Each tablet contains:
Zidovudine, a thymidine analogue, is anti-retroviral drug acting against human immunodeficiency virus (HIV). Lamivudine-TP and zidovudine-TP are substrates for and competitive inhibitors of HIV reverse transcriptase.
However, their main antiviral activity is through incorporation of the monophosphate form into the viral DNA chain, resulting in chain termination. Lamivudine and zidovudine triphosphates show significantly less affinity for host cell DNA polymerases. 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. The activity of nevirapine does not compete with template or nucleoside triphosphates. HIV-2 RT and eukaryotic DNA polymerases (such as human DNA polymerases a , ß, g , or d ) are not inhibited by nevirapine.
The pharmacokinetic properties of lamivudine have been studied in asymptomatic, HlV-infected adult patients after administration of single intravenous (IV) doses ranging from 0.25 to 8 mg/kg, as well as single and multiple (b.i.d. regimen) oral doses ranging from 0.25 to 10 mg/kg.
Absorption and Bio-availability
Lamivudine was rapidly absorbed after oral administration in HIV-infected patients. Absolute bioavailability in 12 adult patients was 86% ± 16% (mean ± SD) for the tablet and 87% ± 13% for the oral solution. After oral administration of 2 mg/kg twice a day to nine adults with HIV, the peak serum lamivudine concentration (Cmax) was 1.5 ± 0.5 μg/ml (mean ± SD). The area under the plasma concentration versus time curve (AUC) and Cmax increased in proportion to oral dose over the range from 0.25 to 10 mg/kg. An investigational 25-mg dosage form of lamivudine was administered orally to 12 asymptomatic, HIV-infected patients on two occasions, once in the fasted state and once with food (1099 kcal; 75 grams fat, 34 grams protein, 72 grams carbohydrate). Absorption of lamivudine was slower in the fed state (Tmax: 3.2 ± 1.3 hours) compared with the fasted state (Tmax: 0.9 ± 0.3 hours); Cmax in the fed state was 40% ± 23% (mean ± SD) lower than in the fasted state. There was no significant difference in systemic exposure (AUC¥) in the fed and fasted states; therefore, EPIVIR Tablets and Oral Solution may be administered with or without food.
The accumulation ratio of lamivudine in HIV-positive asymptomatic adults with normal renal function was 1.50 following 15 days of oral administration of 2mg/kg b.i.d.
The apparent volume of distribution after IV administration of lamivudine to 20 patients was 1.3 ± 0.4 L/kg, suggesting that lamivudine distributes into extravascular spaces. Volume of distribution was independent of dose and did not correlate with body weight.
Binding of lamivudine to human plasma proteins is low (<36%). In vitro studies showed that, over the concentration range of 0.1 to 100 mg/mL, the amount of lamivudine associated with erythrocytes ranged from 53% to 57% and was independent of concentration.
Metabolism of lamivudine is a minor route of elimination. In man, the only known metabolite of lamivudine is the trans- sulfoxide metabolite. Within 12 hours after a single oral dose of lamivudine in six HIV-infected adults, 5.2% ± 1.4% (mean ± SD) of the dose was excreted as the trans-sulfoxide metabolite in the urine. Serum concentrations of this metabolite have not been determined.
The majority of lamivudine is eliminated unchanged in urine. In 20 patients given a single IV dose, renal clearance was 0.22 ± 0.06 L/hr•kg (mean ± SD), representing 71% ± 16% (mean ± SD) of total clearance of lamivudine.
In most single-dose studies in HIV-infected patients with serum sampling for 24 hours after dosing, the observed mean elimination half-life (T 1⁄2) ranged from 5 to 7 hours. Total clearance was 0.37 ± 0.05 L/hr•kg (mean ± SD). Oral clearance and elimination half-life were independent of dose and body weight over an oral dosing range from 0.25 to 10 mg/kg.
