Heptovir 100 mg

The likelihood of metabolic interactions is low due to limited metabolism and plasma protein binding and almost complete renal elimination of unchanged drug.

Lamivudine is predominantly eliminated by active organic cationic secretion. The possibility of interactions with other drugs administered concurrently should be considered, particularly when their main route of elimination is active renal secretion via the organic cationic transport system (e.g. trimethoprim). Other drugs (e.g. ranitidine, cimetidine) are eliminated only in part by this mechanism and were shown not to interact with lamivudine.

Drugs shown to be predominately excreted either via the active organic anionic pathway, or by glomerular filtration are unlikely to yield clinically significant interactions with lamivudine.

Data available in patients undergoing intermittent haemodialysis (≤4 hours dialysis 2-3 times weekly), indicate that following the initial dosage reduction of HEPTOVIR to correct for the patient's creatinine clearance, no further dosage adjustments are required while undergoing dialysis.

Discontinuation of HEPTOVIR (lamivudine) may be considered in immunocompetent patients when HBeAg and/or HBsAg seroconversion occurs and when loss of efficacy occurs as indicated by recurrent signs of hepatitis. There are limited data regarding the maintenance of seroconversion long term after stopping treatment with HEPTOVIR. If HEPTOVIR is discontinued, patients should be periodically monitored for evidence of recurrent hepatitis (see Warnings and Precautions).

The formulation and dosage of lamivudine in HEPTOVIR are not appropriate in patients dually infected with Hepatitis B and HIV. If lamivudine is administered to such patients, the higher dosage indicated for HIV therapy should be used as part of a combination treatment regimen and the Product Monographs for 3TC and HEPTOVIR should be consulted.

The recommended dose of HEPTOVIR for adults and adolescents who are at least 16 years old is 100 mg once daily. Optimum duration of therapy has not been established.

HEPTOVIR can be taken with or without food.

If the patients forget to take their medicine, they should take it as soon as they remember, then continue as before.

The following events have been reported during therapy for HIV disease with lamivudine alone and in combination with other antiretroviral agents. With many it is unclear whether they are related to the medicinal products or are as a result of the underlying disease process.

The following convention has been utilised for the classification of undesirable effects: Very common (>1/10), common (>1/100, <1/10), uncommon (>1/1000, <1/100), rare (>1/10 000, <1/1000), very rare (<1/10 000).

Uncommon: transient rises in liver enzymes (AST, ALT).

Common: hyperlactataemia. Rare: lactic acidosis (see Warnings and Precautions).

Redistribution/accumulation of body fat. The incidence of this event is dependent on multiple factors including the particular antiretroviral drug combination.

Common: fatigue, malaise, fever.

Common: headache. Very rare: paraesthesia. Peripheral neuropathy has been reported although a causal relationship to treatment is uncertain.

Uncommon: neutropenia, anaemia, thrombocytopenia. Very rare: pure red cell aplasia.

Common: rash, alopecia.

Common: nausea, vomiting, upper abdominal pain, diarrhea. Rare: pancreatitis, although a causal relationship to treatment is uncertain. Rises in serum amylase.

The incidence of laboratory abnormalities in chronic hepatitis B patients were similar in the HEPTOVIR and placebo treated groups with the exception of ALT elevations which were more common post-treatment in patients treated with HEPTOVIR. In controlled trials however, there was no appreciable difference post-treatment in clinically severe ALT elevations, associated with bilirubin elevations and/or signs of hepatic insufficiency, between HEPTOVIR and placebo treated patients. The relationship of these recurrent hepatitis events to HEPTOVIR treatment or to the previous underlying disease is uncertain (see Warnings and Precautions).

In patients with HIV infection, cases of pancreatitis and peripheral neuropathy (or paraesthesia) have been reported, although no relationship to treatment with lamivudine (3TC) has been clearly established. In patients with chronic hepatitis B there was no observed difference in incidence of these events between placebo and HEPTOVIR treated patients.

Cases of lactic acidosis, usually associated with severe hepatomegaly and hepatic steatosis, have been reported with the use of combination nucleoside analogue therapy in patients with HIV. There have been occasional reports of these adverse events in hepatitis B patients with decompensated liver disease, however, the association of HEPTOVIR with these events has not been established.

Common: arthralgia, muscle disorders. Rare: rhabdomyolysis.

