Chemical formula: C₁₂H₁₅N₅O₃ Molecular mass: 277.279 g/mol PubChem compound: 153941
Entecavir interacts in the following cases:
The clearance of entecavir decreases with decreasing creatinine clearance (see section 5.2). Dose adjustment is recommended for patients with creatinine clearance <50 ml/min, including those on haemodialysis or continuous ambulatory peritoneal dialysis (CAPD). A reduction of the daily dose using entecavir oral solution, as detailed in the table, is recommended. As an alternative, in case the oral solution is not available, the dose can be adjusted by increasing the dosage interval, also shown in the table. The proposed dose modifications are based on extrapolation of limited data, and their safety and effectiveness have not been clinically evaluated. Therefore, virological response should be closely monitored.
| Creatinine clearance (ml/min) | entecavir dosage* | |
|---|---|---|
| Nucleoside naïve patients | Lamivudine-refractory or decompensated liver disease | |
| ≥50 | 0.5 mg once daily | 1 mg once daily |
| 30-49 | 0.25 mg once daily* OR 0.5 mg every 48 hours | 0.5 mg once daily |
| 10-29 | 0.15 mg once daily* OR 0.5 mg every 72 hours | 0.3 mg once daily* OR 0.5 mg every 48 hours |
| <10 Haemodialysis or CAPD** | 0.05 mg once daily* OR 0.5 mg every 5-7 days | 0.1 mg once daily* OR 0.5 mg every 72 hours |
* for doses <0.5 mg entecavir oral solution is recommended.
** on haemodialysis days, administer entecavir after haemodialysis.
Renal function should be carefully evaluated before and during entecavir therapy in liver transplant recipients receiving cyclosporine or tacrolimus.
Occurrences of lactic acidosis (in the absence of hypoxaemia), sometimes fatal, usually associated with severe hepatomegaly and hepatic steatosis, have been reported with the use of nucleoside analogues. As entecavir is a nucleoside analogue, this risk cannot be excluded. Treatment with nucleoside analogues should be discontinued when rapidly elevating aminotransferase levels, progressive hepatomegaly or metabolic/lactic acidosis of unknown aetiology occur. Benign digestive symptoms, such as nausea, vomiting and abdominal pain, might be indicative of lactic acidosis development. Severe cases, sometimes with fatal outcome, were associated with pancreatitis, liver failure/hepatic steatosis, renal failure and higher levels of serum lactate. Caution should be exercised when prescribing nucleoside analogues to any patient (particularly obese women) with hepatomegaly, hepatitis or other known risk factors for liver disease. These patients should be followed closely.
To differentiate between elevations in aminotransferases due to response to treatment and increases potentially related to lactic acidosis, physicians should ensure that changes in ALT are associated with improvements in other laboratory markers of chronic hepatitis B.
There are no adequate data from the use of entecavir in pregnant women. Studies in animals have shown reproductive toxicity at high doses. The potential risk for humans is unknown. Entecavir should not be used during pregnancy unless clearly necessary. There are no data on the effect of entecavir on transmission of HBV from mother to newborn infant. Therefore, appropriate interventions should be used to prevent neonatal acquisition of HBV.
It is unknown whether entecavir is excreted in human milk. Available toxicological data in animals have shown excretion of entecavir in milk. A risk to the infants cannot be excluded. Breast-feeding should be discontinued during treatment with entecavir.
Given that the potential risks to the developing foetus are unknown, women of childbearing potential should use effective contraception.
Toxicology studies in animals administered entecavir have shown no evidence of impaired fertility.
No studies on the effects on the ability to drive and use machines have been performed. Dizziness, fatigue and somnolence are common side effects which may impair the ability to drive and use machines.
In clinical studies in patients with compensated liver disease, the most common adverse reactions of any severity with at least a possible relation to entecavir were headache (9%), fatigue (6%), dizziness (4%) and nausea (3%). Exacerbations of hepatitis during and after discontinuation of entecavir therapy have also been reported.
Assessment of adverse reactions is based on experience from postmarketing surveillance and four clinical studies in which 1,720 patients with chronic hepatitis B infection and compensated liver disease received double-blind treatment with entecavir (n=862) or lamivudine (n=858) for up to 107 weeks. In these studies, the safety profiles, including laboratory abnormalities, were comparable for entecavir 0.5 mg daily (679 nucleoside-naive HBeAg positive or negative patients treated for a median of 53 weeks), entecavir 1 mg daily (183 lamivudine-refractory patients treated for a median of 69 weeks), and lamivudine.
