LSN 40mg tab

(i) ROUTE OF ADMINISTRATION

Oral

DOSAGE AND ADMINISTRATION

Adults

Health 2000 Lamivudine 150 mg, Stavudine 40 mg and Nevirapine 200mg Tablets
1 tablet twice daily for patients weighing > 60 kg

Health 2000 Lamivudine 150 mg, Stavudine 40 mg and Nevirapine 200mg Tablets should not be administered to patients who have just initiated therapy with nevirapine. This is because an initial lead-in dosing of 200 mg nevirapine once daily for 2 weeks is recommended. Following this lead-in dose, a dose escalation (maintenance dose) to 200 mg nevirapine bd may be carried out in the absence of any hypersensitivity reactions (e.g. rash, liver function test abnormalities; see Warnings and Precautions).

Monitoring of patients
Clinical chemistry tests, which include liver function tests, should be performed prior to initiating lead-in nevirapine therapy and at appropriate intervals during therapy (see Warnings and Precautions).

Dosage Adjustment
Lamivudine
Because it is a fixed-dose combination, Health 2000 Lamivudine 150 mg, Stavudine 40 mg and Nevirapine 200mg Tablets should not be prescribed for patients requiring dosage adjustment, such as those with low body weight (<50 kg).
Nevirapine
Health 2000 Lamivudine 150 mg, Stavudine 40 mg and Nevirapine 200mg Tablets should be discontinued if patients experience severe rash or a rash accompanied by constitutional findings (See Warnings and Precautions). Patients experiencing mild to moderate rash during the 14-day lead-in period of 200 mg/day should not have their nevirapine dose increased or start therapy with Health 2000 Lamivudine 150 mg, Stavudine 40 mg and Nevirapine 200mg Tablets until the rash has resolved (see Warnings and Precautions).

Health 2000 Lamivudine 150 mg, Stavudine 40 mg and Nevirapine 200mg Tablets administration should be interrupted in patients experiencing moderate or severe liver function tests abnormalities (excluding GGT), until the liver function test elevations have returned to baseline. Nevirapine may then be restarted at 200 mg per day. Increasing the daily dose to 200 mg twice daily (using Health 2000 Lamivudine 150 mg, Stavudine 40 mg and Nevirapine 200mg Tablets) should be done with caution, after extended observation. Nevirapine should be permanently discontinued if moderate or severe liver function test abnormalities recur (see Warnings and Precautions).
Patients who interrupt nevirapine dosing for more than 7 days should restart the recommended dosing, using one 200 mg Nevirapine tablet daily for the first 14 days (lead-in) in combination with the other antiretrovirals, followed by 200 mg twice daily using Health 2000 Lamivudine 150 mg, Stavudine 40 mg and Nevirapine 200mg Tablets in the absence of any signs of hypersensitivity.
No data are available to recommend a dosage of nevirapine in patients with hepatic dysfunction, renal insufficiency or undergoing dialysis.
(ii) THERAPEUTIC / DIAGNOSTIC CLAIMS
Health 2000 Lamivudine 150 mg, Stavudine 40 mg and Nevirapine 200mg Tablets is indicated for the treatment of HIV-1 infection in adults, once patients have been stabilized on the maintenance regimen of nevirapine 200 mg bd, and have demonstrated adequate tolerability to nevirapine.
(iii) DESCRIPTION OF DOSAGE FORM

Health 2000 Lamivudine 150 mg, Stavudine 40 mg and Nevirapine 200mg Tablets is a combination of 3 drugs commonly used in the management of Human Immunodeficiency Virus (HIV-1) infection. Both stavudine and lamivudine belong to the nucleoside analogue class of antiretroviral drugs. Both drugs act by terminating the growth of the DNA chain and inhibiting the reverse transcriptase of HIV. Nevirapine is a non-nucleoside reverse transcriptase inhibitor. It acts by directly inhibiting reverse transcriptase.Studies using the combination of stavudine + lamivudine + nevirapine have demonstrated its efficacy in patients with HIV infection

Each tablet of Health 2000 Lamivudine 150 mg, Stavudine 40 mg and Nevirapine 200mg Tablet contains half of the commonly prescribed daily doses of stavudine, lamivudine and nevirapine. All three drugs are to be administered twice daily, permitting a fixed-dose combination to be formulated. With the availability of this combination formulation, patients may be better able to adhere to triple drug regimens, thereby enhancing compliance

(iv) CONTRAINDICATIONS

Health 2000 Lamivudine 150 mg, Stavudine 40 mg and Nevirapine 200mg Tablets is contraindicated in patients with clinically significant hypersensitivity to any of the components contained in the formulation.