Each mL of oral solution, colorless to pale yellow, strawberry-banana flavored, clear liquid, contains: lamivudine 5 mg. Nonmedicinal ingredients: artificial strawberry and banana flavors, citric acid (anhydrous), methylparaben, propylene glycol, propylparaben, sodium citrate, and sucrose. Plastic bottles of 240 mL.

Each butterscotch-colored, film-coated, capsule-shaped tablet, engraved “GXCG5” on one face, contains: lamivudine 100 mg. Nonmedicinal ingredients: hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycol 400, polysorbate 80, sodium starch glycolate, synthetic red iron oxide, synthetic yellow iron oxide and titanium dioxide. Bottles of 60.

The safety and efficacy of HEPTOVIR have not been established in patients with decompensated liver disease.

Patients with marginal liver function are at greater risk from active viral replication. In these patients, hepatitis reactivation at discontinuation of lamivudine or loss of efficacy during treatment may induce severe and even fatal decompensation. It is recommended that these patients are monitored for parameters associated with hepatitis B, for liver and renal functions, and for antiviral response during treatment. If treatment is discontinued for any reason, it is recommended that these patients are monitored closely for at least 6 months post cessation of treatment.

Lamivudine use at higher doses in HIV disease, has resulted in very rare occurrences of pure red cell aplasia. To date no definitive occurrences have been seen in hepatitis B patients at the recommended dose.

HBV viral subpopulations (YMDD variant HBV) with reduced susceptability to lamivudine have been identified during extended therapy. In a minority of cases this variant can lead to recurrent hepatitis.

If HEPTOVIR is discontinued or there is a loss of efficacy, some patients may experience clinical or laboratory evidence of recurrent hepatitis. Exacerbation of hepatitis has primarily been detected by serum ALT elevations, in addition to the re-emergence of HBV DNA. Most events appear to have been self-limited. Fatalities due to exacerbation of hepatitis after discontinuation of HEPTOVIR are uncommon.

Some chronic hepatitis B patients may be co-infected with HIV. The possibility of such co-infection should be considered prior to initiating HEPTOVIR therapy. Co-infected patients receiving or requiring an antiretroviral treatment regimen including lamivudine for HIV should be treated with the dose of lamivudine usually recommended for HIV infection. For co-infected patients not requiring antiretroviral therapy, the benefit of using lamivudine for treating chronic hepatitis B needs to be weighed against the potential compromise of a therapeutic option to subsequent progressive HIV and the possible emergence of drug-resistant HIV.

There is no clinical data on the efficacy of lamivudine in patients <16 years of age or co-infected with Delta hepatitis.

Patients should be monitored regularly during treatment by a physician experienced in the management of chronic hepatitis B.

Optimum duration of therapy has not been established.

The efficacy of lamivudine has not been established in patients not responding to alpha-interferon therapy.

Chronic hepatitis B is a highly variable condition and it is possible the patient may experience re-bound during therapy (i.e., viral load increase or increase in liver enzyme levels) or other discordant results (e.g. increased HBV DNA and improved liver histology). Since, there are no strong correlations between serological and histological markers of response, the decision on whether or not to continue HEPTOVIR (lamivudine) therapy should be based on clinical status and serological marker trends rather than a single result.

Patients should be advised that therapy of chronic hepatitis B, with HEPTOVIR has not been proven to reduce the risk of transmission of hepatitis B virus to others through sexual contact or blood contamination and therefore, appropriate precautions should still be taken.

Several serious adverse events have been reported with use of lamivudine in HIV-infected patients. Reports of anaphylaxis, rhabdomyolysis and peripheral neuropathy have been rare (<1 in 1000).

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of antiretroviral nucleoside analogues alone or in combination, including lamivudine, in the treatment of HIV infection. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Most of these reports have described patients receiving nucleoside analogues for the treatment of HIV infection, but there have been rare reports of lactic acidosis in patients receiving lamivudine for hepatitis B. Particular caution should be exercised when administering 3TC or HEPTOVIR to any patient with known risk factors for liver disease (other than hepatitis B). However, cases have been reported in patients with no known risk factors. Treatment with HEPTOVIR should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity.

If HEPTOVIR is discontinued, patients should be periodically monitored both clinically and by assessment of serum liver function tests (ALT and bilirubin levels), for at least four months for evidence of recurrent hepatitis; patients should then be followed as clinically indicated. For patients who develop evidence of recurrent hepatitis post-treatment, there are insufficient data on the benefits of re-initiation of HEPTOVIR treatment.