Adverse reactions considered at least possibly related to treatment with entecavir are listed by body system organ class. Frequency is defined as very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Rare: anaphylactoid reaction
Common: insomnia
Common: headache, dizziness, somnolence
Common: vomiting, diarrhoea, nausea, dyspepsia
Common: increased transaminases
Uncommon: rash, alopecia
Common: fatigue
Cases of lactic acidosis have been reported, often in association with hepatic decompensation, other serious medical conditions or drug exposures.
Treatment beyond 48 weeks: continued treatment with entecavir for a median duration of 96 weeks did not reveal any new safety signals.
Laboratory test abnormalities: In clinical studies with nucleoside-naive patients, 5% had ALT elevations >3 times baseline, and <1% had ALT elevations >2 times baseline together with total bilirubin >2 times upper limit of normal (ULN) and >2 times baseline. Albumin levels <2.5 g/dl occurred in <1% of patients, amylase levels >3 times baseline in 2%, lipase levels >3 times baseline in 11% and platelets <50,000/mm³ in <1%.
In clinical studies with lamivudine-refractory patients, 4% had ALT elevations >3 times baseline, and <1% had ALT elevations >2 times baseline together with total bilirubin >2 times ULN and >2 times baseline. Amylase levels >3 times baseline occurred in 2% of patients, lipase levels >3 times baseline in 18% and platelets <50,000/mm³ in <1%.
In studies with nucleoside naive patients, on treatment ALT elevations >10 times ULN and >2 times baseline occurred in 2% of entecavir treated patients vs 4% of lamivudine treated patients. In studies with lamivudine-refractory patients, on treatment ALT elevations >10 times ULN and >2 times baseline occurred in 2% of entecavir treated patients vs 11% of lamivudine treated patients. Among entecavir-treated patients, on-treatment ALT elevations had a median time to onset of 4-5 weeks, generally resolved with continued treatment, and, in a majority of cases, were associated with a ≥2 log10/ml reduction in viral load that preceded or coincided with the ALT elevation. Periodic monitoring of hepatic function is recommended during treatment.
Acute exacerbations of hepatitis have been reported in patients who have discontinued anti-hepatitis B virus therapy, including therapy with entecavir. In studies in nucleoside-naive patients, 6% of entecavir-treated patients and 10% of lamivudine-treated patients experienced ALT elevations (>10 times ULN and >2 times reference [minimum of baseline or last end-of-dosing measurement]) during post-treatment follow-up. Among entecavir-treated nucleoside-naive patients, ALT elevations had a median time to onset of 23-24 weeks, and 86% (24/28) of ALT elevations occurred in HBeAg negative patients. In studies in lamivudine-refractory patients, with only limited numbers of patients being followed up, 11% of entecavir-treated patients and no lamivudine-treated patients developed ALT elevations during post-treatment follow-up.
In the clinical trials entecavir treatment was discontinued if patients achieved a prespecified response. If treatment is discontinued without regard to treatment response, the rate of post-treatment ALT flares could be higher.
Experience in patients with decompensated liver disease: the safety profile of entecavir in patients with decompensated liver disease was assessed in a randomized open-label comparative study in which patients received treatment with entecavir 1 mg/day (n=102) or adefovir dipivoxil 10 mg/day (n=89) (study 048). Relative to the adverse reactions noted in section b. List of adverse reactions, one additional adverse reaction [decrease in blood bicarbonate (2%)] was observed in entecavir-treated patients through week 48. The on-study cumulative death rate was 23% (23/102), and causes of death were generally liver-related, as expected in this population. The on-study cumulative rate of hepatocellular carcinoma (HCC) was 12% (12/102). Serious adverse events were generally liver-related, with an on-study cumulative frequency of 69%. Patients with high baseline CTP score were at higher risk of developing serious adverse events.
Through week 48 among entecavir-treated patients with decompensated liver disease, none had ALT elevations both >10 times ULN and >2 times baseline, and 1% of patients had ALT elevations >2 times baseline together with total bilirubin >2 times ULN and >2 times baseline. Albumin levels <2.5 g/dl occurred in 30% of patients, lipase levels >3 times baseline in 10% and platelets <50,000/mm³ in 20%.
The safety profile of entecavir in a limited number of HIV/HBV co-infected patients on lamivudine-containing HAART (highly active antiretroviral therapy) regimens was similar to the safety profile in monoinfected HBV patients.
There was no apparent difference in the safety profile of entecavir with respect to gender (≈25% women in the clinical trials) or age (≈5% of patients >65 years of age).
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