Therapy should be initiated by a physician experienced in the management of chronic hepatitis B infection.
- Pharmacotherapeutic Group
antiviral for systemic use, nucleoside and nucleotide reverse transcriptase inhibitors
- Mechanism of Action
Entecavir, a guanosine nucleoside analogue with activity against HBV polymerase, is efficiently phosphorylated to the active triphosphate (TP) form, which has an intracellular half-life of 15 hours. By competing with the natural substrate deoxyguanosine TP, Entecavir-TP functionally inhibits the 3 activities of the viral polymerase
Antiviral activity: Entecavir inhibited HBV DNA synthesis (50% reduction, EC50) at a concentration of 0.004 µM in human HepG2 cells transfected with wild-type HBV. The median EC50 value for Entecavir against LVDr HBV (rtL180M and rtM204V) was 0.026 µM (range 0.010-0.059 µM). Recombinant viruses encoding Adefovir-resistant substitutions at either rtN236T or rtA181V remained fully susceptible to Entecavir.
- Priming of the HBV polymerase,
- Reverse transcription of the negative strand DNA from the pregenomic messenger RNA, and
- synthesis of the positive strand HBV DNA.
- Absorption
Entecavir is rapidly absorbed with peak plasma concentrations occurring between 0.5-1.5 hours. The absolute bioavailability has not been determined. Based on urinary excretion of unchanged drug, the bioavailability has been estimated to be at least 70%. There is a dose- proportionate increase in Cmax and AUC values following multiple doses ranging from 0.1-1 mg. Steady-state is achieved between 6-10 days after once daily dosing with ≈ 2 times accumulation. Cmax and Cmin at steady-state are 4.2 and 0.3 ng/ml, respectively, for a dose of 0.5 mg, and 8.2 and 0.5 ng/ml, respectively, for 1 mg. Administration of 0.5 mg Entecavir with a standard high-fat meal (945 kcal, 54.6 g fat) or a light meal (379 kcal, 8.2 g fat) resulted in a minimal delay in absorption (1-1.5 hour fed vs. 0.75 hour fasted), a decrease in Cmax of 44-46%, and a decrease in AUC of 18-20%. The lower Cmax and AUC when taken with food is not considered to be of clinical relevance in nucleoside-naive patients but could affect efficacy in lamivudine-refractory patients.
- Distribution
The estimated volume of distribution for Entecavir is in excess of total body water. Protein binding to human serum protein in vitro is ≈ 13%.
- Biotransformation
Entecavir is not a substrate, inhibitor or inducer of the CYP450 enzyme system. Following administration of 14C-Entecavir, no oxidative or acetylated metabolites and minor amounts of the phase II metabolites, glucuronide and sulfate conjugates, were observed.
- Elimination
Entecavir is predominantly eliminated by the kidney with urinary recovery of unchanged drug at steady-state of about 75% of the dose. Renal clearance is independent of dose and ranges between 360-471 ml/min suggesting that Entecavir undergoes both glomerular filtration and net tubular secretion. After reaching peak levels, Entecavir plasma concentrations decreased in a bi- exponential manner with a terminal elimination half-life of ≈ 128-149 hours. The observed drug accumulation index is ≈ 2 times with once daily dosing, suggesting an effective accumulation half-life of about 24 hours.
- Hepatic impairment
pharmacokinetic parameters in patients with moderate or severe hepatic impairment were similar to those in patients with normal hepatic function.
- No interactions on level of cytochrome P450 are expected to occur because Itopride is metabolized mainly by Flavine Monooxygenase. No interaction was detected when Itopride was administered concomitantly with Warfarin, Diazepam, Diclofenac, Ticlopidine, Nifedipine and Nicardipine.
- Itopride has Gastro-Kinetic effect that could influence the absorption of concomitantly orally administered medicinal products. Particular attention should be taken to drugs with a narrow therapeutic index, drugs with prolonged-release of active substance and enteric-coated drug formulations.
- Itopride has Gastro-Kinetic effect that could influence the absorption of concomitantly orally administered medicinal products. Particular attention should be taken to drugs with a narrow therapeutic index, drugs with prolonged-release of active substance and enteric-coated drug formulations.
- Substances as Cimetidine, Ranitidine, Teprenone and Cetrexate do not affect Prokinetic activity of Itopride.
- Treatment of Gastrointestinal symptoms of functional Non-Ulcer Dyspepsia, like feelings of Bloating, Gastric Fullness, Upper Abdominal pain, Anorexia, Heartburn, Nausea and Vomiting.
- The medicinal product is indicated in Adults.
- Nucleoside naïve patients
the recommended dose in adults is 0.5 mg once daily, with or without food.
- Lamivudine-refractory patients (i.e. with evidence of viraemia while on lamivudine or the presence of lamivudine resistance [LVDr] mutations):
The recommended dose in adults is 1 mg once daily, which must be taken on an empty stomach (more than 2 hours before and more than 2 hours after a meal. In the presence of LVDr mutations, combination use of Gunavir plus a second antiviral agent (which does not share cross-resistance with either lamivudine or Entecavir) should be considered in preference to Gunavir monotherapy.
- Decompensated liver disease
The recommended dose for adult patients with decompensated liver disease is 1 mg once daily, which must be taken on an empty stomach (more than 2 hours before and more than 2 hours after a meal). For patients with lamivudine-refractory hepatitis B.
- Duration of therapy
The optimal duration of treatment is unknown. Treatment discontinuation may be considered as follows: - In HBeAg positive adult patients, treatment should be administered at least until 12 months after achieving HBeseroconversion (HBeAg loss and HBV DNA loss with anti-HBe detection on two consecutive serum samples at least 3-6 months apart) or until HBs seroconversion or there is loss of efficacy .
- In HBeAg negative adult patients, treatment should be administered at least until HBs seroconversion or there is evidence of loss of efficacy. With prolonged treatment for more than 2 years, regular reassessment is recommended to confirm that continuing the selected therapy remains appropriate for the patient.
In patients with decompensated liver disease or cirrhosis, treatment cessation is not recommended.
- Pediatric population
For appropriate dosing in the pediatric population, Gunavir 0.5 mg film-coated tablets are available and for dosages below 0.5 mg an oral solution may be available.
The decision to treat pediatric patients should be based on careful consideration of individual patient needs and with reference to current pediatric treatment guidelines including the value of baseline histological information. The benefits of long-term virologic suppression with continued therapy must be weighed against the risk of prolonged treatment, including the emergence of resistant hepatitis B virus.
Serum ALT should be persistently elevated for at least 6 months prior to treatment of pediatric patients with compensated liver disease due to HBeAg positive chronic hepatitis B; and for at least 12 months in patients with HBeAg negative disease.
Pediatric patients with body weight of at least 32.6 kg, should be administered a daily dose of one 0.5 mg tablet with or without food. An oral solution may be available for patients with body weight less than 32.6 kg.
