This FDC contains the nucleoside reverse transcriptase inhibitors Lamivudine and Stavudine and the non-nucleoside reverse transcriptase inhibitor Nevirapine.
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.
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.
Management of Human Immunodeficiency Virus (HIV) infection.
|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|
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.
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.
The maximum recommended doses of Nevirapine, Lamivudine and Stavudine in children are 400 mg, 300 mg and 60 mg respectively, per day.
Contraindicated in patients hypersensitive to any of the components of the formulation.
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.