STV PLUS TABLETS

(Stavudine & Lamivudine Tablets)

Composition:
Each tablet contains:
Stavudine 40mg
Lamivudine 150mg

Presentation:
10x10's

Pharmacology:
STV PLUS is a combination of two drugs commonly used in the management of Human Immunodeficiency Virus (HIV) infection. Both stavudine and lamivudine belong to the nucleoside analogue class of antiretroviral drugs. Both drugs act by inhibiting the reverse transcriptase of HIV, and by terminating the growth of the DNA chain. Stavudine in combination with lamivudine has been shown to have synergistic antiretroviral activity.
Each tablet of STV PLUS contains half of the commonly prescribed daily doses of both stavudine 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/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.

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.

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

Contra-indications:
Lamivudine + Stavudine 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 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 both stavudine 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.

Special precautions:

PREGNANCY
Both lamivudine and stavudine are classified under category C. There are no adequate and well-controlled studies in pregnant women. Lamivudine 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 or lamivudine are excreted in human milk.

PAEDIATRICS
Lamivudine and Stavudine is 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).

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

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.