Prescribing Information:

For the use of a Registered Medical Practitioner or Hospital or Laboratory only


Lamivudine, Stavudine & Nevirapine Dispersible Tablet Composition:

EMTRI JUNIOR
Each uncoated dispersible tablet contains:
Stavudine IP - 10 mg
Lamivudine IP - 40 mg
Nevirapine IP - 70 mg

Description:

This FDC contains the nucleoside reverse transcriptase inhibitors Lamivudine and Stavudine and the non-nucleoside reverse transcriptase inhibitor Nevirapine.

  • Chemically Lamivudine it is (2R,cis)-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one with molecular formula of C8H11N3O3S & molecular weight of 229.3.
  • Chemically Stavudine is 2’, 3’-didehydro-3’-deoxythymidine with molecular formula C10H12N2O4 & molecular weight of 224.2.
  • Chemically Nevirapine is 11-cyclopropyl-5, 11-dihydro-4-methyl-6H-dipyrido [3, 2-b: 2’, 3’-] [1, 4] diazepin-6-one with molecular formula of C15H14N4O and molecular weight: 266.3.

Clinical Pharmacology:

Mechanism of Action:

Lamivudine is a synthetic nucleoside analogue. Intracellularly, Lamivudine is phosphorylated to its active 5’-triphosphate metabolite (L-TP). The principal mode of action of L-TP is inhibition of HIV reverse transcription via viral DNA chain termination. L-TP also inhibits the RNA-and DNA-dependent DNA polymerase activities of reverse transcriptase (RI). Stavudine, a nucleoside analogue of thymidine, inhibits the replication of HIV. It is phosphorylated by cellular kinases to the active metabolite Stavudine triphosphate. Stavudine triphosphate inhibits the activity of HIV reverse transcriptase by two mechanisms: firstly by competing with the natural substrate deoxythymidine triphosphate and secondly by its incorporation into viral DNA causing a termination of DNA chain elongation because Stavudine lacks the essential 3’-OH group. Stavudine triphosphate inhibits cellular DNA polymerase beta and gamma, and markedly reduces the synthesis of mitochondrial DNA.

Nevirapine is a non-nucleoside reverse transcriptase inhibitor (NNRTI) of HIV-1. Nevirapine binds directly to reverse transcriptase (RT) and blocks the RNA-dependent and DNA-dependent DNA polymerase activities by causing a disruption of the enzyme's catalytic site.


Pharmacokinetics:

Lamivudine: Oral absorption is rapid, with a mean absolute bioavailability of 82-87%. Food has no significant effect on systemic exposure to Lamivudine. Plasma protein binding is <36%. Intracellularly, Lamivudine is phosphorylated to its active 5'-triphosphate metabolite (L-TP), which has an intracellular half-life of 10.5—15.5 hours. Hepatic metabolism is a minor route of elimination for Lamivudine; most of an oral dose of Lamivudine (70-71%) is excreted unchanged in the urine. The only known metabolite of Lamivudine in humans is the trans-sulfoxide metabolite, which accounts for less than 5% of a dose appearing in the urine. The mean elimination half-life after a single dose of Lamivudine ranges 5-7 hours.

Stavudine: Stavudine is rapidly absorbed with an oral bioavailability of 77 to 86%. It may be taken with food or on an empty stomach. It reaches a Cmax of approximately 1.4 µg/ml (6.2 µmoles/l) after a single oral dose of 70mg after 0.5 - 1.5 hrs. Approximately 40% of the drug is excreted unchanged in the urine in 6 - 24 hours. Protein binding of Stavudine is negligible. It is phosphorylated intracellularly to Stavudine triphosphate, the active substance for HIV-reverse transcriptase inhibition. In case of normal renal function, the half-life of the drug in adults ranges from 1 - 1.6 hours. In subjects with impaired renal function (Creatinine Clearance <25mL/min [<0.42 ml/sec]) the half-life is approximately 4.8 hours. Approximately 50% of the administered dose undergoes non-renal elimination. Although the exact metabolic fate is unknown, Stavudine may be cleaved to thymine, and the subsequent degradation and/or utilization of thymine may account for the unrecovered Stavudine.

