Hepsera Information
Hepsera () Indications And Usage
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
Hepsera () Dosage And Administration
The recommended dose of Hepsera () 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 () is not recommended for use in children less than 12 years of age.
Significantly increased drug exposures were seen when Hepsera () was administered to adult patients with renal impairment . Therefore, the dosing interval of Hepsera () should be adjusted in adult patients with baseline creatinine clearance
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 () . 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
No clinical data are available to make dosing recommendations in adolescent patients with renal insufficiency
Hepsera () 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.
Hepsera () Contraindications
Hepsera () is contraindicated in patients with previously demonstrated hypersensitivity to any of the components of the product.
Hepsera () Warnings And Precautions
Severe acute exacerbation of hepatitis has been reported in patients who have discontinued anti-hepatitis B therapy, including therapy with Hepsera () . 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 () . If appropriate, resumption of anti-hepatitis B therapy may be warranted.
In clinical trials of Hepsera () , 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 () . 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 () (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 () , 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 () treatment should be carefully evaluated prior to discontinuing Hepsera () 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 () 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 () 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 () were at greater risk of developing resistance than patients with serum HBV DNA levels below 1000 copies/mL at Week 48 of therapy.
Hepsera () 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 () .
Adverse reactions to Hepsera () 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 () (n=294) or placebo (n=228) for 48 weeks is presented in Table 2. Patients who received open-label Hepsera () 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 () 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 () -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 () 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 () 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
The safety profile of Hepsera () in patients ≥12 to
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 () Drug Interactions
Since adefovir is eliminated by the kidney, co-administration of Hepsera () 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 () is co-administered with drugs that are excreted renally or with other drugs known to affect renal function [].
Hepsera () should not be administered in combination with VIREAD [].
Hepsera () 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 () , 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 () is not recommended for use in children below 12 years of age.
Hepsera () 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 () , a four-hour hemodialysis session removed approximately 35% of the adefovir dose.
Hepsera () Description
Hepsera () 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 () 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 () Clinical Studies
Study 518 was a double-blind, placebo-controlled, study in which 173 pediatric patients (ages 2 to
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 vs. 1 of 58 (2%) of placebo treated patients responded to treatment by Week 48 .
Hepsera () How Supplied / 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.
Hepsera () Patient Counseling Information
See
Manufactured for: Gilead Sciences, Inc. Foster City, CA 94404
Hepsera () is a trademark of Gilead Sciences, Inc. ©2009 Gilead Sciences, Inc.
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