Health 2000 Lamivudine 150 mg, Stavudine 40 mg and Nevirapine 200mg Tablets is also contraindicated for patients who are just initiating therapy with nevirapine. These patients require a lead-in dose of nevirapine 200 mg o.d., whereas this formulation contains the maintenance dose of nevirapine 200 mg b.d. (see Indications).

WARNINGS AND PRECAUTIONS :
Lactic acidosis/severe hepatomegaly with steatosis
Lactic acidosis/severe hepatomegaly with steatosis , including fatal cases, have been reported with the use of antiretroviral nucleoside analogues alone or in combination, including stavudine and lamivudine.A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Caution should be exercised when administering stavudine to any patient, and particularly to those with known risk factors for liver disease. Cases have also been reported in patients with no known risk factors. Treatment should be discontinued in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or hepatotoxicity (which may include hepatomegaly and steatosis)even in the absence of marked amino-transferase elevations.

Peripheral neuropathy
Stavudine therapy can be associated with severe peripheral neuropathy, which is dose-related and occurs more frequently in patients with advanced HIV infection or who have previously experienced peripheral neuropathy.
Patients should be monitored for the development of neuropathy that is usually characterized by numbness, tingling or pain in the feet or hands. Stavudine-related peripheral neuropathy may resolve if therapy is withdrawn promptly. In some cases, symptoms may worsen temporarily following discontinuation of therapy.
If symptoms resolve completely, resumption of treatment may be considered using the following dosage schedule for adults:

20 mg twice daily for patients > 60 kg
15 mg twice daily for patients < 60 kg
In this case, therapy with Health 2000 Lamivudine 150 mg, Stavudine 40 mg and Nevirapine 200mg Tablets is no longer appropriate.

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.

Hypersensitivity reactions
Severe, life-threatening skin reactions, including fatal cases, have occurred in patients treated with nevirapine. These have included cases of Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity reactions characterized by rash, constitutional findings, and organ dysfunction. Patients developing signs or symptoms of severe skin reactions or hypersensitivity reactions (including, but not limited to, severe rash or rash accompanied by fever, blisters, oral lesions, conjunctivitis, facial edema, muscle or joint aches, general malaise and/or significant hepatic abnormalities must discontinue nevirapine as soon as possible. Nevirapine therapy must be initiated with a 14-day lead - in period of 200 mg/day (4 mg/kg/day in paediatric patients), which has been shown to reduce the frequency of rash. If rash is observed during this lead-in period, dose escalation and administration of Health 2000 Lamivudine 150 mg, Stavudine 40 mg and Nevirapine 200mg Tablets should not occur until the rash has resolved (See Dosage and Administration).
Severe or life-threatening hepatotoxicity, including fatal fulminant hepatitis (transaminase elevations, with or without hyperbilirubinemia, prolonged partial thromboplastin time, or eosinophilia), has occurred in patients treated with nevirapine. Some of these cases began in the first few weeks of therapy, and some were accompanied by rash. Nevirapine administration should be interrupted in patients experiencing moderate or severe ALT or AST abnormalities until these return to baseline values. Nevirapine should be permanently discontinued if liver function abnormalities recur upon readministration. Monitoring of ALT and AST is strongly recommended, especially during the first six months of nevirapine treatment. (See Side Effects, Dosage and Administration).

Drug Interactions
Trimethoprim 160 mg/sulphamethoxazole 800 mg once daily has been shown to increase lamivudine exposure (AUC).

Nevirapine
The induction of CYP3A by nevirapine may result in lower plasma concentrations of other concomitantly administered drugs that are extensively metabolized by CYP3A. Thus, if a patient has been stabilized on a dosage regimen for a drug metabolized by CYP3A, and begins treatment with nevirapine, dose adjustments may be necessary.
Rifampin/Rifabutin: There are insufficient data to assess whether dose adjustments are necessary when nevirapine and rifampin or rifabutin are coadministered. Therefore, these drugs should only be used in combination if clearly indicated and with careful monitoring.

Ketoconazole: Nevirapine and ketoconazole should not be administered concomitantly. Coadministration of nevirapine and ketoconazole results in a significant reduction in ketoconazole plasma concentrations.

