A fixed dose combination of Lamivudine, Zidovudine and Nevirapine is recommended for HIV-1 infected patients who are able to tolerate maintenance therapy with Nevirapine 200 mg twice daily. All three drugs are to be administered twice daily, and each tablet contains half of the daily dose for each component. The twice-daily formulation as a single tablet for three drugs is convenient for patients to take, ensuring a higher rate of compliance.

Lamivudine, Zidovudine & Nevirapine synergistically reduce viral resistance and inhibit reverse transcriptase via DNA chain termination.

Lamivudine: Intracellularly, Lamivudine is phosphorylated to its active 5'-triphosphate metabolite, Lamivudine triphosphate (L-TP). The principal mode of action of L-TP is inhibition of reverse transcription (RT) via DNA chain termination after incorporation of the nucleoside analogue. Following oral administration, Lamivudine is rapidly absorbed and extensively distributed. Binding to plasma protein is low.

Zidovudine: Intracellularly, Zidovudine is phosphorylated to its active 5'-triphosphate metabolite, Zidovudine triphosphate (ZDV-TP). The principal mode of action of ZDV-TP is inhibition of RT via DNA chain termination after incorporation of the nucleoside analogue. Following oral administration, Zidovudine is rapidly absorbed and extensively distributed. Binding to plasma protein is low. Zidovudine is eliminated primarily by hepatic metabolism.

Nevirapine: 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. The activity of nevirapine does not compete with template or nucleoside triphosphates.

Adult dose: One tablet twice daily. This fixed dose combination is not recommended for patients who have not been on initial lower dose of Nevirapine 200 mg once daily for 2 weeks and /or have not tolerated this dose. After successful therapy with low dose Nevirapine for two weeks, patients can be switched over to 200 mg bid dose provided they have not demonstrated any hypersensitivity reaction (rash, abnormal liver function tests) during their initial exposure to Nevirapine. Monitoring of patients for their liver function tests etc. is desirable prior to initiating therapy with Nevirapine and monitoring at frequent intervals once therapy with fixed dose combination is continued.

Dosage adjustment-

• Lamivudine: For patients with low body weight (<50 kg) where dosage adjustment may be required, it is preferable not to use this fixed dose combination.
• Zidovudine: Because it is a fixed dose combination, this should not be prescribed for patients requiring dosage adjustment such as those with reduced renal function (creatinine clearance 50 ml/min) or those experiencing dose imiting adverse events.
• Nevirapine: For patients who experience severe rash or rash with constitutional complaints during the initial low dose Nevirapine phase of 14 days with once daily dose of 200 mg; neither, dose should be increased to twice daily nor they should receive triple fixed dose combination until the rash is resolved. Similarly for patients with abnormal liver function tests, Nevirapine therapy should be stopped till liver function return to normal and careful restart is advisable after extended observation. In event of recurrence, Nevirapine therapy can not be restarted.
• For patients where Nevirapine therapy has to be restarted after an interruption, daily dose of Nevirapine 200 mg for 14 days should be followed with twice daily dose in absence of any hypersensitivity reaction. Studies have not been documented to suggest dosage of Nevirapine in patients with hepatic dysfunction, renal insufficiency or undergoing dialysis.

Zidovudine: Acyclovir and valacyclovir may increase CNS depression. Increased risk of hematologic toxicity with ganciclovir, valganciclovir, dapsone, doxorubicin, vincristine, and vinblastine. Doxorubicin may reduce phosphorylation; fluconazole may increase levels/effects; increased risk of hepatic decompensation or hematologic toxicities with interferon and ribavirin (also increases risk of pancreatitis and lactic acidosis). Methadone may increase effects/levels. Increased risk of myalgia, malaise and/or fever, maculopapular rash, and effects/levels with probenecid. Stavudine may decrease antiviral activity; valproic acid may increase plasma levels (AUC increased by 80%).

Lamivudine: Increased risk of hepatic decompensation or hematologic toxicities with interferon and ribavirin (also increases risk of mitochondrial toxicity, pancreatitis, and lactic acidosis). Ganciclovir and valganciclovir may increase effects and toxicity; sulfamethoxazole/trimethoprim may increase AUC and decrease clearance (increasing levels and effects).

History of hypersensitivity to Lamivudine, Zidovudine, Nevirapine, or to any of the excipients available in the formulation. Not to be used as initial therapy because initial therapy requires 200 mg once daily of Nevirapine, whereas the fixed-dose combination allows for 200 mg twice daily of Nevirapine.

Lamivudine: Pancreatitis, paresthesia, peripheral neuropathy, cough, dizziness, fatigue, gastrointestinal problems, headache, insomnia, anemia, neutropenia, drug-induced skin rash, hair loss.

Zidovudine: Headache (which may be severe, reported in up to 63% of patients receiving Zidovudine) and asthenia (reported in 9-69%), malaise and fatigue, fever or chills, nausea (61% of cases), diaphoresis, dyspnea, rash, and taste perversion have been reported. Skin rashes and myalgia have been reported in patients receiving Zidovudine. Myopathy and myositis with pathologic changes similar to those produced by HIV infection have been associated with prolonged use of Zidovudine. The major adverse effect is bone marrow toxicity resulting in severe anemia and/or neutropenia. Patients with low serum folate or vitamin B12 concentrations may be at increased risk for developing bone marrow toxicity during Zidovudine therapy. There are also limited data suggesting that the bone marrow of patients with fulminant acquired immunodeficiency syndrome (AIDS) may be more sensitive to Zidovudine-induced toxicity than that of patients with less advanced disease (e.g., AIDS-related complex). Anemia and granulocytopenia usually resolve when Zidovudine is discontinued or when the dosage is decreased. Lactic acidosis (in the absence of hypoxemia) and severe hepatomegaly with steatosis, including some fatalities, have been reported in patients receiving Zidovudine.

Nevirapine: More frequent incidences are skin rash, diarrhea, gastrointestinal problems, headache, nausea, and stomach pain. Less frequent incidences include aphthous stomatitis, fever, hepatitis, and Stevens-Johnson syndrome.

Pregnancy Category C. Animal reproduction studies have shown an adverse effect on the fetus, and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

For the following conditions, assess risk to the patient and take action as needed: chronic hepatitis B, hepatomegaly with steatosis, lactic acidosis, liver function impairment, severe renal function impairment, peripheral neuropathy.

Drugs for HIV / Anti-retroviral drugs

Should be stored in a cool and dry place.