Stavex

Uses

Lamivudine is used for the treatment of chronic hepatitis B associated with evidence of hepatitis B viral replication and active liver inflammation.

Nevirapine is used for combination antiretroviral treatment of HIV-1 infection in adults and in pediatric patients 15 days and older.

Additional important information regarding the use of Nevirapine for the treatment of HIV-1 infection:

• Based on serious and life-threatening hepatotoxicity observed in controlled and uncontrolled trials, Nevirapine should not be initiated in adult females with CD4+ cell counts greater than 250 cells/mm³ or in adult males with CD4+ cell counts greater than 400 cells/mm³ unless the benefit outweighs the risk.
• The 14-day lead-in period with Nevirapine 200 mg daily dosing must be strictly followed; it has been demonstrated to reduce the frequency of rash.
• If rash persists beyond the 14-day lead-in period, do not dose escalate to 200 mg twice daily. The 200 mg once-daily dosing regimen should not be continued beyond 28 days, at which point an alternative regimen should be sought.

Zidovudine, a nucleoside reverse transcriptase inhibitor, is used for combination with other antiretroviral agents for the treatment of HIV-1 infection.Prevention Of Maternal-Fetal HIV-1 Transmission Zidovudine is used for the prevention of maternal-fetal HIV-1 transmission. The indication is based on a dosing regimen that included 3 components:

• Antepartum therapy of HIV-1–infected mothers
• Intrapartum therapy of HIV-1–infected mothers
• Post-partum therapy of HIV-1–exposed neonate

Points to consider prior to initiatingZidovudine in pregnant women for the prevention of maternal-fetal HIV-1 transmission include:

• In most cases,Zidovudine for prevention of maternal-fetal HIV-1 transmission should be given in combination with other antiretroviral drugs.
• Prevention of HIV-1 transmission in women who have receivedZidovudine for a prolonged period before pregnancy has not been evaluated.
• Because the fetus is most susceptible to the potential teratogenic effects of drugs during the first 10 weeks of gestation and the risks of therapy withZidovudine during that period are not fully known, women in the first trimester of pregnancy who do not require immediate initiation of antiretroviral therapy for their own health may consider delaying use; this indication is based on use after 14 weeks’ gestation.

Stavex 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 Stavex 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

Stavex dosage

The recommended oral dose of Lamivudine for the treatment of chronic hepatitis B in adults is 100 mg once daily.

Adult Patients: The recommended dose for Nevirapine is one 200 mg tablet daily for the first 14 days, followed by one 200 mg tablet twice daily, in combination with other antiretroviral agents. The lead-in period has been observed to decrease the incidence of rash. For concomitantly administeredantiretroviral therapy, the manufacturer's recommended dosage and monitoring should be followed.

Pediatric Patients: The recommended oral dose for pediatric patients 15 days and older is 150 mg/m² once daily for 14 days followed by 150 mg/m² twice daily thereafter. The total daily dose should not exceed 400 mg for any patient.

Prophylaxis of HIV infection in neonates:

• Child:2 mg/kg 6 hrly, starting within 12 hr after birth and continuing for 6 wk.

HIV infection:

• Adult:250 mg or 300 mg bid, in combination with other antiretroviral agents.
• Child:As soln: 4 to <9 kg: 12 mg/kg bid; 9 to <30 kg: 9 mg/kg bid; ≥30 kg: 250 mg or 300 mg bid. As cap/tab: 8-13 kg: 100 mg bid; 14-21 kg: 100 mg in the morning, 200 mg in the evening; 22-30 kg: 200 mg bid; ≥30 kg: 250 mg or 300 mg bid. Alternatively (based on BSA), 480 mg/m2daily in 2-3 divided doses. Doses are given in combination with other antiretroviral agents.

Prophylaxis of maternal-fetal HIV transmission:

• Adult:100 mg 5 times daily, starting on the 14th wk of gestation until the start of labour.

May be taken with or without food.

