Adefovir Drug Information
Generic name: ADEFOVIR DIPIVOXIL
Uses of Adefovir
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.
Dosage & Administration of Adefovir
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.
Dose Adjustment in Renal Impairment
Significantly increased drug exposures were seen when adefovir dipivoxil tablets were administered to adult patients with renal impairment. 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 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.
| 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 |
| 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 |
Side Effects of Adefovir
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.
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. The incidence of adverse reactions is derived from treatment-related events as identified by the study investigators. 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). The creatinine elevation resolved in 1 patient who permanently discontinued treatment and remained stable in 3 patients who continued treatment. See Adverse Reactions for changes in serum creatinine in patients with underlying renal insufficiency at baseline.
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.
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.
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
| 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% |
Warnings & Cautions for Adefovir
Exacerbation of Hepatitis after Discontinuation of Treatment Severe acute exacerbation of hepatitis has been reported in patients who have discontinued anti-hepatitis B therapy, including therapy with adefovir dipivoxil. Hepatic function should be monitored at repeated intervals with both clinical and laboratory follow-up for at least several months in patients who discontinue adefovir dipivoxil. If appropriate, resumption of anti-hepatitis B therapy may be warranted.
In clinical trials of adefovir dipivoxil, exacerbations of hepatitis (ALT elevations 10 times the upper limit of normal or greater) occurred in up to 25% of patients after discontinuation of adefovir dipivoxil. These events were identified in studies GS-98-437 and GS-98-438 (N=492). Most of these events occurred within 12 weeks of drug discontinuation.
These exacerbations generally occurred in the absence of HBeAg seroconversion, and presented as serum ALT elevations in addition to re-emergence of viral replication. In the HBeAg-positive and HBeAg-negative studies in patients with compensated liver function, the exacerbations were not generally accompanied by hepatic decompensation. However, patients with advanced liver disease or cirrhosis may be at higher risk for hepatic decompensation.
Although most events appear to have been self-limited or resolved with re-initiation of treatment, severe hepatitis exacerbations, including fatalities, have been reported. Therefore, patients should be closely monitored after stopping treatment.
Nephrotoxicity
Nephrotoxicity characterized by a delayed onset of gradual increases in serum creatinine and decreases in serum phosphorus was historically shown to be the treatment-limiting toxicity of adefovir dipivoxil therapy at substantially higher doses in HIV-infected patients (60 and 120 mg daily) and in chronic hepatitis B patients (30 mg daily). Chronic administration of adefovir dipivoxil (10 mg once daily) may result in delayed nephrotoxicity. The overall risk of nephrotoxicity in patients with adequate renal function is low.
However, this is of special importance in patients at risk of or having underlying renal dysfunction and patients taking concomitant nephrotoxic agents such as cyclosporine, tacrolimus, aminoglycosides, vancomycin and non-steroidal anti-inflammatory drugs. It is recommended that creatinine clearance is calculated in all patients prior to initiating therapy with adefovir dipivoxil. It is important to monitor renal function for all patients during treatment with adefovir dipivoxil, particularly for those with pre-existing or other risks for renal impairment.
Patients with renal insufficiency at baseline or during treatment may require dose adjustment. The risks and benefits of adefovir dipivoxil treatment should be carefully evaluated prior to discontinuing adefovir dipivoxil in a patient with treatment-emergent nephrotoxicity. Pediatric Patients The efficacy and safety of adefovir dipivoxil have not been studied in patients less than 18 years of age with different degrees of renal impairment and no data are available to make dosage recommendations in these patients.
Caution should be exercised when prescribing adefovir dipivoxil to adolescents with underlying renal dysfunction, and renal function in these patients should be closely monitored.
HIV Resistance Prior to initiating adefovir dipivoxil therapy, HIV antibody testing should be offered to all patients. Treatment with anti-hepatitis B therapies, such as adefovir dipivoxil, that have activity against HIV in a chronic hepatitis B patient with unrecognized or untreated HIV infection may result in emergence of HIV resistance. Adefovir dipivoxil has not been shown to suppress HIV RNA in patients; however, there are limited data on the use of adefovir dipivoxil to treat patients with chronic hepatitis B co-infected with HIV.
Lactic Acidosis/Severe Hepatomegaly with Steatosis
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs alone or in combination with antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors.
Particular caution should be exercised when administering nucleoside analogs to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with adefovir dipivoxil should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).
Coadministration with Other Products
Adefovir dipivoxil should not be used concurrently with products containing tenofovir disoproxil fumarate or tenofovir alafenamide.
