LAMI-100 TABLETS/ LAMI-150 TABLETS

(Lamivudine Tablets 100mg/150mg)

Composition:
I) Each Tablet contains:
Lamivudine 100mg

II) Each Tablet contains:
Lamivudine 150mg

Presentation:
10x10's

Microbiology:

Antiviral Activity In Vitro:
The relationship between in vitro susceptibility of HIV to lamivudine and the inhibition of HIV replication in humans has not been established. In vitro activity of lamivudine against HIV-1 was assessed in a number of cell lines (including monocytes and fresh human peripheral blood lymphocytes) using standard susceptibility assays. IC50 values (50% inhibitory concentrations) were in the range of 2 nM to 15 mM. Lamivudine had anti-HIV-1 activity in all acute virus-cell infections tested. In HIV-1-infected MT-4 cells, lamivudine in combination with zidovudine had synergistic antiretroviral activity. Synergistic activity of lamivudine/zidovudine was also shown in a variable-ratio study.

Pharmacokinetics:
Lamivudine was rapidly absorbed after oral administration in HIV-infected patients. Absolute bioavailability in 12 adult patients was 86% ± 16% (mean ± SD) for the tablet and 87% ± 13% for the oral solution. After oral administration of 2 mg/kg twice a day to nine adults with HIV, the peak serum lamivudine concentration (Cmax) was 1.5 ± 0.5 µg/ml (mean ± SD). The area under the plasma concentration versus time curve (AUC) and Cmax increased in proportion to oral dose over the range from 0.25 to 10 mg/kg.
An investigational 25-mg dosage form of lamivudine was administered orally to 12 asymptomatic, HIV-infected patients on two occasions, once in the fasted state and once with food (1099 kcal; 75 grams fat, 34 grams protein, 72 grams carbohydrate). Absorption of lamivudine was slower in the fed state (Tmax: 3.2 ± 1.3 hours) compared with the fasted state (Tmax: 0.9 ± 0.3 hours); Cmax in the fed state was 40% ± 23% (mean ± SD) lower than in the fasted state. There was no significant difference in systemic exposure (AUC¥) in the fed and fasted states; therefore, Lamivudine may be administered with or without food.
The accumulation ratio of lamivudine in HIV-positive asymptomatic adults with normal renal function was 1.50 following 15 days of oral administration of 2mg/kg b.i.d.
The apparent volume of distribution after IV administration of lamivudine to 20 patients was 1.3 ± 0.4 L/kg, suggesting that lamivudine distributes into extravascular spaces. Volume of distribution was independent of dose and did not correlate with body weight.
Binding of lamivudine to human plasma proteins is low (<36%). In vitro studies showed that, over the concentration range of 0.1 to 100 mg/mL, the amount of lamivudine associated with erythrocytes ranged from 53% to 57% and was independent of concentration.

Metabolism of lamivudine is a minor route of elimination. In man, the only known metabolite of lamivudine is the trans-sulfoxide metabolite. Within 12 hours after a single oral dose of lamivudine in six HIV-infected adults, 5.2% ± 1.4% (mean ± SD) of the dose was excreted as the trans-sulfoxide metabolite in the urine. Serum concentrations of this metabolite have not been determined.
The majority of lamivudine is eliminated unchanged in urine. In 20 patients given a single IV dose, renal clearance was 0.22 ± 0.06 L/hrkg (mean ± SD), representing 71% ± 16% (mean ± SD) of total clearance of
lamivudine.
In most single-dose studies in HIV-infected patients with serum sampling for 24 hours after dosing, the observed mean elimination half-life (T 1/2) ranged from 5 to 7 hours. Total clearance was 0.37 ± 0.05 L/hrkg (mean ± SD). Oral clearance and elimination half-life were independent of dose and body weight over an oral dosing range from 0.25 to 10 mg/kg.

Indications:
Lamivudine is a nucleoside reverse transcriptase inhibitor structurally related to cytosine with activity against retroviruses including HIV. It is used, usually in combination with zidovudine, in the treatment of HIV infection. It is also used for the treatment of hepatitis B.

Contra-indications:
Patients known to be hypersensitive to Lamivudine.

Dosage and directions for use:
For HIV infection, the recommended dose of lamivudine for adults is 150 mg by mouth twice daily. A suggested dose for children aged between 3 months and 12 years is 4mg per kg body weight twice daily to a maximum of 150mg twice daily.
For chronic hepatitis B the recommended dose is 100mg once daily by mouth; in patients with concomitant HIV and hepatitis B infection the dosage regimen appropriate for HIV should be used.
Reduction of dosage is recommended for patients with impaired renal function.
Lamivudine should usually be taken without food. Ingestion with food reduces the C max considerably but does not alter the area under the curve (AUC). Therefore, ingestion with food might be considered when required due to clinical reasons.

