Composition:
Each tablet contains:
Stavudine 30 mg
Lamivudine 150 mg
Nevirapine 200 mg

Pharmacology:
STV Comp - 30 is a combination of three drugs commonly used in the management of Human Immunodeficiency Virus (HIV) infection. Stavudine, Nevirapine and lamivudine belong to the nucleoside analogue class of antiretroviral drugs. These drugs act by inhibiting the reverse transcriptase of HIV, and by terminating the growth of the DNA chain. Stavudine in combination with lamivudine & Nevirapine has been shown to have synergistic antiretroviral activity. Each tablet of STV Comp – 30 contains half of the commonly prescribed daily doses of stavudine, Nevirapine and lamivudine. With the availability of this combination tablet patients may be better able to adhere to complex drug treatment regimens, thereby enhancing compliance.

Pharmacokinetics:
Lamivudine:
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/hr•kg (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/hr•kg (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.

Stavudine:
The pharmacokinetics of stavudine have been evaluated in HIV-infected adult and pediatric patients. Peak plasma concentrations (Cmax) and area under the plasma concentration-time curve (AUC) increased in proportion to dose after both single and multiple doses ranging from 0.03 to 4 mg/kg. There was no significant accumulation of stavudine with repeated administration every 6, 8, or 12 hours.

Absorption: Following oral administration, stavudine is rapidly absorbed, with peak plasma concentrations occurring within 1 hour after dosing. The systemic exposure to stavudine is the same following administration as capsules or solution.
Distribution: Binding of stavudine to serum proteins was negligible over the concentration range of 0.01 to 11.4 μg/mL.
Stavudine distributes equally between red blood cells and plasma.
Metabolism: The metabolic fate of stavudine has not been elucidated in humans. Excretion- Renal elimination accounted for about 40% of the overall clearance regardless of the route of administration. The mean renal clearance was about twice the average endogenous creatinine clearance, indicating active tubular secretion in addition to glomerular filtration. Nevirapine

Absorption: Nevirapine is readily absorbed (>90%) after oral administration in healthy volunteers and in adults with HIV-1 infection. Peak plasma nevirapine concentrations of 2 ± 0.4 mc g/mL (7.5 mc M) were attained by 4 hours following a single 200 mg dose. Following multiple doses, nevirapine peak concentrations appear to increase linearly in the dose range of 200 to 400 mg/day. Steady state trough nevirapine concentrations of 4.5 ± 1.9 mc g/mL (17 ± 7 mc M), (n = 242) were attained at 400 mg/day. When Nevirapine (200 mg) was administered to 24 healthy adults (12 female, 12 male), with either a high fat breakfast (857 kcal, 50 g fat, 53% of calories from fat) or antacid (Maalox® 30 mL), the extent of nevirapine absorption (AUC) was comparable to that observed under fasting conditions. In a separate study in HIV-1-infected patients (n=6), nevirapine steady-state systemic exposure (AUCt ) was not significantly altered by ddI, which is formulated with an alkaline buffering agent. Nevirapine may be administered with or without food, antacid or ddI.

Distribution: Nevirapine is highly lipophilic and is essentially nonionized at physiologic pH. Following intravenous administration to healthy adults, the apparent volume of distribution (Vdss) of nevirapine was 1.21 ± 0.09 L/kg, suggesting that nevirapine is widely distributed in humans. Nevirapine readily crosses the placenta and is found in breast milk. Nevirapine is about 60% bound to plasma proteins in the plasma concentration range of 1-10 mc g/mL. Nevirapine concentrations in human cerebrospinal fluid (n=6) were 45% (± 5%) of the concentrations in plasma; this ratio is approximately equal to the fraction not bound to plasma protein.

Metabolism/Elimination: In vivo studies in humans and in vitro studies with human liver microsomes have shown that nevirapine is extensively biotransformed via cytochrome P450 (oxidative) metabolism to several hydroxylated metabolites. In vitro studies with human liver microsomes suggest that oxidative metabolism of nevirapine is mediated primarily by cytochrome P450 isozymes from the CYP3A family, although other isozymes may have a secondary role. In a mass balance/excretion study in eight healthy male volunteers dosed to steady state with nevirapine 200 mg given twice daily followed by a single 50 mg dose of 14C-nevirapine, approximately 91.4 ± 10.5% of the radiolabeled dose was recovered, with urine (81.3 ± 11.1%) representing the primary route of excretion compared to feces (10.1 ± 1.5%).