Oral Contraceptives: There are no clinical data on the effects of nevirapine on the pharmacokinetics of oral contraceptives. Nevirapine may decrease plasma concentrations of oral contraceptives (also other hormonal contraceptives); therefore, these drugs should not be administered concomitantly with nevirapine.

Methadone: Based on the known metabolism of methadone, nevirapine may decrease plasma concentrations of methadone by increasing its hepatic metabolism. Narcotic withdrawal syndrome has been reported in patients treated with nevirapine and methadone concomitantly. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly.

Impaired renal function
Reduction of the dosage of both stavudine and lamivudine is required in patients with a creatinine clearance of 50 ml/min or less. Hence, Health 2000 Lamivudine 150 mg, Stavudine 40 mg and Nevirapine 200mg Tablets cannot be used in this patient population. There are no data available on dosage in patients with renal insufficiency or undergoing dialysis.

Pregnancy
Lamivudine, stavudine and nevirapine are all classified under category C. There are no adequate and well-controlled studies in pregnant women. Health 2000 Lamivudine 150 mg, Stavudine 40 mg and Nevirapine 200mg Tablets should be used during pregnancy only if the potential benefits outweigh the potential risk.

Lactation
It is recommended that HIV-infected mothers do not breast-feed their infants to avoid risking postnatal transmission of HIV infection. It is not known whether stavudine or lamivudine are excreted in human milk. Nevirapine is present in breast milk.

Paediatrics
Health 2000 Lamivudine 150 mg, Stavudine 40 mg and Nevirapine 200mg Tablets is not intended for use in paediatric patients.
(v) SIDE EFFECTS

Lamivudine
Pancreatitis has been reported with the use of lamivudine.
Lactic acidosis and hepatic steatosis, hepatitis and liver failure have been reported with the use of antiretroviral nucleoside analogs, alone or in combination.
Other side effects associated with the use of lamivudine are diarrhea, malaise and fatigue, headache, nausea and vomiting, abdominal pain and discomfort, peripheral neuropathy, arthralgias, myalgias, skin rash, pruritus, transient neutropenia and thrombocytopenia and rarely, pancreatitis. Transiently elevated levels of hepatic enzymes and bilirubin (> 5 times the normal level) have also been observed occasionally during treatment with the drug. Resolution of transient neutropenia and raised hepatic and bilirubin levels occurred without dosage modification or discontinuation of therapy.

Stavudine
Therapy with stavudine can be associated with severe peripheral neuropathy, which is dose related and occurs more frequently in patients with advanced HIV infection or who have previously experienced peripheral neuropathy.
Lactic acidosis and hepatic steatosis, hepatitis and liver failure have been reported with the use of antiretroviral nucleoside analogues, alone or in combination.
Rash, diarrhoea, nausea/vomiting, pancreatitis, dementia and other peripheral neurologic symptoms have also been associated with the use of stavudine.

Nevirapine
The most clinically important adverse events associated with nevirapine therapy are rash and increases in liver function tests. Cases of hypersensitivity reactions have been observed.

The major clinical toxicity of nevirapine is rash, with nevirapine-attributable rash occurring in 16% of patients in combination regimens in Phase II/III controlled studies. Thirty-five percent of patients treated with nevirapine experienced rash compared with 19% of patients treated in control groups of either zidovudine + didanosine or zidovudine alone. Severe or life-threatening rash occurred in 6.6% of nevirapine-treated patients compared with 1.3% of patients treated in the control groups.

Rashes are usually mild to moderate, maculopapular erythematous cutaneous eruptions; with or without pruritus, located on the trunk, face and extremities. The majority of severe rashes occurred within the first 28 days of treatment. 25% of the patients with severe rashes required hospitalization, and one patient required surgical intervention. Overall, 7% of patients discontinued nevirapine due to rash.

With respect to laboratory abnormalities, asymptomatic elevations in GGT levels are more frequent in nevirapine recipients than in controls. Because clinical hepatitis has been reported in nevirapine-treated patients, monitoring of ALT (SGPT) and AST (SGOT) is strongly recommended, especially during the first six months of nevirapine treatment (See Warnings and Precautions). Decreased neutrophils (< 750/mm3), platelets (< 50,000/mm3) and Hb (< 8.0 g/dL), and increased total bilirubin (> 2.5 mg/dL) have also been reported.