Clinical Resistance Resistance to adefovir dipivoxil can result in viral load rebound which may result in exacerbation of hepatitis B and, in the setting of diminished hepatic function, lead to liver decompensation and possible fatal outcome. In order to reduce the risk of resistance in patients with lamivudine resistant HBV, adefovir dipivoxil should be used in combination with lamivudine and not as adefovir dipivoxil monotherapy. In order to reduce the risk of resistance in all patients receiving adefovir dipivoxil monotherapy, a modification of treatment should be considered if serum HBV DNA remains above 1000 copies/mL with continued treatment.
Drug Interactions with Adefovir
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. 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. Adefovir dipivoxil should not be administered in combination with VIREAD.
Monitor for adefovir dipivoxil associated adverse events.
Pregnancy Safety for Adefovir
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 (C max ) 23 times higher in rats and 40 times higher in rabbits than those at the recommended human dose (RHD) of adefovir dipivoxil (see Data).
No adverse developmental effects were observed at up to the highest dose tested, at systemic exposure (C max ) 40 times that in humans at the RHD of adefovir dipivoxil. 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. 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.
Pediatric Use of Adefovir
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%). 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.
Contraindications for Adefovir
Adefovir dipivoxil tablets are contraindicated in patients with previously demonstrated hypersensitivity to any of the components of the product.
Overdosage Information for Adefovir
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.
Clinical Studies of Adefovir
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 adefovir dipivoxil. 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 log 10 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. 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 48 Intent-to-Treat population (patients with ≥1 dose of study drug) with assessable baseline biopsies.
Table 5 illustrates the changes in Ishak Fibrosis Score by treatment group. Table 5 Changes in Ishak Fibrosis Score at Week 48 At Week 48, improvement was seen with respect to mean change in serum HBV DNA (log 10 copies/mL), normalization of ALT, and HBeAg seroconversion as compared to placebo in patients receiving adefovir dipivoxil (Table 6). Table 6 Change in Serum HBV DNA, ALT Normalization, and HBeAg Seroconversion at Week 48, continued treatment with adefovir dipivoxil 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 adefovir dipivoxil on seroconversion is unknown. In Study 438, patients who received adefovir dipivoxil during the first 48 weeks were re-randomized in a blinded manner to continue on adefovir dipivoxil or receive placebo for an additional 48 weeks.
HBV DNA and ALT levels returned towards baseline in most patients who stopped treatment with adefovir dipivoxil. As these patients had already received adefovir dipivoxil for at least 48 weeks and appeared to be experiencing a benefit, they are not necessarily representative of patients initiating adefovir dipivoxil. Of these patients, 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, 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)
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. 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. There was a mean decrease in serum HBV DNA of 0.31 ± 0.93 log 10 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 primary efficacy endpoint was HBV DNA less than 1000 copies/mL plus normalization of ALT at the end of Week 48. 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.
| Study 437 | Study 438 | |||
|---|---|---|---|---|
| Adefovir Dipivoxil 10 mg (N=168) | Placebo (N=161) | Adefovir Dipivoxil 10 mg (N=121) | Placebo (N=57) | |
| Improvement Histological improvement defined as ≥2 point decrease in the Knodell necro-inflammatory score with no worsening of the Knodell fibrosis score. | 53% | 25% | 64% | 35% |
| No Improvement | 37% | 67% | 29% | 63% |
| Missing/Unassessable Data | 10% | 7% | 7% | 2% |
| Study 437 | Study 438 | |||
|---|---|---|---|---|
| Number of Adequate Biopsy Pairs | Adefovir Dipivoxil 10 mg (N=152) | Placebo (N=149) | Adefovir Dipivoxil 10 mg (N=113) | Placebo (N=56) |
| Ishak Fibrosis Score Improved Change of 1 point or more in Ishak Fibrosis Score. | 34% | 19% | 34% | 14% |
| Unchanged | 55% | 60% | 62% | 50% |
| Worsened | 11% | 21% | 4% | 36% |
| Study 437 | Study 438 | |||
|---|---|---|---|---|
| Adefovir Dipivoxil 10 mg (N=171) | Placebo (N=167) | Adefovir Dipivoxil 10 mg (N=123) | Placebo (N=61) | |
| Mean change ± SD in serum HBV DNA from baseline (log 10 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% | NA Patients with HBeAg-negative disease cannot undergo HBeAg seroconversion. | NA |
| Efficacy Parameter 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. | Pre-Liver Transplantation (N=226) | Post-Liver Transplantation (N=241) |
|---|---|---|
| Mean change ± SD in HBV DNA from baseline (log 10 copies/mL) | –3.7 ± 1.6 (N=117) | –4.0 ± 1.6 (N=164) |
| Proportion with undetectable HBV DNA (< 1000 copies/mL) 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. | 77/109 (71%) | 64/159 (40%) |
| Stable or improved Child-Pugh-Turcotte score | 86/90 (96%) | 107/115 (93%) |
| Normalization of: Denominator is patients with abnormal values at baseline and non-missing value at Week 48. | ||
| 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%) |
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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