Greater than 80% of the radioactivity in urine was made up of glucuronide conjugates of hydroxylated metabolites. Thus cytochrome P450 metabolism, glucuronide conjugation, and urinary excretion of glucuronidated metabolites represent the primary route of nevirapine biotransformation and elimination in humans. Only a small fraction (<5%) of the radioactivity in urine (representing <3% of the total dose) was made up of parent compound; therefore, renal excretion plays a minor role in elimination of the parent compound. Nevirapine has been shown to be an inducer of hepatic cytochrome P450 metabolic enzymes. The pharmacokinetics of autoinduction are characterized by an approximately 1.5 to 2 fold increase in the apparent oral clearance of nevirapine as treatment continues from a single dose to two-to-four weeks of dosing with 200 - 400 mg/day. Autoinduction also results in a corresponding decrease in the terminal phase half-life of nevirapine in plasma from approximately 45 hours (single dose) to approximately 25-30 hours following multiple dosing with 200 - 400 mg/day.

Indications:
Lamivudine + Stavudine + Nevirapine is indicated for the treatment of HIV infection.

Contra-indications:
Lamivudine + Stavudine + Nevirapine Tablets is contraindicated in patients with clinically significant hypersensitivity to the active substance or to any of the excipients.

Dosage and directions for use:
1 tablet twice daily for patients weighing > 60 kg Dose Adjustment: Because it is a fixed-dose combination, it should not be prescribed for patients requiring dosage adjustment, such as those with reduced renal function (creatinine clearance < 50 ml/min), those with low body weight (< 50 kg or 110 lbs), or those experiencing dose-limiting adverse events.

Warning:
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, Nevirapine 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 aminotransferase elevations).

PERIPHERAL NEUROPATHY
Stavudine therapy can be associated with severe peripheral neuropathy, which is dose-related. It has occurred more frequently in patients with advanced HIV infection, a history of neuropathy, or concurrent neurotoxic drug therapy, including didanosine. 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 with stavudine 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

IMPAIRED RENAL FUNCTION
Reduction of the dosage of stavudine, Nevirapine and lamivudine is required in patients with a creatinine clearance of 50 ml/min or less. Hence, it cannot be used in this patient population.

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.

Side-effects & special precautions:
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
Rash, usually within first six weeks of therapy. D/C drug for severe rash or rash accompanied by other symptoms; Stevens-Johnson syndrome has occurred. Fever, headache, nausea, diarrhea, abdominal pain, thrombocytopenia, anemia, leukopenia, ulcerative stomatitis, hepatitis, peripheral neuropathy, paresthesia, or myalgia may also occur. Grenulocytopenia has been more commonly observed in children. The safety profile of nevirapine in neonates has not been established.

Special precautions:
PREGNANCY
Lamivudine, nevirapine and stavudine are classified under category C. There are no adequate and well-controlled studies in pregnant women. Lamivudine, nevirapine and Stavudine 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, nevirapine or lamivudine are excreted in human milk.

PAEDIATRICS
Lamivudine, nevirapine and Stavudine are not intended for use in paediatric patients.

Drug Interaction:
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.

RifampinlRifabutin: 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.

Known symptoms of overdosage and particulars of its treatment:
Lamivudine
There is no known antidote for lamivudine. It is not known whether lamivudine can be removed by peritoneal dialysis or hemodialysis.

Stavudine
Stavudine can be removed by hemodialysis. Experience with adults treated with 12 to 24 times the recommended daily dosage revealed no acute toxicity. Complications of chronic overdosage include peripheral neuropathy and hepatic toxicity.

Nevirapine
There is no known antidote for nevirapine overdosage. Cases of nevirapine overdose at doses ranging from 800 to 1800 mg per day for up to 15 days have been reported. Patients have experienced events including edema, erythema nodosum, fatigue, fever, headache, insomnia, nausea, pulmonary infiltrates, rash, vertigo, vomiting and weight decrease. All events subsided following discontinuation of nevirapine.

Storage conditions:
Store in cool, dry & dark place, preferably below 25°C.

Shelf life:
2 years.

Presentation:
HDPE Bottle pack of 1x60’s