LAMIVUDINE Lamivudine 10 mg/ML Solution

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Each ml contains:
Lamivudine 10 mg

Lamivudine is a selective inhibitor of HIV-1 and HIV-2 replication in vitro, including zidovudine-resistant clinical isolates of the human immunodeficiency virus (HIV). Lamivudine is metabolised intracellularly to the active 5'- triphosphate which inhibits the RNA-and DNA dependant activities of HIV reverse transcriptase by termination of the viral DNA chain. Lamivudine does not interfere with cellular deoxynucleotide metabolism and has little effect on mammalian cell and mitochondrial DNA content. In vitro, lamivudine demonstrates low cytotoxicity to peripheral blood lymphocytes, to established lymphocyte and monocyte-macrophage cell lines, and to a variety of bone marrow progenitor cells. In vitro, lamivudine therefore has a high therapeutic index. Reduced in-vitro sensitivity to lamivudine has been reported for HIV isolated from patients who have received lamivudine therapy before.

Pharmacokinetics in adults:
Following oral administration, lamivudine is well absorbed with bioavailability of approximately 80%. The mean time (Tmax) to maximum serum concentration (Cmax) is about an hour. At therapeutic dose levels of 4 mg/kg/day (as two 12- hourly doses), Cmaxis in the order of 1-1.5 micrograms/mL.

The mean volume of distribution from intravenous studies has been reported as 1.3 L/kg and the mean terminal half-life of elimination as 5 to 7 hours. The mean systemic clearance of lamivudine is approximately 0.32 L/kg/h, with predominantly renal clearance of more than 70% via active tubular secretion, but little hepatic metabolism, at less than 10 L. The intracellular half-life of the lamivudine triphosphate active metabolite is prolonged, averaging over 10 hours in peripheral blood lymphocytes. A delay in Tmax, and reduction in Cmax have been observed when co-administered with food, but no dose adjustment is needed, as lamivudine bioavailability is not altered. Lamivudine displays limited binding to albumin and exhibits linear pharmacokinetics over the therapeutic dose range. Co-administration of zidovudine results in a 13% increase in zidovudine exposure and a 28% increase in peak plasma levels. No dosage adjustments are necessary, as this is not considered to be of significance to patient safety. Limited data shows lamivudine penetrates the central nervous system and reaches the cerebrospinal fluid (CSF). The true extent of penetration or relationship with any clinical efficacy is unknown.

Pharmacokinetics in children:
In general, lamivudine pharmacokinetics in paediatric patients are similar to adults. However, absolute bioavailability is reduced to approximately 65%, in paediatric patients, with an increased clearance of 0.52 L/kg/hr.
There are limited pharmacokinetic data for patients <3 months of age.

LAMIVUDINE is indicated as part of antiretroviral combination therapy for treatment of HIV infected adults and children.

Hypersensitivity to any of the ingredients.

Patients receiving LAMIVUDINE and other antiretroviral agents may continue to develop opportunistic infections and other complications of HIV infection. Patients should therefore remain under close supervision by medical practitioners experienced in the treatment of patients with HIV-associated diseases. Current antiretroviral therapy, including LAMIVUDINE, has not been proven to prevent the risk of transmission of HIV to others through sexual contact or blood contamination.

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of lamivudine alone or in combination, in the treatment of HIV infection.

Zidovudine plasma levels are not significantly altered when co-administered with LAMIVUDINE (see Pharmacokinetics).
An interaction with trimethoprim, a constituent of co-trimoxazole. causes a 40% increase in lamivudine plasma concentrations at therapeutic doses. This does not require dose adjustment unless the patient also has renal impairment. Administration of co-trimoxazole with the LAMIVUDINE/zidovudine combinations in patients with renal impairment should be carefully assessed. LAMIVUDINE may inhibit the intracellular phosphorylation of zalcitabine when the two medicinal products are used concurrently. LAMIVUDINE is therefore not recommended to be used in
combination with zalcitabine.

Safety in pregnancy and lactation has not been established.

Adults and adolescents more than 12 years of age:
The recommended dose of LAMIVUDINE is 300 mg daily. This may be administered as either 300 mg once daily or
150 mg twice daily.
The package insert for zidovudine must be consulted for information on its dosage and administration.
For patients with low body weights (less than 50 kg), the recommended oral dose of LAMIVUDINE is 2 mg/kg
twice daily.
Children >3 months to 12 years of age:
The recommended dose is 4 mg/kg twice daily up to a maximum of 300 mg daily.
Children <3 months of age:
There are limited data to propose specific dosage recommendations (see Pharmacokinetics).

