Lamivudine, Zidovudine And Nevirapine

Lamivudine, Zidovudine And Nevirapine Uses, Dosage, Side Effects, Food Interaction and all others data.

Lamivudine, Zidovudine & Nevirapine synergistically reduce the 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.

Trade Name Lamivudine, Zidovudine And Nevirapine
Generic Lamivudine + Zidovudine + Nevirapine
Weight 150mg, 300mg, 200mg
Type Tablet
Therapeutic Class Drugs for HIV / Anti-retroviral drugs
Manufacturer Cipla Limited
Available Country India, Nigeria
Last Updated: September 19, 2023 at 7:00 am
Lamivudine, Zidovudine And Nevirapine
Lamivudine, Zidovudine And Nevirapine

Uses

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. Twice daily formulation in single tablet for three drugs is convenient for patients to take, ensuring higher rate of compliance.

Lamivudine, Zidovudine And Nevirapine is also used to associated treatment for these conditions: Hepatitis B Chronic Infection, Human Immunodeficiency Virus (HIV) InfectionsHuman Immunodeficiency Virus (HIV) InfectionsHIV Transmission, Human Immunodeficiency Virus (HIV) Infections, Perinatal HIV transmission

How Lamivudine, Zidovudine And Nevirapine works

Lamivudine is a synthetic nucleoside analogue and is phosphorylated intracellularly to its active 5'-triphosphate metabolite, lamivudine triphosphate (L-TP). This nucleoside analogue is incorporated into viral DNA by HIV reverse transcriptase and HBV polymerase, resulting in DNA chain termination.

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.

Zidovudine, a structural analog of thymidine, is a prodrug that must be phosphorylated to its active 5′-triphosphate metabolite, zidovudine triphosphate (ZDV-TP). It inhibits the activity of HIV-1 reverse transcriptase (RT) via DNA chain termination after incorporation of the nucleotide analogue. It competes with the natural substrate dGTP and incorporates itself into viral DNA. It is also a weak inhibitor of cellular DNA polymerase α and γ.

Dosage

Lamivudine, Zidovudine And Nevirapine dosage

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.

May be taken with or without food.

Side Effects

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

Zidovudine: Headache (which may be severe, has been reported in up to 63% of patients receiving Zidovudine and asthenia has been reported in 9-69%), malaise and fatigue, fever or chills, nausea (61% cases), diaphoresis, dyspnoea, rash and taste perversion have been reported. Skin rashes and myalgia has been reported in patients receiving Zidovudine. Myopathy and myositis with pathologic changes similar to that produced by HIV infection, have been associated with prolonged use of Zidovudine. The major adverse effect is bone marrow toxicity resulting in severe anaemia 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 also are limited data suggesting that 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 (eg, AIDS related complex). Anaemia and granulocytopenia usually resolve when Zidovudine is discontinued or when dosage is decreased. Lactic acidosis (in the absence of hypoxaemia) and severe hepatomegaly with steatosis, including some fatalities, have been reported in patients receiving Zidovudine.

Nevirapine: More frequent incidences are skin rash, diarrhoea, gastrointestinal problems, headache, nausea and stomach pain. Incidence of less frequents are aphthous stomatitis, fever, hepatitis and Stevens Johnson syndrome.

Toxicity

The most common reported adverse reactions (incidence ≥15%) in adults were headache, nausea, malaise and fatigue, nasal signs and symptoms, diarrhea, and cough.

Symptoms of overdose include edema, erythema nodosum, fatigue, fever, headache, insomnia, nausea, pulmonaryinfiltrates, rash, vertigo, vomiting, and weight decrease. The most common adverse reaction is rash.

Symptoms of overdose include fatigue, headache, nausea, and vomiting. LD50 is 3084 mg/kg (orally in mice).

Precaution

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

Interaction

Zidovudine: acyclovir and valacyclovir may increase CNS depression. Increased risk of haematologic toxicity with ganciclovir, valganciclovir, dapsone, doxorubicin, vincristine and vinblastine. Doxorubicin may reduce phophorylation; fluconazole may increase levels/effects; increased risk of hepatic decompensation or haematologic 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 haematologic 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).

Volume of Distribution

Apparent volume of distribution, IV administration = 1.3 ± 0.4 L/kg. Volume of distribution was independent of dose and did not correlate with body weight.

  • 1.21 ± 0.09 L/kg [apparent volume of distribution, healthy adults, IV] Nevirapine is capable of crossing the placenta and is found in breast milk.

Apparent volume of distribution, HIV-infected patients, IV administration = 1.6 ± 0.6 L/kg

Elimination Route

Lamivudine was rapidly absorbed after oral administration in HIV-infected patients. Absolute bioavailability in 12 adult patients was 86% ± 16% (mean ± SD) for the 150-mg tablet and 87% ± 13% for the oral solution. The peak serum lamivudine concentration (Cmax) was 1.5 ± 0.5 mcg/mL when an oral dose of 2 mg/kg twice a day was given to HIV-1 patients. When given with food, absorption is slower, compared to the fasted state.