The pharmacokinetics of zidovudine has been evaluated in 22 adult HIV-infected patients in a Phase 1 dose-escalation study. After oral dosing (tablets), zidovudine was rapidly absorbed from the gastrointestinal tract with peak serum concentrations occurring within 0.5 to 1.5 hours. Dose-independent kinetics was observed over the range of 2 mg/kg every 8 hours to 10 mg/kg every 4 hours. The mean zidovudine half-life was approximately 1 hour and ranged from 0.78 to 1.93 hours following oral dosing.
Zidovudine is rapidly metabolized to 3’-azido-3’-deoxy-5’-O-a-D-glucopyra-nuronosylthymidine (GZDV), which has an apparent elimination half-life of 1 hour (range 0.61 to 1.73 hours). Following oral administration, urinary recovery of zidovudine and GZDV accounted for 14% and 74% of the dose, respectively, and the total urinary recovery averaged 90% (range 63% to 95%), indicating a high degree of absorption. However, as a result of first-pass metabolism, the average oral tablet bioavailability of zidovudine is 65% (range 52% to 75%). A second metabolite, 3-amino- 3- deoxythymidine (AMT), has been identified in the plasma following single-dose intravenous (IV) administration of zidovudine. AMT area-under-the-curve (AUC) was one fifth of the AUC of zidovudine and had a half-life of 2.7 ± 0.7 hours. In comparison, GZDV AUC was about three-fold greater than the AUC of zidovudine.
Additional pharmacokinetic data following intravenous dosing indicated dose-independent kinetics over the range of 1 to 5 mg/kg with a mean zidovudine half-life of 1.1 hours (range 0.48 to 2.86 hours). Total body clearance averaged 1900 mL/min per 70 kg and the apparent volume of distribution was 1.6 L/kg. Renal clearance is estimated to be 400 mL/min per 70 kg, indicating glomerular filtration and active tubular secretion by the kidneys. Zidovudine plasma protein binding is 34% to 38%, indicating that drug interactions involving binding site displacement are not anticipated. The zidovudine cerebrospinal fluid (CSF)/ plasma concentration ratio was determined in 39 patients receiving chronic therapy with zidovudine. The median ratio measured in 50 paired samples drawn 1 to 8 hours after the last dose of zidovudine was 0.6.
Adults with Impaired Renal Function
The pharmacokinetics of zidovudine has been evaluated in patients with impaired renal function following a single 200- mg oral dose. In 14 patients (mean creatinine clearance 18 ± 2 mL/min) the half-life of zidovudine was 1.4 hours compared to 1.0 hour for control subjects with normal renal function; AUC values were approximately twice those of controls. Additionally, GZDV half-life in these patients was 8.0 hours (vs 0.9 hours for control) and AUC was 17 times higher than for control subjects. The pharmacokinetics and tolerance were evaluated in a multiple-dose study in patients undergoing hemodialysis (n = 5) or peritoneal dialysis (n = 6). Patients received escalating doses of zidovudine up to 200 mg five times daily for 8 weeks. Daily doses of 500 mg or less were well tolerated despite significantly elevated plasma levels of GZDV. Apparent oral clearance of zidovudine was approximately 50% of that reported in patients with normal renal function. The plasma concentrations of AMT are not known in patients with renal insufficiency. Daily doses of 300 to 400 mg should be appropriate in HIV-infected patients with severe renal dysfunction. Hemodialysis and peritoneal dialysis appear to have a negligible effect on the removal of zidovudine, whereas GZDV elimination is enhanced.
The pharmacokinetics and bioavailability of zidovudine have been evaluated in 21 HIV-infected pediatric patients, aged 6 months through 12 years, following intravenous doses administered over the range of 80 to 160 mg/m2 every 6 hours, and following oral doses of the IV solution administered over the range of 90 to 240 mg/m2 every 6 hours. After discontinuation of the IV infusion, zidovudine plasma concentrations decayed biexponentially, consistent with two- compartment pharmacokinetics. Proportional increases in AUC and in zidovudine concentrations were observed with increasing dose, consistent with dose-independent kinetics over the dose range studied. The mean terminal half-life and total body clearance across all dose levels administered were 1.5 hours and 30.9 mL/min per kg, respectively. These values compare to mean half-life and total body clearance in adults of 1.1 hours and 27.1 mL/min per kg. The mean oral bioavailability of 65% was independent of dose. This value is the same as the bioavailability in adults. Doses of 1 80 mg/m2 four times daily in pediatric patients produced similar systemic exposure (24-hour AUC 10.7 hr•μg/ mL) as doses of 200 mg six times daily in adult patients (10.9 hr•μg/ mL).
