(i) ROUTE OF ADMINISTRATION

Oral

DOSAGE AND ADMINISTRATION

Adults and Adolescents (12 to 16 years) The recommended oral dose of Health 2000 Lamivudine 150 mg Tablets for adults and adolescents is 150 mg twice daily administered in combination with zidovudine. The complete prescribing information for zidovudine should be consulted for information on its dosage and administration.
For adults with low body weights (less than 50 kg or 110 lb), the recommended oral dose of Health 2000 Lamivudine 150 mg Tablets is 2 mg/kg twice daily administered in combination with zidovudine. No data are available to support a dosage recommendation for adolescents with low body weight (less than 50 kg).

Paediatric patients The recommended oral dose of Health 2000 Lamivudine 150 mg Tablets for paediatric patients 3 months to up to 12 years of age is 4 mg/kg twice daily (up to a maximum of 150 mg twice a day) administered in combination with zidovudine. The complete prescribing information for zidovudine should be consulted for information on its dosage and administration.

Dose Adjustment It is recommended that doses of Health 2000 Lamivudine 150 mg Tablets be adjusted in accordance with renal function in patients older than age 16 years, as given in the table below:

Creatinine Recommended Clearance Dosage of (ml/min) Lamivudine > 50 150 mg twice daily 49 150 mg once daily 5-29 150 mg first dose, then 100 mg once daily 5-14 150 mg first dose, then 50 mg once daily < 5 50 mg first dose, then 25 mg once daily
Insufficient data are available to recommend a dosage of Health 2000 Lamivudine 150 mg Tablets in patients undergoing dialysis.

(ii) THERAPEUTIC / DIAGNOSTIC CLAIMS

Lamivudine Tablets in combination with zidovudine is indicated for the treatment of HIV infection when therapy is warranted.

(iii) DESCRIPTION OF DOSAGE FORM

Health 2000 Lamivudine 150 mg is a synthetic nucleoside analogue with activity against the human immunodeficiency virus (HIV).

(iv) CONTRAINDICATIONS

Lamivudine is contraindicated in patients with previously demonstrated clinically significant hypersensitivity to any of the components of the products.

WARNING AND PRECAUTIONS

In paediatric patients with a history of pancreatitis or other significant risk factors for the development of pancreatitis, the combination of lamivudine and zidovudine should be used with extreme caution and only if there is no satisfactory alternative therapy. Treatment with lamivudine should be stopped immediately if clinical signs, symptoms, or laboratory abnormalities suggestive of pancreatitis occur.
The complete prescribing information for zidovudine should be consulted before combination therapy with lamivudine and zidovudine is initiated.

LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS
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. A majority of these cases have been in women. Caution should be exercised when administering lamivudine to any patient, and particularly to those with known risk factors for liver disease. Treatment with lamivudine should be suspended in any patient who develops clinical or laboratory findings suggestiveof lactic acidosis or hepatotoxicity.
IMPAIRED RENAL FUNCTION Reduction of the dose of Health 2000 Lamivudine 150 mg Tablets is recommended for patients with impaired renal function (see Dosage and Administration)

PATIENTS WITH HIV AND HEPATITIS B VIRUS COINFECTION In clinical trials, some patients with HIV infection who have chronic liver disease due to hepatitis B virus infection experienced clinical or laboratory evidence of recurrent hepatitis upon discontinuation of lamivudine. Consequences may be more severe in patients with decompensated liver disease.

DRUG INTERACTIONS Trimethoprim 160 mg and sulfamethoxazole 800 mg once daily has been shown to increase lamivudine exposure (AUC). The effect of higher doses of trimethoprim and sulfamethoxazole on lamivudine pharmacokinetics has not been investigated.

PREGNANCY
Pregnancy Category C. There are no adequate and well-controlled studies in pregnant women. Lamivudine should be used during pregnancy only if the potential benefits outweigh the risks.

LACTATION
It is recommended that HIV-infected mothers do not breast-feed their infants to avoid risking postnatal transmission of HIV infection. Although it is not known if lamivudine is excreted in human milk, there is the potential for adverse effects from lamivudine in nursing infants. Mothers should be instructed to discontinue nursing if they are receiving lamivudine.

PEADIATRICUSE
The safety and effectiveness of lamivudine in combination with other antiretroviral agents have been established in paediatric patients three months of age and older.

(v) SIDE EFFECTS

The most common side effects are gastrointestinal - upset stomach, nausea, vomiting. A more serious side effect neutropenia - a blood disorder - can mean stopping therapy. Pancreatitis or inflammation of the pancreas can also occur, but is more common in children.

(vi) TOXIC EFFECTS

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including lamivudine and other antiretrovirals. Female gender, obesity, and prolonged exposure to antiretroviral nucleoside analogues may be risk factors. Cases have occurred in patients with and without known risk factors for liver disease. Treatment with lamivudine should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).

Post-treatment exacerbations of hepatitis B virus infection have been reported in non-HIV infected patients treated with lamivudine for chronic hepatitis B virus (HBV) infection when lamivudine therapy was discontinued. Similar exacerbations of HBV infection have been reported in patients infected with both HIV and HBV when lamivudine therapy was switched to a non-lamivudine containing regimen. The causal relationship between discontinuation of lamivudine therapy and exacerbation of HBV infection is unknown.

Other reported adverse events affecting specific organ systems include: body as a whole (headache, malaise, fatigue, fever, chills), general (weakness), endocrine and metabolic (hyperglycemia), gastrointestinal (nausea, vomiting, diarrhea, abdominal pain and cramps, dyspepsia, anorexia and/or decreased appetite, stomatitis), hemic and lymphatic (anemia, lymphadenopathy, pure red cell aplasia, pancreatitis, splenomegaly), nervous (peripheral neuropathy, paresthesia, depressive disorders, dizziness, insomnia and other sleep disorders), respiratory (cough, nasal signs and symptoms, abnormal breath sounds), musculoskeletal (musculoskeletal pain and/or weakness, myalgia, arthralgia, increased creatine phosphokinase levels [CPK], rhabdomyolysis), skin (pruritus, rash, alopecia), and hypersensitivity reactions (anaphylaxis, urticaria).

Pancreatitis, which has been fatal in some cases, has been observed in antiretroviral nucleoside-experienced pediatric patients receiving lamivudine alone or in combination with other antiretroviral agents. In pediatric patients with a history of antiretroviral nucleoside exposure, a history of pancreatitis, or other significant risk factors for the development of pancreatitis, lamivudine should be used with caution. Treatment with lamivudine should be stopped immediately if clinical signs, symptoms, or laboratory abnormalities suggestive of pancreatitis occur.

Peripheral neuropathy occurred in 13% of pediatric patients with advanced HIV disease receiving lamivudine monotherapy. Lamivudine should be used with caution in patients with peripheral neuropathy or a history of peripheral neuropathy Pediatric patients receiving both zidovudine and lamivudine as part of a study experienced neutropenia, anemia, thrombocytopenia, fever, hepatomegaly, nausea and vomiting, diarrhea, stomatitis, splenomegaly, cough, abnormal breath sounds/wheezing, ear symptoms (pain, discharge erythema, swelling), nasal congestion or discharge, skin rashes, and lymphadenopathy.