Nevirapine is readily absorbed (greater than 90%) after oral administration in healthy subjects and adults with HIV-1 infection. The absolute bioavailability in healthy adults following a single dose administration is 93 ± 9% (mean ± SD) for a 50 mg tablet and 91 ± 8% for an oral solution. Peak plasma nevirapine concentrations of 2 ± 0.4 mcg/mL (7.5 micromolar) were attained by 4 hours following a single 200 mg dose. Nevirapine tablets and suspension have been shown to be comparably bioavailable and interchangeable at doses up to 200 mg. When the oral tablet is given with a high-fat meal, the extent of absorption is compared to that of the fasted-state.

Rapid and nearly complete absorption from the gastrointestinal tract following oral administration; however, because of first-pass metabolism, systemic bioavailability of zidovudine capsules and solution is approximately 65% (range, 52 to 75%). Bioavailability in neonates up to 14 days of age is approximately 89%, and it decreases to approximately 61% and 65% in neonates over 14 days of age and children 3 months to 12 years, respectively. Administration with a high-fat meal may decrease the rate and extent of absorption.

Half Life

5 to 7 hours (healthy or HBV-infected patients)

45 hours

Elimination half life, HIV-infected patients, IV administration = 1.1 hours (range of 0.5 - 2.9 hours)

Clearance

  • Renal clearance = 199.7 ± 56.9 mL/min [300 mg oral dose, healthy subjects]
  • Renal clearance = 280.4 ± 75.2 mL/min [single IV dose, HIV-1-infected patients]
  • Total clearance = 398.5 ± 69.1 mL/min [HIV-1-infected patients]
  • 0.65 +/- 0.29 L/hr/kg [HIV-infected, Birth to 14 Days of Age]
  • 1.14 +/- 0.24 L/hr/kg [HIV-infected, 14 Days to 3 Months of Age]
  • 1.85 +/- 0.47 L/hr/kg [HIV-infected, 3 Months to 12 Years of Age]. The transporters, ABCB1, ABCC4, ABCC5, and ABCG2 are involved with the clearance of zidovudine.

Elimination Route

The majority of lamivudine is eliminated unchanged in urine by active organic cationic secretion. 5.2% ± 1.4% (mean ± SD) of the dose was excreted as the trans-sulfoxide metabolite in the urine. Lamivudine is excreted in human breast milk and into the milk of lactating rats.

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.

As in adult patients, the major route of elimination was by metabolism to GZDV. After intravenous dosing, about 29% of the dose was excreted in the urine unchanged and about 45% of the dose was excreted as GZDV.

Pregnancy & Breastfeeding use

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

Contraindication

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

Special Warning

It is recommended that doses of Lamivudine should be adjusted in accordance with renal function. Dosage adjustment of Lamivudine in accordance with creatinine clearance is as follows:

  • CrCl 50 ml/min: 100 mg once daily
  • CrCl 30-49 ml/min: 100 mg first dose, then 50 mg once daily
  • CrCl 15-29 ml/min: 100 mg first dose, then 25 mg once daily
  • CrCl 5-14 ml/min: 35 mg first dose, then 15 mg once daily
  • CrCl <5 ml/min: 35 mg first dose, then 10 mg once daily

Use in children: Safety and efficacy of lamivudine for the treatment of chronic hepatitis B in children have not been established.

Pediatric Use: The safety, pharmacokinetic profile, and virologic and immunologic responses of Nevirapine have been evaluated in HIV-1 infected pediatric subjects age 3 months to 18 years. The safety and pharmacokinetic profile of Nevirapine has been evaluated in HIV-1 infected pediatric subjects age 15 days to less than 3 months.

The most frequently reported adverse events related to Nevirapine in pediatric subjects were similar to those observed in adults, with the exception of granulocytopenia, which was more commonly observed in children receiving both zidovudine and Nevirapine.

Geriatric Use: Clinical trials of Nevirapine did not include sufficient numbers of subjects aged 65 and older to determine whether elderly subjects respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.

Renal Impairment: In subjects with renal impairment (mild, moderate or severe), there were no significant changes in the pharmacokinetics of nevirapine. Nevirapine is extensively metabolized by the liver and nevirapine metabolites are extensively eliminated by the kidney. Nevirapine metabolites may accumulate in patients receiving dialysis; however, the clinical significance of this accumulation is not known. No adjustment in nevirapine dosing is required in patients with CrCL greater than or equal to 20 mL per min. The pharmacokinetics of nevirapine have not been evaluated in patients with CrCl less than 20 mL per min. In patients undergoing chronic hemodialysis, an additional 200 mg dose following each dialysis treatment is indicated.

Hepatic Impairment: Because increased nevirapine levels and nevirapine accumulation may be observed in patients with serious liver disease, do not administer Nevirapine to patients with moderate or severe (Child-Pugh Class B or C, respectively) hepatic impairment.

Renal Impairment:

  • ESRD maintained on haemodialysis or peritoneal dialysis: 100 mg 6-8 hrly.
  • CrCl <10-15 mL/min: 100 mg 6-8 hrly.

Hepatic Impairment: Dose reduction may be needed.

Acute Overdose

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.

Symptoms: Vomiting, CNS effects (e.g. fatigue, dizziness, drowsiness, lethargy, confusion), haematologic effects (e.g. anaemia, decreased Hb). Bone marrow hypoplasia, mild ataxia, tonic-clonic seizure and increased serum concentration of AST and ALT may also occur. Management: Supportive and symptomatic treatment. Induce emesis and admin activated charcoal to prevent further absorption of unrecovered drug.

Storage Condition

Should be stored in cool and dry place

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