(vi) TOXIC EFFECTS:

CARCINOGENICITY

Lamivudine: Lamivudine long-term carcinogenicity studies in mice and rats showed no evidence of carcinogenic potential at exposures up to 10 times (mice) and 58 times (rats) those observed in humans at the recommended therapeutic dose.

Stavudine:There are no data on the carcinogenicity of stavudine. In in vitro assay there was an increase in the frequency of transformed foci in mouse fibroblast cells, with and without metabolic activation. Another nucleoside analogue reverse transcriptase inhibitor causes vaginal neoplasms at high doses in mice and rats.

Nevirapine:In carcinogenicity studies, nevirapine increased the incidence of liver tumours in mice (at doses up to 750 mg/kg/day) and rats (at doses up to 35 mg/kg/day). However, these findings are most likely related to nevirapine being a strong inducer of liver enzymes, and not due to a genotoxic mode of action.

MUTAGENICITY

Lamivudine: Lamivudine was negative in a microbial mutagenicity screen, in an in vitro cell transformation assay, in a rat micronucleus test, in a rat bone marrow cytogenetic assay, and in an assay for unscheduled DNA synthesis in rat liver. It was mutagenic in a L5178Y/TK+/- mouse lymphoma assay and clastogenic in acytogenetic assay using cultured human lymphocytes.
Stavudine: Stavudine was not mutagenic in the Ames, E. coli reverse mutation, or the CHO/HGPRT mammalian cell forward gene mutation assays, with and without metabolic activation. Stavudine increased the frequency of chromosome aberrations in human lymphocytes without metabolic activation. In vivo micronucleus assay showed clastogenic activity in bone marrow cells following stavudine administration to mice at dosages of 600 to 2,000 mg/kg/day for 3 days.
Fertility was not impaired in rats with exposures (based on Cmax) up to 216 times that observed at 1mg/kg/day, the approximate clinical dosage.

Nevirapine :In genetic toxicology assays, nevirapine showed no evidence of mutagenic or clastogenic activity in a battery of in vitro and in vivo assays including microbial assays for gene mutation (Ames: Salmonella strains and E.coli), mammalian cell gene mutation assays (CHO/HGPRT), cytogenic assays using Chinese hamster ovary cell line and a mouse bone marrow micronucleus assay following oral administration. In reproductive toxicology studies, evidence of impaired fertility was seen in female rats at doses providing systemic exposure, based on AUC, approximately equivalent to that provided with recommended clinical dose of Nevirapine.

TERATOGENECITY

Lamivudine:Reproduction studies have been performed in rats and rabbits at orally administered doses up to approximately 130 and 60 times, respectively, the usual adult dose and have revealed no evidence of harm to the fetus due to lamivudine. Some evidence of early embryolethality was seen in the rabbit at doses similar to those produced by the usual adult dose and higher, but there was no indication of this effect in the rat at orally administered doses up to 130 times the usual adult dose. Studies in pregnant rats and rabbits showed that lamivudine is transferred to the fetus through the placenta. There are no adequate and well controlled studies in pregnant women. Because animal reproductive toxicity studies are not always predictive of human response, lamivudine should be used during pregnancy only if the potential benefits outweigh the risks.

Stavudine:Reproduction studies have been performed in rats and rabbits with exposures ( based on Cmax ) up to 399 and 183 times, respectively, of that seen at a clinical dosage of 1 mg/kg/day and have revealed no evidence or teratogenecity. The incidence in fetuses of a common skeletal variation, unossified or incomplete ossification of sternebra, was increased in rats at 399 times human exposure.A slight post-implantation loss was noted at 216 times the human exposure with no effect noted at approximately 135 times the human exposure.An increase in early rat neonatal mortality
( birth to 4 days of age ) occurred at 399 times the human exposure. A study in rat showed that stavudine is transferred to the fetus through the placenta. The concentration in fetal tissue was approximately one half the concentration in maternal plasma. There are no adequate and well controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response,stavudine should be used during pregnancy only if clearly needed.

Nevirapine :No observable tetratogenicity was detected in reproductive studies performed in pregnant rats and rabbits. In rats, a significant decrease in fetal body weight occurred at doses providing systemic exposure approximately 50% higher, based on AUC, than that seen at the recommended human clinical dose. The maternal and developmental no-observable effect level dosage in rats and rabbits produced systemic exposures approximately equivalent to or approximately 50% higher, respectively, than those seen at the recommended daily human dose, based on AUC. There are no adequate and well controlled studies in pregnant women. Nevirapine should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.