Dosing
The
recommended dosage
of entecavir is a single 0.5 mg tablet once-daily for chronic hepatitis
B patients beginning treatment for the first time (nucleoside-naïve patients),
and a single 1 mg tablet once-daily for patients experiencing resistance
to lamivudine.
Entecavir comes in tablet and oral suspension
forms and is taken by mouth without food. The tablets are film-coated, triangular-shaped
and contain 0.5 or 1.0 mg entecavir. The oral solution
contains 0.05 mg/ml entecavir in a 260 ml bottle.
Entecavir should be taken 2 hours after a meal
and 2 hours before the next meal. Based on the pharmacokinetic
profile of entecavir after oral dosing, the estimated apparent volume of distribution
is in excess of total body water, suggesting that entecavir is extensively distributed into tissues.
Pharmacology
Pregnancy
Entecavir is in FDA
Pregnancy Category C. There are no adequate and well-controlled
studies in pregnant women. Reproduction studies have been performed in rats and
rabbits at orally administered doses of 200 and 16 mg/kg/day and showed no embryo-toxicity
or maternal toxicity in rat and rabbit at doses producing systemic exposures approximately
28 and 212 times those achieved at the highest recommended dose of 1 mg/day in
humans.
In rats,
maternal toxicity, embryo-fetal toxicity (resorptions),
lower fetal body weights, tail and vertebral malformations, reduced ossification
(vertebrae, sternebrae, and phalanges), and extra lumbar vertebrae and
ribs were observed at exposures 3,100 times those in humans.
Because
animal reproduction studies are not always predictive of human response, entecavir
should be used during pregnancy only if clearly needed and after careful consideration
of the risks and benefits. To monitor fetal outcomes of pregnant women exposed
to entecavir, an Antiretroviral Pregnancy Registry has
been established. Healthcare providers are encouraged to register patients online
at http://www.APRegistry.com
or by calling 1-800-258-4263.
Food and Drug Interactions
Food
Interactions
Oral
administration of entecavir 0.5 mg with a standard high-fat meal (945 kcal,
54.6 g fat) or a light meal (379 kcal, 8.2 g fat) resulted in delayed absorption
(1.0 to 1.5 hour fed vs. 0.75 hours fasted), a decrease in Cmax of 44% to 46%, and a decrease in AUC of 18% to 20%. For
this reason, and for best results, it is recommended to take entecavir
2 hours after a meal and 2 hours before the next meal.
The
pharmacokinetics of entecavir following a single 1 mg dose were
studied in patients without chronic hepatitis B infection with selected degrees
of renal impairment. Dosage adjustment is recommended for patients with a creatinine clearance of less than 50 ml/min, including patients
on hemodialysis or continuous ambulatory peritoneal
dialysis (CAPD). Entecavir should be administered after
hemodialysis. CAPD removed approximately 0.3% of the
dose over 7 days.
Drug
Interactions
Coadministration of the HIV nucleoside/tide analogues with entecavir does not appear to reduce the antiviral efficacy
of entecavir against HBV or of any of these agents against
HBV. In HBV combination assays in vitro, (Ziagen),
(Videx), (Epivir-HBV),
(Zerit), (Viread),
and (Retrovir)
were not antagonistic to the anti-HBV activity of entecavir
over a wide range of concentrations. In HIV antiviral assays, entecavir
was not antagonistic to the in vitro anti-HIV activity of these NRTIs
at greater than 4 times the Cmax of entecavir.
Cross
resistance has been observed among HBV nucleoside analogues. In cell-based assays
entecavir had 8- to 30-fold less inhibition of replication
of HBV that contained lamivudine resistance mutations
rtL180M and rtM204V/I than of wild-type vius.
Important
Safety Information
Lactic
acidosis and severe hepatomegaly with steatosis, including fatal cases, have been
reported with the use of nucleoside analogues alone or in combination with antiretrovirals.
•
Severe acute exacerbations of hepatitis B have been reported in
patients who have discontinued anti-hepatitis B therapy, including BARACLUDE.
Hepatic function should be monitored closely with both clinical and laboratory
follow-up for at least several months in patients who discontinue anti-hepatitis
B therapy. If appropriate, initiation of anti-hepatitis B therapy may be warranted.
•
Limited clinical experience suggests there is a potential for the
development of resistance to HIV (human immunodeficiency virus) nucleoside reverse
transcriptase inhibitors if BARACLUDE is used to treat chronic hepatitis B virus
infection in patients with HIV infection that is not being treated. Therapy with
BARACLUDE is not recommended for HIV/HBV co-infected patients who are not also
receiving highly active antiretroviral therapy (HAART). Before initiating BARACLUDE
therapy, HIV antibody testing should be offered to all patients.
•
BARACLUDE has not been studied as a treatment for HIV infection
and is not recommended for this use.
•
Dosage adjustment of BARACLUDE is recommended for patients with
a creatinine clearance <50 mL/min, patients with age-related decreases in renal
function, and those on hemodialysis or continuous ambulatory peritoneal dialysis
(CAPD).
•
Since entecavir is primarily eliminated by the kidneys, coadministration
of BARACLUDE with drugs that reduce renal function or compete for active tubular
secretion may increase serum concentrations of either entecavir or the coadministered
drug.
•
The safety and efficacy of BARACLUDE in liver transplant recipients
are unknown. Renal function must be carefully monitored both before and during
treatment with BARACLUDE in a liver transplant recipient who has received or is
receiving an immunosuppressant that may affect renal function, such as cyclosporine
or tacrolimus.
•
Patients should be advised that treatment with BARACLUDE has not
been shown to reduce the risk of transmission of HBV to others through sexual
contact or blood contamination.
•
There are no adequate and well-controlled studies of BARACLUDE administered
to pregnant women. BARACLUDE should be used during pregnancy only if clearly needed
and after careful consideration of the risks and benefits. There are no studies
on the effect of BARACLUDE on transmission of HBV from mother to infant. Therefore,
appropriate interventions should be used to prevent neonatal acquisition of HBV.
Women should be instructed not to breast-feed if they are taking BARACLUDE.
•
Safety and effectiveness of BARACLUDE in pediatric patients below
the age of 16 years have not been established.
The most common adverse
events of moderate to severe intensity among patients treated with BARACLUDE in
clinical trials included: headache (4%), fatigue (3%), diarrhea (1%), and dyspepsia
(1%).
The recommended
dose of BARACLUDE is 0.5 mg once daily in nucleoside-naïve adults, and 1
mg once daily in lamivudine-refractory adults. BARACLUDE should be administered
on an empty stomach (at least 2 hours after a meal and at least 2 hours before
the next meal). The optimal duration of treatment with BARACLUDE for patients
with chronic hepatitis B infection and the relationship between treatment and
long-term outcomes such as cirrhosis and hepatocellular carcinoma are unknown.
FDA-approved
Treatments
Articles on Entecavir (Baraclude)