GUNAVIR

Each tablet contains Entecavir monohydrate equivalent to 0.5mg/1mg Entecavir.

Pack Size: 3*10, strips.

Pharmacodynamics properties

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:

(1) Priming of the HBV polymerase,
(2) Reverse transcription of the negative strand DNA from the pregenomic messenger RNA, and
(3) synthesis of the positive strand HBV DNA.

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.

Pharmacokinetic properties

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.

Adult indication

Treatment of chronic hepatitis B virus (HBV) infection in adults with:

• Compensated liver disease and evidence of active viral replication, persistently elevated serum alanine aminotransferase (ALT) levels and histological evidence of active inflammation and/or fibrosis.
• Decompensated liver disease.

For both compensated and decompensated liver disease, this indication is based on clinical trial data in nucleoside naive patients with HBeAg positive and HBeAg negative HBV infection. With respect to patients with lamivudine-refractory hepatitis B.

Pediatric population

Treatment of chronic HBV infection in nucleoside naive pediatric patients from 2 to 18 years of age with compensated liver disease that have evidence of active viral replication and persistently elevated serum ALT levels, or histological evidence of moderate to severe inflammation and/or fibrosis, with respect to the decision to initiate treatment in pediatric patients.

Therapy should be initiated by a physician experienced in the management of chronic hepatitis B infection.

Compensated liver disease

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.

Immune system disorders:

Rare: anaphylactic reaction

Psychiatric disorders:

Common: insomnia

Nervous system disorders:

Common: headache, dizziness, somnolence

Gastrointestinal disorders:

Common: vomiting, diarrhoea, nausea, dyspepsia

Hepatobiliary disorders:

Common: increased transaminases

Skin and subcutaneous tissue disorders:

Uncommon: rash, alopecia

General disorders and administration site conditions:

Common: fatigue

• Renal impairment: dosage adjustment is recommended for patients with renal impairment.
• Exacerbations of hepatitis: spontaneous exacerbations in chronic hepatitis B are relatively common and are characterized by transient increases in serum ALT. After initiating antiviral therapy, serum ALT may increase in some patients as serum HBV DNA levels decline.
• Among Entecavir treated nucleoside naive patients, post-treatment exacerbations had a median time to onset of 23-24 weeks, and most were reported in HBeAg negative patients.
• Patients with decompensated liver disease: a higher rate of serious hepatic adverse events (regardless of causality) has been observed in patients with decompensated liver disease, in particular in those with Child-Turcotte-Pugh (CTP) class C disease, compared with rates in patients with compensated liver function. Also, patients with decompensated liver disease may be at higher risk for lactic acidosis and for specific renal adverse events such as hepatorenal syndrome. Therefore, clinical and laboratory parameters should be closely monitored in this patient population.
• Lactic acidosis and severe hepatomegaly with steatosis: 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 etiology 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.
• Resistance and specific precaution for lamivudine-refractory patients: mutations in the HBV polymerase that encode lamivudine-resistance substitutions may lead to the subsequent emergence of secondary substitutions, including those associated with Entecavir associated resistance (ETVr). In a small percentage of lamivudine-refractory patients, ETVr substitutions at residues rtT184, rtS202 or rtM250 were present at baseline. Patients with lamivudine-resistant HBV are at higher risk of developing subsequent Entecavir resistance than patients without lamivudine resistance. The cumulative probability of emerging genotypic Entecavir resistance after 1, 2, 3, 4 and 5 years treatment in the lamivudine-refractory studies was 6%, 15%, 36%, 47% and 51%, respectively. Virological response should be frequently monitored in the lamivudine-refractory population and appropriate resistance testing should be performed. In patients with a suboptimal virological response after 24 weeks of treatment with Gunavir, a modification of treatment should be considered. When starting therapy in patients with a documented history of lamivudine-resistant HBV, 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 Entecavirmonotherapy.
• Pre-existing lamivudine-resistant HBV is associated with an increased risk for subsequent Entecavir resistance regardless of the degree of liver disease; in patients with decompensated liver disease, virologic breakthrough may be associated with serious clinical complications of the underlying liver disease. Therefore, in patients with both decompensated liver disease and lamivudine-resistant HBV, 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 Entecavir monotherapy.
• Pediatric population: A lower rate of virologic response (HBV DNA < 50 IU/ml) was observed in pediatric patients with baseline HBV DNA ≥ 8.0 log10 IU/ml. Gunavir should be used in these patients only if the potential benefit justifies the potential risk to the child (e.g. .resistance). Since some pediatric patients may require long-term or even lifetime management of chronic active hepatitis B, consideration should be given to the impact of Gunavir on future treatment options.
• Liver transplant recipients: renal function should be carefully evaluated before and during Gunavir therapy in liver transplant recipients receiving cyclosporine or Tacrolimus
• Co-infection with hepatitis C or D: there are no data on the efficacy of Gunavir in patients co-infected with hepatitis C or D virus.
• Human immunodeficiency virus (HIV)/HBV co-infected patients not receiving concomitant antiretroviral therapy: Gunavir has not been evaluated in HIV/HBV co-infected patients not concurrently receiving effective HIV treatment. Emergence of HIV resistance has been observed when Gunavir was used to treat chronic hepatitis B infection in patients with HIV infection not receiving highly active antiretroviral therapy (HAART). Therefore, therapy with Gunavir should not be used for HIV/HBV co-infected patients who are not receiving HAART. E Gunavir has not been studied as a treatment for HIV infection and is not recommended for this use.
• HIV/HBV co-infected patients receiving concomitant antiretroviral therapy: No data are available on the efficacy of Gunavir in HBeAg-negative patients co-infected with HIV. There are limited data on patients co-infected with HIV who have low CD4 cell counts (< 200 cells/mm3).
• General: patients should be advised that therapy with Gunavir has not been proven to reduce the risk of transmission of HBV and therefore appropriate precautions should still be taken.
• Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose- galactosemal absorption should not take this medicine. A lactose-free Entecavir oral solution is available for these individuals.
• Women of childbearing potential: given that the potential risks to the developing foetus are unknown, women of childbearing potential should use effective contraception.
• Pregnancy: there are no adequate data from the use of Gunavir in pregnant women. Studies in animals have shown reproductive toxicity at high doses. The potential risk for humans is unknown. Gunavir should not be used during pregnancy unless clearly necessary. There are no data on the effect of Gunavir on transmission of HBV from mother to newborn infant.
• Therefore, appropriate interventions should be used to prevent neonatal acquisition of HBV.
• Breast-feeding: 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 Gunavir film coated tablets.
• Fertility: toxicology studies in animals administered Gunavir have shown no evidence of impaired fertility.

Hypersensitivity to the active substance or to any of the excipients