 0.1 μM. Adefovir diphosphate is a weak inhibitor of human DNA polymerases α and γ with Ki values of 1.18 μM and 0.97 μM, respectively.

Antiviral Activity

The concentration of adefovir that inhibited 50% of viral DNA synthesis (EC50) in HBV transfected human hepatoma cell lines ranged from 0.2 to 2.5 μM. The combination of adefovir with lamivudine showed additive anti-HBV activity.

Resistance

Clinical isolates with genotypic changes conferring reduced susceptibility in cell culture to nucleoside analog reverse transcriptase inhibitors for the treatment of HBV infection have been observed. Long-term resistance analyses performed by genotyping samples from all adefovir dipivoxil-treated patients with detectable serum HBV DNA demonstrated that amino acid substitutions rtN236T and rtA181T/V have been observed in association with adefovir resistance. In cell culture, the rtN236T substitution demonstrated 4-to 14-fold, the rtA181V substitution 2.5-to 4.2-fold, and the rtA181T substitution 1.3-to 1.9-fold reduced susceptibility to adefovir.

In HBeAg-positive nucleoside-naïve patient isolates (Study GS-98-437, N=171), no adefovir resistance-associated substitutions were observed at Week 48. Sixty-five patients continued on long term treatment after a median duration on adefovir dipivoxil of 235 weeks (range 110–279 weeks). Isolates from 16 of 38 (42%) patients developed adefovir resistance-associated substitutions in the setting of virologic failure (confirmed increase of at least 1 log10 HBV DNA copies/mL above nadir or never suppressed below 103 copies/mL). The substitutions included rtN236T (N=2), rtA181V (N=4), rtA181T (N=3), rtA181T+rtN236T (N=5), and rtA181V+rtN236T (N=2). In HBeAgnegative nucleoside-naïve patients (Study GS-98-438), isolates from 30 patients were identified with adefovir resistance-associated substitutions with a cumulative probability of 0%, 3%, 11%, 19%, and 30% at 48, 96, 144, 192, and 240 weeks, respectively. Of those 30 patients, 22 had a confirmed increase of at least 1 log10 HBV DNA copies/mL above nadir or never achieved HBV DNA levels below 103 copies/mL; an additional 8 patients had adefovir resistance-associated substitutions without virologic failure. In addition, the long term (4 to 5 years) development of resistance to adefovir dipivoxil was significantly lower in patients who had serum HBV DNA below the limit of quantification (less than 1,000 copies/mL) at Week 48 as compared to patients who had serum HBV DNA above 1,000 copies/mL at Week 48.

In an open-label study of pre-and post-liver transplantation patients (Study GS-98-435), isolates from 129 patients with clinical evidence of lamivudine-resistant hepatitis B virus at baseline were evaluated for adefovir resistance-associated substitutions. The incidence of adefovir resistance-associated (rtN236T or rtA181T/V) substitutions was 0% at 48 weeks. Isolates from four patients developed the rtN236T substitution after 72 weeks of adefovir dipivoxil therapy. Development of the rtN236T substitution was associated with serum HBV DNA rebound. All 4 patients who developed the rtN236T substitution in their HBV had discontinued lamivudine therapy before the development of genotypic resistance and all 4 lost the lamivudine resistance-associated substitutions present at baseline. In a study of 35 HIV/HBV co-infected patients with lamivudineresistant HBV (Study 460i) who added adefovir dipivoxil to lamivudine, no adefovir resistance-associated substitutions were observed in HBV isolates from 15/35 patients tested up to 144 weeks of therapy.

Clinical resistance in pediatric patients

In a Phase 3 pediatric Study GS-US-103-518, HBV isolates from 49 of 56 pediatric subjects (aged 12 to 17 years) had serum HBV DNA greater than 169 copies/mL and were evaluated for adefovir resistance-associated substitutions. rtN236T and/or rtA181V adefovir resistance-associated substitutions were not observed at Week 48. However, the rtA181T substitution was present in baseline and Week 48 isolates from 2 pediatric patients.

Cross-resistance

Recombinant HBV variants containing lamivudine-resistance-associated substitutions (rtL180M, rtM204I, rtM204V, rtL180M + rtM204V, rtV173L + rtL180M + rtM204V) were susceptible to adefovir in cell culture. Adefovir dipivoxil has also demonstrated anti-HBV activity (median reduction in serum HBV DNA of 4.1 log10 copies/mL) in patients with HBV containing lamivudine-resistance-associated substitutions (Study 435). Adefovir also demonstrated in cell culture activity against HBV variants with entecavir resistance-associated substitutions (rtT184G, rtS202I, rtM250V). HBV variants with DNA polymerase substitutions rtT128N and rtR153Q or rtW153Q associated with resistance to hepatitis B virus immunoglobulin were susceptible to adefovir in cell culture.