LAMIVUDINE can be taken with or without food.
Renal and Hepatic Impairment:
Renal impairment, whether disease- or age-related, affects lamivudine elimination. For recommended dosage
regimens in patients with a creatinine clearance below 50 mL/min see table below.

Adults and adolescents >12 years of age:

Creatinine Clearance (mL/min) Recommended dose of LAMIVUDINE

>50 150 mg twice daily

30-49 150 mg once daily

15-29 150 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

Children > 3 months to 12 years:

Creatinine Clearance (mL/min) Recommended dose of LAMIVUDINE

>50 4 mg/kg first dose, then 4 mg/kg twice daily

30-49 4 mg/kg first dose; then 4 mg/kg once daily

15-29 4 mg/kg first dose. then 2.6 mg/kg once daily

5-14 4 mg/kg first dose, then 1.3 mg/kg once daily

<5 1.3 mg/kg first dose, then 0.7 mg/kg once daily


Gastro-intestinal disorders:
Pancreatitis, upper abdominal pain, nausea; vomiting and diarrhoea have been reported.

Blood and lymphatic system disorders:
Neutropenia, thrombocytopenia and anaemia have occurred.

Skin and appendages disorders:
Alopecia has been reported.
Central and Peripheral Nervous system disorders:
Peripheral neuropathy, paraesthesia, and headache have been reported.

Musculo-skeletal system disorders:
Arthralgia, muscle disorders including less frequently, rhabdomyolysis have been reported.
Body as a whole:
Malaise, fatigue and fever have occurred.

Hypersensitivity reactions:
Skin rash.

Changes in laboratory test parameters:
Transient rises in serum liver enzymes (AST; ALT) and rises in serum amylase have been reported.

Special precautions:
LAMIVUDINE should be used with caution in patients with advanced cirrhotic liver disease due to chronic Hepatitis B infection, as there is a small risk of rebound hepatitis post treatment.

Pancreatitis has been observed in some patients receiving LAMIVUDINE. However it is unclear whether this is due to LAMIVUDINE or to underlying HIV disease.

Lactic acidosis/severe hepatomegaly with steatosis:
Long-term use of LAMIVUDINE can result in potentially fatal lactic acidosis. Symptomatic hyperlactacaemia and lactic acidosis are uncommon. Clinical features are non-specific, and include nausea, vomiting, abdominal pain, dyspnoea, fatigue and weight loss. Suspicious biochemical features include mild raised transaminases, raised lactate dehydrogenase (LDH) and/or creatine kinase.
In patients with suspicious symptoms or biochemistry. measure the venous lactate level (normal <2 mmol/L),
and respond as follows:

Lactate 2 - 5 mmol/L: monitor regularly, and be alert for clinical signs.
Lactate 5 - 10 mmol/L without symptoms: monitor closely.
Lactate 5 - 10 mmol/L with symptoms: STOP all therapy. Exclude other causes (e.g. sepsis,
uraemia. diabetic ketoacidosis, thyrotoxicosis, lymphoma).
Lactate 5 - 10 mmol/L: STOP all therapy (80% mortality in case studies).

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of LAMIVUDINE alone or in combination, in the treatment of HIV infection. Most cases were women. Caution should be exercised when administering LAMIVUDINE to patients with 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 hepatotoxicity.

Opportunistic infections:
Patients receiving LAMIVUDINE may continue to develop opportunistic infections and other complications of HIV infection, and therefore they should remain under close observation by medical practitioners experienced in the treatment of patients with associated HIV disease (see WARNINGS).

The risk of HIV transmission to others:
Patients should be advised that current antiretroviral therapy, including LAMIVUDINE, has not been proven to prevent the risk of transmission of HIV to others through sexual contact or blood contamination. Appropriate precautions should continue to be employed.
Patients with moderate to severe renal impairment: In patients with moderate to severe renal impairment, the terminal half-life of lamivudine is increased due to decreased clearance. The dose should therefore be adjusted (see DOSAGE AND DIRECTIONS FOR TREATMENT).

Treatment is symptomatic and supportive.

Clear colourless to light pale yellow syrupy liquid contained in an amber PET bottle

Amber PET bottle (100 ml or 240 ml):
Amber color, plastic (PET) bottle with a screw on cap, contained in a carton.

Store below 30oC. Protect from light.

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