Administration: Orally.

Warning:
Lamivudine is not recommended for use as monotherapy. Cases of pancreatitis have occurred rarely. However, it is not clear whether these cases were due to drug treatment or to the underlying HIV. disease. Treatment with Lamivudine should be stopped immediately if clinical signs, symptoms or laboratory abnormalities suggestive of pancreatitis occur. There are insufficient data on the use of Lamivudine in children <12 years.
Patients receiving Lamivudine or any other antiretroviral therapy may continue to develop opportunistic infection and other complications of HIV infection, and therefore should remain under close clinical observation by physicians experienced in the treatment of patients with associated HIV diseases.

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.
In patients with moderate to severe renal impairment, the terminal plasma half-life of lamivudine is increased due to decreased clearance. The dose should be adjusted.
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 if treatment is discontinued.

Side-effects & special precautions:
Adverse effect commonly associated with lamivudine includes abdominal pain, nausea, vomiting, diarrhoea, headache, fever, rash, malaise, insomnia, cough, nasal symptoms, and musculokeletal pain. Peripheral neuropathy and pancreatitis have been reported rarely. Neutropenia and anaemia (when given in combination with zidovudine), thrombocytopenia, and increases in liver enzymes and serum amylase have occurred.
Lamivudine therapy should be stopped in patients who develop abdominal pain, nausea, or vomiting or with abnormal biochemical test results until pancreatitis has been excluded. Dosage reduction may be necessary in patients with impaired renal function. In patients with chronic hepatitis B, there is a risk of rebound hepatitis when lamivudine is discontinued, and liver function should be monitored in such patients. The possibility of HIV infection should be excluded before beginning lamivudine therapy for hepatitis B, since the lower doses used to treat the latter may permit the development of lamivudine resistant strains of HIV.

Special precautions:

Use in Pregnancy:
The safety of lamivudine in human pregnancy has not been established. Reproductive studies in animals have not shown evidence of teratogenicity and showed no effect on male or female fertility.
Lamivudine induces early embryolethality then administered to pregnant rabbits at exposure levels comparable to those achieved in man. Lamivudine crosses the placenta in animals but there is no information on placental transfer in humans.
Although animal reproductive studies are not always predictive of the human response, administration during the first 3 months of pregnancy is not recommended.

Use in lactation:
A study in lactating rats showed that, following oral administration, lamivudine was concentrated 4-fold and excreted in the milk. It is not known if lamivudine is excreted in human breast milk. Since the drug may pass into breast milk, it is recommended that mothers taking lamivudine do not breastfeed their infants. Some health experts recommend that HIV-infected women do not breastfeed their infants under any circumstances in order to avoid transmission of HIV.

Drug Interaction:
The likelihood of metabolic interactions is low due to limited metabolism and plasma protein - binding and almost complete renal clearance. A modest increase in Cmax (28%) was observed for zidovudine when administered with lamivudine, however overall exposure (AUC) is not significantly altered. Zidovudine has no effect on the pharmacokinetics of lamivudine.

The possibility of interactions with other drugs administered concurrently should be considered, particularly when the main route of elimination is active renal secretion via the organic cationic transport system, eg trimethoprim. Other drugs (e. g, ranitidine, cimetidine) are eliminated only in part by this mechanism and were shown not to interact with lamivudine. The nucleoside analogues (e. g, didanosine and zalcitabine, like zidovudine, are not eliminated by this mechanism and are unlikely to interact with lamivudine.
The renal excretion of lamivudine may be inhibited by concomitant administration of other drugs mainly eliminated by active renal secretion, for example trimethoprim. Usual prophylactic doses of trimethoprim are unlikely to necessitate reductions in lamivudine dosage unless the patient has impaired renal function, but the co-administration of lamivudine with the high therapeutic doses of trimethoprim used in Pneumocystis carinii pneumonia and toxoplasmosis should be avoided.

Known symptoms of overdosage and particulars of its treatment:
Administration of lamivudine at very high dose levels in acute animal studies did not result in any organ toxicity. Limited data are available on the consequences of ingestion of acute overdose in humans. No fatalities occurred and the patients recovered. No specific signs or symptoms have been identified following such overdose.
If overdosage occurs, the patient should be monitored and standard supportive treatment applied as required. Since lamivudine is dialysable, continuous haemodialysis could be used in the treatment of overdosage, although this has not been studied.

Storage conditions and period.

Store in cool, dry & dark place, preferably below 25°C. Shelf life is 2 years.

Package: 10 tablets packed in blister strip, 10 such blisters packed in a carton.