HBV variants expressing the adefovir resistance-associated substitution rtN236T showed no change in susceptibility to entecavir in cell culture, and a 2-to 3-fold decrease in lamivudine susceptibility. HBV mutants with the adefovir resistance-associated substitution rtA181V showed a range of decreased susceptibilities to lamivudine of 1-to 14-fold and a 12-fold decrease in susceptibility to entecavir. In patients whose HBV expressed the rtA181V substitution (N=2) or the rtN236T substitution (N=3), a reduction in serum HBV DNA of 2.4 to 3.1 and 2.0 to 5.1 log10 copies/mL, respectively, was observed when treatment with lamivudine was added to treatment with adefovir dipivoxil.

Animal Toxicology and/or Pharmacology

Toxicology Studies

Animal reproduction studies were conducted in rats and rabbits with orally administered adefovir dipivoxil and intravenously administered adefovir.

In rats and rabbits, no embryotoxicity or teratogenicity was shown from oral administration of adefovir dipivoxil at maternal doses producing systemic exposures approximately 23 times (rats) and 40 times (rabbits) that achieved in humans at the therapeutic dose of 10 mg/day.

When pregnant rats were administered intravenous adefovir at maternally toxic doses associated with systemic exposure 38 times that in humans, embryotoxicity and an increased incidence of fetal malformations (anasarca, depressed eye bulge, umbilical hernia, and kinked tail) were observed. No adverse effects on development were seen with intravenous adefovir administered to pregnant rats at a systemic exposure 12 times that in humans.

Animal Toxicology Studies

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.

Clinical Studies

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 HEPSERA. 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 log10 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 log10 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.

Table 4 : Histological Response at Week 48a

  Study 437 Study 438
HEPSERA 10 mg
(N=168)
Placebo
(N=161)
HEPSERA 10 mg
(N=121)
Placebo
(N=57)
Improvementb 53% 25% 64% 35%
No Improvement 37% 67% 29% 63%
Missing/Unassessable Data 10% 7% 7% 2%
aIntent-to-Treat population (patients with ≥ 1 dose of study drug) with assessable baseline biopsies.
bHistological 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

Number of Adequate Biopsy Pairs Study 437 Study 438
HEPSERA 10 mg (N=152) Placebo (N=149) HEPSERA 10 mg (N=113) Placebo (N=56)
Ishak Fibrosis Score Improveda 34% 19% 34% 14%
Unchanged 55% 60% 62% 50%
Worseneda 11% 21% 4% 36%
aChange of 1 point or more in Ishak Fibrosis Score.

At Week 48, improvement was seen with respect to mean change in serum HBV DNA (log10 copies/mL), normalization of ALT, and HBeAg seroconversion as compared to placebo in patients receiving HEPSERA (Table 6).

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

  Study 437 Study 438
HEPSERA 10 mg
(N=171)
Placebo
(N=167)
HEPSERA 10 mg
(N=123)
Placebo
(N=61)
Mean change ± SD in serum HBV DNA from baseline (log10 copies/mL) –3.57 ± 1.64 –0.98 ± 1.32 –3.65 ± 1.14 –1.32 ± 1.25
ALT normalization 48% 16% 72% 29%
HBeAg seroconversion 12% 6% NAa NAa
aPatients with HBeAg-negative disease cannot undergo HBeAg seroconversion.

Treatment Beyond 48 Weeks

In Study 437, continued treatment with HEPSERA 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 HEPSERA on seroconversion is unknown.

In Study 438, patients who received HEPSERA during the first 48 weeks were re-randomized in a blinded manner to continue on HEPSERA or receive placebo for an additional 48 weeks. At Week 96, 50 of 70 (71%) of patients who continued treatment with HEPSERA 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 HEPSERA.

From 141 eligible patients, there were 125 (89%) patients in Study 438 who chose to continue HEPSERA for up to 192 weeks or 240 weeks (4 years or 5 years). As these patients had already received HEPSERA for at least 48 weeks and appeared to be experiencing a benefit, they are not necessarily representative of patients initiating HEPSERA. 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.

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

HEPSERA 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 HEPSERA 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 Parametera Pre-Liver Transplantation
(N=226)
Post-Liver Transplantation
(N=241)
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)b 77/109 (71%) 64/159 (40%)
Stable or improved Child-Pugh-Turcotte score 86/90 (96%) 107/115 (93%)
Normalization of:c :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%)
aData 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.
bDenominator 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.
cDenominator is patients with abnormal values at baseline and non-missing value at Week 48.

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 HEPSERA monotherapy or HEPSERA 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 HEPSERA and 3.46 ± 1.10 log10 copies/mL for patients treated with HEPSERA 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 HEPSERA, in 53% of patients treated with HEPSERA 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.

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 HEPSERA 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, Use In Specific Populations].

