Hepsera Information
Hepsera (Adefovir dipivoxil) Indications And Usage
Hepsera (Adefovir dipivoxil) 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 <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.
Hepsera (Adefovir dipivoxil) Dosage And Administration
The recommended dose of Hepsera (Adefovir dipivoxil) in chronic hepatitis B patients for patients ≥12 years of age with adequate renal function is 10 mg, once daily, taken orally, without regard to food. The optimal duration of treatment is unknown.
Hepsera (Adefovir dipivoxil) is not recommended for use in children less than 12 years of age.
Significantly increased drug exposures were seen when Hepsera (Adefovir dipivoxil) was administered to adult patients with renal impairment . Therefore, the dosing interval of Hepsera (Adefovir dipivoxil) should be adjusted in adult patients with baseline creatinine clearance <50 mL/min using the following suggested guidelines (see ). 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 Hepsera (Adefovir dipivoxil) . Therefore, clinical response to treatment and renal function should be closely monitored in these patients.
The pharmacokinetics of adefovir have not been evaluated in non-hemodialysis patients with creatinine clearance <10 mL/min; therefore, no dosing recommendation is available for these patients.
No clinical data are available to make dosing recommendations in adolescent patients with renal insufficiency
Hepsera (Adefovir dipivoxil) Dosage Forms And Strengths
Hepsera (Adefovir dipivoxil) 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.
Hepsera (Adefovir dipivoxil) Contraindications
Hepsera (Adefovir dipivoxil) is contraindicated in patients with previously demonstrated hypersensitivity to any of the components of the product.
Hepsera (Adefovir dipivoxil) Warnings And Precautions
Severe acute exacerbation of hepatitis has been reported in patients who have discontinued anti-hepatitis B therapy, including therapy with Hepsera (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 Hepsera (Adefovir dipivoxil) . If appropriate, resumption of anti-hepatitis B therapy may be warranted.
In clinical trials of Hepsera (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 Hepsera (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 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 Hepsera (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 important to monitor renal function for all patients during treatment with Hepsera (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 Hepsera (Adefovir dipivoxil) treatment should be carefully evaluated prior to discontinuing Hepsera (Adefovir dipivoxil) in a patient with treatment-emergent nephrotoxicity.
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 Hepsera (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).
Hepsera (Adefovir dipivoxil) should not be used concurrently with VIREAD (tenofovir disoproxil fumarate) or tenofovir disoproxil fumarate-containing products including TRUVADA (emtricitabine/tenofovir disoproxil fumarate combination tablet) and ATRIPLA (efavirenz/emtricitabine/tenofivir disoproxil fumarate combination tablet).
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.
Long-term (144 week) data from Study 438 (n=124) show that patients with HBV DNA levels greater than 1000 copies/mL at Week 48 of treatment with Hepsera (Adefovir dipivoxil) were at greater risk of developing resistance than patients with serum HBV DNA levels below 1000 copies/mL at Week 48 of therapy.
Hepsera (Adefovir dipivoxil) Adverse Reactions
The following adverse reactions are discussed in other sections of the labeling:
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 Hepsera (Adefovir dipivoxil) .
Adverse reactions to Hepsera (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 Hepsera (Adefovir dipivoxil) (n=294) or placebo (n=228) for 48 weeks is presented in Table 2. Patients who received open-label Hepsera (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.
No patients treated with Hepsera (Adefovir dipivoxil) developed a confirmed serum creatinine increase ≥0.5 mg/dL or confirmed phosphorus decrease ≤2 mg/dL from baseline by Week 48. By Week 96, 2% of Hepsera (Adefovir dipivoxil) -treated patients, by Kaplan-Meier estimate, had increases in serum creatinine ≥0.5 mg/dL from baseline (no placebo-controlled results were available for comparison beyond Week 48). For patients who chose to continue Hepsera (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 Hepsera (Adefovir dipivoxil) for up to 240 weeks in Study 437, 6 had a confirmed increase in serum creatinine of ≥0.5 mg/dL from baseline with 2 patients discontinuing from the study due to the elevated serum creatinine concentration. for changes in serum creatinine in patients with underlying renal insufficiency at baseline.
