"The European Medicines Agency (EMA) has launched a review of the six direct-acting antivirals approved for use in the European Union for treating chronic hepatitis C virus infection, the agency said today.
They are daclatasvir (Dak"...
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 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 [See ADVERSE REACTIONS and CLINICAL PHARMACOLOGY]. It is recommended that creatinine clearance is calculated in all patients prior to initiating therapy with HEPSERA.
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 [See DOSAGE AND ADMINISTRATION]. The risks and benefits of HEPSERA treatment should be carefully evaluated prior to discontinuing HEPSERA in a patient with treatment-emergent nephrotoxicity.
The efficacy and safety of HEPSERA 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 [See DOSAGE AND ADMINISTRATION]. Caution should be exercised when prescribing HEPSERA to adolescents with underlying renal dysfunction, and renal function in these patients should be closely monitored.
Prior to initiating HEPSERA therapy, HIV antibody testing should be offered to all patients. Treatment with anti-hepatitis B therapies, such as HEPSERA, that have activity against HIV in a chronic hepatitis B patient with unrecognized or untreated HIV infection may result in emergence of HIV resistance. HEPSERA has not been shown to suppress HIV RNA in patients; however, there are limited data on the use of HEPSERA to treat patients with chronic hepatitis B co-infected with HIV.
Lactic Acidosis/Severe Hepatomegaly with Steatosis
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).
Coadministration with Other Products
HEPSERA should not be used concurrently with VIREAD (tenofovir disoproxil fumarate) or tenofovir disoproxil fumarate-containing products including ATRIPLA® (efavirenz/emtricitabine/tenofovir disoproxil fumarate combination tablet), COMPLERA® (emtricitabine/rilpivirine/tenofovir disoproxil fumarate combination tablet), STRIBILD™ (elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate combination tablet), and TRUVADA® (emtricitabine/tenofovir 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.
Patient Counseling Information
Instructions for Safe Use
See FDA-approved patient labeling (PATIENT INFORMATION)
- Physicians should inform patients of the potential risks and benefits of HEPSERA and of alternative modes of therapy.
- Physicians should instruct their patients to:
- Read the Patient Package Insert before starting HEPSERA therapy.
- Follow a regular dosing schedule to avoid missing doses.
- Immediately report any severe abdominal pain, muscle pain, yellowing of the eyes, dark urine, pale stools, and/or loss in appetite.
- Inform their doctor or pharmacist if they develop any unusual symptom(s), or if any known symptom persists or worsens.
- Patients should remain under the care of a physician when using HEPSERA.
- Patients should be advised that:
- The optimal duration of HEPSERA treatment and the relationship between treatment response and long-term outcomes such as hepatocellular carcinoma or decompensated cirrhosis are not known.
- Patients should not discontinue HEPSERA without first informing their physician [See WARNINGS AND PRECAUTIONS].
- Routine laboratory monitoring and follow-up with a physician is important during HEPSERA therapy.
- Obtaining HIV antibody testing prior to starting HEPSERA is important [See WARNINGS AND PRECAUTIONS].
- HEPSERA should not be administered concurrently with ATRIPLA or COMPLERA or STRIBILD or TRUVADA or VIREAD [See WARNINGS AND PRECAUTIONS].
- Lamivudine-resistant patients should use HEPSERA in combination with lamivudine and not as HEPSERA monotherapy [See WARNINGS AND PRECAUTIONS].
Pregnancy and Breastfeeding
- Physicians should inform women of childbearing age about the risks associated with exposure to HEPSERA during pregnancy.
- Patients should inform their physician if they become pregnant while using HEPSERA.
- Pregnant patients using HEPSERA should be informed about the HEPSERA pregnancy registry and offered the opportunity to enroll.
- Patients should be informed that it is not known whether HEPSERA is excreted into human milk or if it can harm a nursing infant. Therefore, a decision should be made whether to discontinue breastfeeding or drug.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term oral carcinogenicity studies of adefovir dipivoxil in mice and rats were carried out at exposures up to approximately 10 times (mice) and 4 times (rats) those observed in humans at the therapeutic dose for HBV infection. In both mouse and rat studies, adefovir dipivoxil was negative for carcinogenic findings. Adefovir dipivoxil was mutagenic in the in vitro mouse lymphoma cell assay (with or without metabolic activation). Adefovir induced chromosomal aberrations in the in vitro human peripheral blood lymphocyte assay without metabolic activation. Adefovir dipivoxil was not clastogenic in the in vivo mouse micronucleus assay and adefovir was not mutagenic in the Ames bacterial reverse mutation assay using S. typhimurium and E. coli strains in the presence or absence of metabolic activation. In reproductive toxicology studies, no evidence of impaired fertility was seen in male or female rats at systemic exposure approximately 19 times that achieved in humans at the therapeutic dose.
Use In Specific Populations
Teratogenic Effects - Pregnancy Category C
There are no adequate and well-controlled studies of HEPSERA in pregnant women. Chronic hepatitis B is a serious condition that requires treatment. HEPSERA 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, HEPSERA should be used during pregnancy only if clearly needed and after careful consideration of the risks and benefits [See Nonclinical Toxicology].
To monitor fetal outcomes of pregnant women exposed to HEPSERA, 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 HEPSERA on transmission of HBV from mother to infant. Therefore, appropriate infant immunizations should be used to prevent neonatal acquisition of hepatitis B virus.
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.
Pediatric patients 12 to less than 18 years
The safety, efficacy, and pharmacokinetics of HEPSERA 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 HEPSERA 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, DOSAGE AND ADMINISTRATION and ADVERSE REACTIONS].
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.
HEPSERA is not recommended for use in children below 12 years of age.
Clinical studies of HEPSERA 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 HEPSERA 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 and WARNINGS AND PRECAUTIONS].This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 12/7/2012
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