Adefovir Dipivoxil Dosage and Administration

Administration

Oral Administration

Administer orally without regard to food.1

Dosage

Available as adefovir dipivoxil; dosage expressed in terms adefovir dipivoxil.1

Pediatric Patients

Chronic Hepatitis B Virus (HBV) Infection Oral

Adolescents 12–17 years of age: 10 mg once daily.1

Optimal duration of treatment unknown.1 9 Has been continued for up to 5 years in adults in controlled clinical studies.1 12 17

Adults

Chronic Hepatitis B Virus (HBV) Infection Oral

10 mg once daily.1

Optimal duration of treatment unknown.1 9 Has been continued for up to 5 years in adults in controlled clinical studies.1 12 17

Special Populations

Hepatic Impairment

Dosage adjustments not necessary in hepatic impairment.1 5

Renal Impairment

Decrease dosage in adults with baseline Clcr <50 mL/minute.1

Dosage for Adults with Renal Impairment1

Clcr (mL/min)

Dosage

30–49

10 mg once every 48 hours

10–29

10 mg once every 72 hours

<10 (not undergoing hemodialysis)

Dosage recommendations not available

Hemodialysis patients

10 mg once every 7 days following dialysis

These dosage guidelines for adults with renal impairment have not been clinically evaluated.1 In addition, these dosages were derived from data involving patients with preexisting renal impairment and may not be appropriate for those in whom renal impairment evolves during adefovir therapy.1 Closely monitor clinical response and renal function.1

Safety and efficacy not studied in adolescents with renal impairment.1 Data insufficient to make dosage recommendations for adolescents 12–17 years of age with underlying renal impairment;1 use caution and closely monitor renal function.1

Use in specific population


Pregnancy

Teratogenic Effects: Pregnancy Category C

There are no adequate and well-controlled studies of Adefovir Dipivoxil Tablets in pregnant women. Chronic hepatitis B is a serious condition that requires treatment. Adefovir Dipivoxil Tablets should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.

Reproduction studies with oral administration of Adefovir Dipivoxil to pregnant rats and rabbits showed no evidence of embryotoxicity or teratogenicity at systemic exposures equivalent to 23 times (rats) and 40 times (rabbits) that achieved in humans at the therapeutic dose. However, embryotoxicity and an increased incidence of fetal malformations (anasarca, depressed eye bulge, umbilical hernia and kinked tail) occurred when adefovir was administered intravenously to pregnant rats at 38 times the human therapeutic exposure. These adverse reproductive effects did not occur following an intravenous dose where exposure was 12 times the human therapeutic exposure.

Because animal reproduction studies are not always predictive of human response, Adefovir Dipivoxil Tablets should be used during pregnancy only if clearly needed and after careful consideration of the risks and benefits [See Nonclinical Toxicology (13.2)].

Pregnancy Registry

To monitor fetal outcomes of pregnant women exposed to Adefovir Dipivoxil, a pregnancy registry has been established. Healthcare providers are encouraged to register patients by calling 1-800-258-4263.

Labor and Delivery

There are no studies in pregnant women and no data on the effect of Adefovir Dipivoxil Tablets on transmission of HBV from mother to infant. Therefore, appropriate infant immunizations should be used to prevent neonatal acquisition of hepatitis B virus.

Nursing Mothers

It is not known whether adefovir is excreted in human milk.

Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in nursing infants from Adefovir Dipivoxil Tablets, a decision should be made whether to discontinue nursing or to discontinue drug, taking into account the importance of the drug to the mother.

Pediatric Use

Pediatric patients 12 to less than 18 years: The safety, efficacy, and pharmacokinetics of Adefovir Dipivoxil Tablets in pediatric patients (aged 12 to less than 18 years) were evaluated in a double-blind, random-ized, 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 Tablets 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%). [See 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.

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.

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)].

What is the most important information i should know about adefovir (hepsera)?

Some people develop lactic acidosis while taking adefovir. Early symptoms may get worse over time and this condition can be fatal. Get emergency medical help if you have even mild symptoms such as: muscle pain or weakness, numb or cold feeling in your arms and legs, trouble breathing, stomach pain, nausea with vomiting, fast or uneven heart rate, dizziness, or feeling very weak or tired.

Adefovir can also cause serious kidney problems, especially if you have kidney disease or take certain medications.

You may develop liver symptoms after you stop taking this medication, even months after stopping. Your doctor may want to check your liver function for several months after you stop using adefovir. Visit your doctor regularly.

Taking this medication will not prevent you from passing hepatitis B to other people. Avoid having unprotected sex or sharing razors or toothbrushes. Talk with your doctor about safe ways to prevent hepatitis transmission during sex. Sharing drug or medicine needles is never safe, even for a healthy person.

Tell your doctor if you have been exposed to HIV, or if you have untreated HIV or AIDS. Taking medicines to treat chronic hepatitis B can cause HIV infection to become resistant to the standard HIV and AIDS medications. You may need to be tested for HIV before you start taking adefovir.

What happens if i miss a dose (hepsera)?

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

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