Nevirapine: It is readily absorbed after oral administration. Bioavailability is greater than 90%. It reaches a Cmax of 2 µg/ml after 4 hours following a single 200mg dose. Nevirapine may be administered with or without food. The volume of distribution of Nevirapine is 1.2 l/kg. It is highly lipophillic and widely distributed. The drug readily crosses the placenta and is excreted in breast milk. It is approximately 60% protein bound. Metabolism of Nevirapine to hydroxylated metabolites occurs primarily via the cytochrome P450 (CYP) 3A family of hepatic enzymes. Its half-life is approximately 45 hours after single dose, and 25 to 30 hours following multiple dosing with 200 to 400 mg per day. About 91% the drug is eliminated in urine, with > 80% of that made up of glucuronide conjugates of hydroxylated metabolites. Less than 5% of the recovered dose consists of the parent drug.


Indication:

Management of Human Immunodeficiency Virus (HIV) infection.


Dosage And Administration:

For children aged 3 months to less than 8 years, the dose according to weight will be as per the table below:

Body Weight (Kg)Dose
7.5-12.5 kg 1 tablet twice daily
12.5-17.5 kg 1.5 tablets twice daily
17.5-22.5 kg 2 tablets twice daily
22.5-27.5 kg 2.5 tablets twice daily

Adverse Reactions:

Lactic acidosis, headache, malaise, fatigue, fever, chills, diarrhea, nausea, vomiting, anorexia and/or decreased appetite, peripheral neuropathy, insomnia and other sleep disorders, nasal signs and symptoms, cough, musculoskeletal pain, rash, headache, abnormal liver function tests.


Drug Interactions:

Zidovudine may competitively inhibit the intracellular phosphorylation of Stavudine. Therefore, use of Zidovudine in combination with Stavudine is not recommended. The induction of CYP3A by Nevirapine may result in lower plasma concentrations of other concomitantly administered drugs that are extensively metabolized by CYP3A4. Thus, if a patient has been stabilized on a dosage regimen for a drug metabolized by CYP3A4 and begins treatment with Nevirapine, dose adjustments may be necessary. There are insufficient data to assess whether dose adjustments are necessary when Nevirapine and rifampin or rifabutin are co-administered. Therefore, these drugs should only be used in combination if clearly indicated and with careful monitoring. Co-administration of Nevirapine and Ketoconazole resulted in a significant reduction in Ketoconazole plasma concentrations. Nevirapine may decrease plasma concentrations of oral contraceptives; therefore, these drugs should not be administered concomitantly with Nevirapine.


Warnings And Precautions:

Lamivudine, Stavudine and Nevirapine should be used with caution in patients with hepatic disease or in those with known risk factors for liver disease. Lamivudine should be used with caution in patients with impaired renal function, including renal failure.

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues including Lamivudine, Stavudine alone or in combination with other antiretrovirals. Lamivudine and Stavudine should be used cautiously in patients with known risk factors for liver disease. Lamivudine and Stavudine treatment should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or hepatotoxicity. Some patients with HIV infection who have chronic liver disease due to hepatitis B virus infection may experience recurrent hepatitis upon discontinuation of Lamivudine.

Motor weakness, Peripheral neuropathy, and pancreatitis may occur with Stavudine. 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. Monitoring of hepatic transaminases is strongly recommended during first six months of Nevirapine treatment. Treatment with Nevirapine should be withheld in patients with moderate or severe AST and ALT abnormalities. Severe life-threatening skin reactions have occurred in patients receiving Nevirapine. These include Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity reactions characterized by rash, constitutional findings and organ dysfunction. Nevirapine should be discontinued in patients developing signs or symptoms of severe skin reactions.

An initial lead-in dosing of 4 mg/kg body weight of Nevirapine once daily for 2 weeks is recommended in children. Following this lead-in dose, a dose escalation (maintenance dose) to 7 mg/kg body weight of Nevirapine twice daily in children aged 3 months to <8 years and 4 mg/kg body weight twice daily in children 8 years and above is recommended, in the absence of any hypersensitivity reactions.

The maximum recommended doses of Nevirapine, Lamivudine and Stavudine in children are 400 mg, 300 mg and 60 mg respectively, per day.


Contraindications:

Contraindicated in patients hypersensitive to any of the components of the formulation.


Overdosage:

Experience with adults treated with 12 to 24 times the recommended daily dosage of Stavudine revealed no acute toxicity. Stavudine can be removed by hemodialysis. Whether Stavudine is eliminated by peritoneal dialysis has not been studied. There is no known antidote for Lamivudine and Nevirapine overdosage. It is not known whether Lamivudine can be removed by peritoneal dialysis or hemodialysis. 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.


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