The pharmacokinetics of zidovudine have been studied in pediatric patients from birth to 3 months of life. In one study of the pharmacokinetics of zidovudine in women during the last trimester of pregnancy, zidovudine elimination was determined immediately after birth in eight neonates who were exposed to zidovudine in utero. The half-life was 13.0 ± 5.8 hours. In another study, the pharmacokinetics of zidovudine were evaluated in pediatric patients (ranging in age of 1 day to 3 months) of normal birth weight for gestational age and with normal renal and hepatic function. In neonates less than or equal to 14 days old, mean ± SD total body clearance was 10.9 ± 4.8 mL/min per kg (n = 18) and half-life was 3.1 ± 1.2 hours (n = 21). In neonates and infants greater than 14 days old, total body clearance was 19.0 ± 4.0 mL/min per kg (n = 16) and half-life was 1.9 ± 0.7 hours (n = 18). Bioavailability was 89% ± 19% (n = 15) in the younger age group and decreased to 61% ± 19% (n = 17) in patients older than 14 days.
The pharmacokinetics of zidovudine have been studied in a Phase 1 study of eight women during the last trimester of pregnancy. As pregnancy progressed, there was no evidence of drug accumulation. The pharmacokinetics of zidovudine were similar to that of nonpregnant adults. Consistent with passive transmission of the drug across the placenta,
zidovudine concentrations in infant plasma at birth were essentially equal to those in maternal plasma at delivery. Although data are limited, methadone maintenance therapy in five pregnant women did not appear to alter zidovudine pharmacokinetics. However, in another patient population, a potential for interaction has been identified.
The U.S. Public Health Service Centers for Disease Control and Prevention advises HIV- infected women not to breastfeed to avoid postnatal transmission of HIV to a child who may not yet be infected. After administration of a single dose of 200 mg zidovudine to 13 HIV-infected women, the mean concentration of zidovudine was similar in human milk and serum.
Effect of Food on Absorption
Administration of zidovudine tablets with food decreased peak plasma concentrations by greater than 50%; however, bioavailability as determined by AUC may not be affected. The effect of food on the absorption of zidovudine from the tablet formulation is not known.
Absorption and Bioavailability:
Nevirapine is readily absorbed (>90%) after oral administration in healthy volunteers and in adults with HIV-1 infection. Absolute bioavailability in 12 healthy adults following single-dose administration was 93 ± 9% (mean ±SD) for a 50 mg tablet and 91 ± 8% for an oral solution. Peak plasma nevirapine concentrations of 2 ± 0.4 mc g/mL (7.5 mc M) were attained by 4 hours following a single 200 mg dose. Following multiple doses, nevirapine peak concentrations appear to increase linearly in the dose range of 200 to 400 mg/day. Steady state trough nevirapine concentrations of 4.5 ± 1.9 mc g/mL (17 ± 7 mc M), (n = 242) were attained at 400 mg/day. Nevirapine tablets and sBPension have been shown to be comparably bioavailable and interchangeable at doses up to 200 mg. When Nevirapine (200 mg) was administered to 24 healthy adults (12 female, 12 male), with either a high fat breakfast (857 kcal, 50 g fat, 53% of calories from fat) or antacid
(Maalox® 30 mL), the extent of nevirapine absorption (AUC) was comparable to that observed under fasting conditions. In a separate study in HIV-1-infected patients (n=6), nevirapine steady-state systemic exposure (AUCt ) was not significantly altered by ddI, which is formulated with an alkaline buffering agent. NEVIRAPINEmay be administered with or without food, antacid or ddI.