Assessment of adverse reactions is based on a placebo-controlled study (Study 518) in which 173 pediatric patients aged 2 to <18 years with chronic hepatitis B and compensated liver disease received double-blind treatment with Hepsera (Adefovir dipivoxil) (n=115), or placebo (n=58) for 48 weeks
The safety profile of Hepsera (Adefovir dipivoxil) in patients ≥12 to <18 years of age (n=56) was similar to that observed in adults. No pediatric patients treated with Hepsera (Adefovir dipivoxil) developed a confirmed serum creatinine increase ≥ 0.5 mg/dL or confirmed phosphorus decrease to <2 mg/dL from baseline by Week 48.
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 (both associated with proximal renal tubulopathy)
Renal and Urinary Disorders: renal failure, Fanconi syndrome, proximal renal tubulopathy
Hepsera (Adefovir dipivoxil) Drug Interactions
Since adefovir is eliminated by the kidney, co-administration of Hepsera (Adefovir dipivoxil) with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of either adefovir and/or these co-administered drugs
Patients should be monitored closely for adverse events when Hepsera (Adefovir dipivoxil) is co-administered with drugs that are excreted renally or with other drugs known to affect renal function [].
Hepsera (Adefovir dipivoxil) should not be administered in combination with VIREAD [].
Hepsera (Adefovir dipivoxil) Use In Specific Populations
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 Hepsera (Adefovir dipivoxil) , a decision should be made whether to discontinue nursing or to discontinue drug, taking into account the importance of the drug to the mother.
Hepsera (Adefovir dipivoxil) is not recommended for use in children below 12 years of age.
Hepsera (Adefovir dipivoxil) 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 Hepsera (Adefovir dipivoxil) , a four-hour hemodialysis session removed approximately 35% of the adefovir dose.
Hepsera (Adefovir dipivoxil) Description
Hepsera (Adefovir dipivoxil) is the tradename for adefovir dipivoxil, a diester prodrug of adefovir. Adefovir is an acyclic nucleotide analog with activity against human hepatitis B virus (HBV).
The chemical name of adefovir dipivoxil is 9-[2-[[bis[(pivaloyloxy)methoxy]-phosphinyl]-methoxy]ethyl]adenine. It has a molecular formula of CHNOP, a molecular weight of 501.48 and the following structural formula:
Adefovir dipivoxil is a white to off-white crystalline powder with an aqueous solubility of 19 mg/mL at pH 2.0 and 0.4 mg/mL at pH 7.2. It has an octanol/aqueous phosphate buffer (pH 7) partition coefficient (log p) of 1.91.
Hepsera (Adefovir dipivoxil) tablets are for oral administration. Each tablet contains 10 mg of adefovir dipivoxil and the following inactive ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate, pregelatinized starch, and talc.
Hepsera (Adefovir dipivoxil) Clinical Studies
Study 518 was a double-blind, placebo-controlled, study in which 173 pediatric patients (ages 2 to <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 <7 years old (cohort 1), 7 to <12 years old (cohort 2), and 12 to <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 <1000 copies/mL plus normalization of ALT at the end of Week 48.
In cohort 3 (n=83), significantly more patients treated with Hepsera (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 vs. 1 of 58 (2%) of placebo treated patients responded to treatment by Week 48 .
Hepsera (Adefovir dipivoxil) How Supplied / Storage And Handling
Hepsera (Adefovir dipivoxil) 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.
Hepsera (Adefovir dipivoxil) Patient Counseling Information
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Manufactured for: Gilead Sciences, Inc. Foster City, CA 94404
Hepsera (Adefovir dipivoxil) is a trademark of Gilead Sciences, Inc. ©2009 Gilead Sciences, Inc.
Hepsera (Adefovir dipivoxil)
Hepsera (Adefovir dipivoxil)
Hepsera (Adefovir dipivoxil)