Side Effects

Several serious adverse events reported with lamivudine (lactic acidosis and severe hepatomegaly with steatosis, post treatment exacerbations of hepatitis B, pancreatitis, and emergence of viral mutants associated with reduced drug susceptibility and diminished treatment response). Malaise, fatigue, fever, ENT infections, sore throat, nausea, vomiting, abdominal discomfort, pain, diarrhea, myalgia, arthralgia, headache, skin rashes may occur. Lactic acidosis and severe hepatomegaly with steatosis, have been reported.

Skin rash, nausea, vomiting, headache, abnormal LFT, fatigue, diarrhoea, abdominal pain.

Dizziness, headache, malaise, myalgia, GI symptoms (e.g. abdominal pain, diarrhoea, nausea, vomiting), anorexia, immune reconstitution syndrome, lipodystrophy, metabolic abnormalities, mitochondrial dysfunction, osteonecrosis; raised liver enzymes, creatine phosphokinase; hyperbilirubinaemia, myalgia, myositis. Rarely, aplastic anaemia, pure red cell aplasia, pancytopenia, thrombocytopenia, rhabdomyolysis, cardiomyopathy, convulsions, pancreatitis.

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

Patients should be assessed before beginning treatment and during treatment with lamivudine by a physician experienced in the management of chronic hepatitis B.

Caution should be taken during pregnancy. Interrupt treatment if severe hepatotoxicity or life-threatening skin reactions develop. Renal or hepatic insufficiency. Monitor liver function periodically.

Severe renal and hepatic impairment. Childn. Pregnancy.

Interaction

Trimethoprim 160 mg / Sulfamethoxazole 800 mg once daily has been shown to increase lamivudine exposure (AUC). The effect of higher doses of trimethoprim /sulfamethoxazole on lamivudine pharmacokinetics has not been investigated.

Mutually increased levels effects when used with drugs extensively metabolised by CYP3A. Reduced levels/effects of methadone.

Decreased plasma concentration with rifampicin resulting in partial or total loss of efficacy of zidovudine. Increased risk of anaemia with ribavirin in patients co-infected with HCV. Antagonistic effect with stavudine or doxorubicn. Increased plasma level with probenecid, atovaquone, valproic acid, fluconazole, or methadone. May alter phenytoin blood levels. Increased adverse effect with potentially nephrotoxic or myelosuppressive drugs (e.g. systemic pentamidine, dapsone, pyrimethamine, co-trimoxazole, amphotericin, flucytosine, ganciclovir, interferon, vincristine, vinblastine, doxorubicin). Reduced absorption with clarithromycin.

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

There is no adequate and well-controlled study in pregnant women. Lamivudine should be used during pregnancy only if the potential benefits outweigh the risks. Although it is not known if lamivudine is excreted in human milk, there is the potential for adverse effects from lamivudine in nursing infants. Mothers should be instructed not to breast feed if they are receiving lamivudine.

Nursing Mothers: The Centers for Disease Control and Prevention recommend that HIV-1 infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV-1. Nevirapine is excreted in breast milk. Because of both the potential for HIV-1 transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving Nevirapine.

Pregnancy Category C. Either studies in animals have revealed adverse effects on the foetus (teratogenic or embryocidal or other) and there are no controlled studies in women or studies in women and animals are not available. Drugs should be given only if the potential benefit justifies the potential risk to the foetus.

Contraindication

Lamivudine is contraindicated in patients hypersensitive to any of the components of the product.

Hypersensitivity. Lactation. Severe hepatic impairment.

Hypersensitivity; abnormally low neutrophil counts (<0.75 x 109/L) or Hb levels (<7.5 g/dL or 4.65 mmol/L); newborn infants with hyperbilirubinaemia requiring treatment other than phototherapy, or with increased transaminase levels >5 times the ULN. Lactation. Concomitant use with interferon alfa (with or witho ribavirin) in HIV and hepatitis B or C virus co-infected patients.

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

Store below 30˚C. Protect from light. Keep out of the reach of children.

Store at 15-30° C

Innovators Monograph

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