To monitor maternal-fetal outcomes of pregnant women exposed to lamivudine, a Pregnancy Registry has been established. Physicians are encouraged to register patients by calling GlaxoSmithKline's Drug Surveillance Department via the Customer Service Unit at 1-800-387-7374.

Diabetic patients should be advised that each dose of HEPTOVIR oral solution (100 mg=20 mL) contains 4 g of sucrose.

Pancreatitis has been reported in patients receiving 3TC (lamivudine), particularly in HIV-infected pediatric patients with prior nucleoside exposure.

In patients with moderate to severe renal impairment, serum lamivudine concentrations are increased due to decreased renal clearance, therefore the dose should be reduced for patients with a creatinine clearance of <50 mL/minute (see Dosage and Administration).

There are no adequate and well-controlled studies in pregnant women.

There are limited data on the use of lamivudine in pregnancy. In the phase III clinical studies, 15 pregnancies have been reported in patients receiving lamivudine for chronic hepatitis B: 2 were terminated in elective abortions, 11 were normal live births, and the outcome is unknown in 2. One of the 11 normal births was later found to have a mitral valve prolapse, which was not regarded as related to lamivudine by the investigator.

Reproductive studies in animals have not shown evidence of teratogenicity, and showed no effect on male or female fertility. Lamivudine induced early embryolethality when administered to pregnant rabbits, at exposure levels comparable to those achieved in man. Consistent with passive transmission of the drug across the placenta, lamivudine concentrations in infant serum at birth were similar to those in maternal and cord serum. However, there was no evidence of embryonic loss in rats at exposure levels of approximately 60 times the clinical exposure (based on C_max).

Use in pregnancy should be considered only if the benefit outweighs the risk. Although the results of animal studies are not always predictive of human response, the findings in the rabbit suggest a potential risk of early embryonic loss. Consequently, HEPTOVIR administration is not recommended during the first three months of pregnancy.

For patients who are on treatment with HEPTOVIR and subsequently become pregnant, consideration should be given to the possibility of a recurrence of hepatitis on discontinuation of HEPTOVIR.

There is no information available on maternal-fetal transmission of hepatitis B virus in pregnant women receiving treatment with HEPTOVIR. The standard recommended procedures for hepatitis B virus immunization in infants should be followed.

Following oral administration, lamivudine was excreted in breast milk at similar concentrations to those found in serum. It is recommended that mothers taking lamivudine do not breast feed to avoid potential adverse effects from lamivudine in nursing infants.

There is no clinical data on the efficacy of lamivudine in patients <16 years of age or co-infected with Delta hepatitis.

The bioavailability of oral lamivudine in adults is normally between 80 and 85%. Following oral administration, the mean time (t_max) to maximal serum concentrations (C_max) is about an hour. At therapeutic dose levels i.e. 100 mg once daily, C_max is in the order of 1.1-1.5 μg/mL.

Co-administration of lamivudine with food resulted in a delay of t_max and a lower C_max (decreased by up to 47%). However, the extent (based on the AUC) of lamivudine absorbed was not influenced, therefore HEPTOVIR (lamivudine) can be administered with or without food.

Lamivudine is well absorbed from the gastrointestinal tract.

Lamivudine is an antiviral agent which is active against hepatitis B virus (HBV) in all cell lines tested and in experimentally infected animals.

Lamivudine is metabolised by both infected and uninfected cells to the triphosphate (TP) derivative which is the active form of the parent compound. The intracellular half-life of the triphosphate in hepatocytes is 17-19 hours in vitro. Lamivudine-TP acts as a substrate for the HBV viral polymerase. The formation of further viral DNA is blocked by incorporation of lamivudine- MP into the chain and subsequent chain termination.

Lamivudine-TP is also a substrate for mammalian DNA polymerases, with the subsequent incorporation into mammalian DNA. However, incorporated lamivudine is removed from mammalian DNA by 3'-5' exonuclease DNA repair enzymes. Viral polymerases do not possess such a DNA repair function. Consequently, at concentrations in vitro which inhibit replication of HBV DNA in infected cells, lamivudine has no effect on mammalian mitochondrial DNA synthesis and has no cytotoxicity. In vitro concentrations of lamivudine which cause reductions of mammalian DNA and cytotoxicity are approximately 1000 times or greater than those which inhibit HBV replication. Thus, lamivudine has a high therapeutic index.

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