Nevirapine is highly lipophilic and is essentially nonionized at physiologic pH. Following intravenous administration to healthy adults, the apparent volume of distribution (Vdss) of nevirapine was 1.21 ± 0.09 L/kg, suggesting that nevirapine is widely distributed in humans. Nevirapine readily crosses the placenta and is found in breast milk. Nevirapine is about 60% bound to plasma proteins in the plasma concentration range of 1-10 mc g/mL. Nevirapine concentrations in human cerebrospinal fluid (n=6) were 45% (± 5%) of the concentrations in plasma; this ratio is approximately equal to the fraction not bound to plasma protein.
In vivo studies in humans and in vitro studies with human liver microsomes have shown that nevirapine is extensively biotransformed via cytochrome P450 (oxidative) metabolism to several hydroxylated metabolites. In vitro studies with human liver microsomes suggest that oxidative metabolism of nevirapine is mediated primarily by cytochrome P450 isozymes from the CYP3A family, although other isozymes may have a secondary role. In a mass balance/excretion study in eight healthy male volunteers dosed to steady state with nevirapine 200 mg given twice daily followed by a single 50 mg dose of 14C-nevirapine, approximately 91.4 ± 10.5% of the radiolabeled dose was recovered, with urine (81.3 ± 11.1%) representing the primary route of excretion compared to feces (10.1 ± 1.5%). Greater than 80% of the radioactivity in urine was made up of glucuronide conjugates of hydroxylated metabolites. 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.
Nevirapine has been shown to be an inducer of hepatic cytochrome P450 metabolic enzymes. The pharmacokinetics of autoinduction are characterized by an approximately 1.5 to 2 fold increase in the apparent oral clearance of nevirapine as treatment continues from a single dose to two-to-four weeks of dosing with 200 - 400 mg/day. Autoinduction also results in a corresponding decrease in the terminal phase half-life of nevirapine in plasma from approximately 45 hours (single dose) to approximately 25-30 hours following multiple dosing with 200 - 400 mg/day.
Zidovudine, Lamivudine & Nevirapine is indicated for the treatment of HIV infection when antiretroviral therapy is
DOSAGE AND DIRECTION OF USE:
The recommended oral dose of Zidovudine, Lamivudine & Nevirapine for adults and adolescents ( at least 12 years of age) is one tablet ( containing 150mg of Lamivudine and 300mg of Zidovudine & 200mg of Nevirapine) twice daily with or without food.
Dose adjustment: Because it is a fixed dose combination, Zidovudine, Lamivudine & Nevirapine should not be prescribed for patients requiring dosage adjustment such as those with reduced renal function ( creatinine clearance< 50ml/min), those with low body weight (<50kg or II 0 lb), or those experiencing dose-limiting adverse events.
Patients who exhibit potentially life-threatening allergic reactions to any of the components of the formulation.
WARNINGS AND PRECAUTIONS:
Since it is a fixed dose combination of Lamivudine, Nevirapine & Zidovudine , it should ordinaly not be administered concomitantly with either Lamivudine or Zidovudine.
BONE MARROW SUPPRESSION
Zidovudine, Lamivudine & Nevirapine should be used with caution in patients who have bone marrow compromise evidenced by granulocyte count <1000 cells/mm3 or hemoglobin <9.5 g/dL. There have been reports of pancytopenia associated with the use of Zidovudine & Lamivudine, which was reversible in most instances after discontinuance of the drug.
Frequent blood counts are strongly recommended in patients with advanced HIV disease who are treated with zidovudine. For patients with asymptomatic or early HIV disease, periodic blood counts are recommended. If anaemia or neutropenia develops, dosage adjustments may be necessary.
Myopathy and myositis with pathological changes, similar to that produced by HIV disease, have been associated with prolonged use of Zidovudine, Lamivudine & Nevirapine.
LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS
Rare occurrences of potentially fatal lactic acidosis in the absence of hypoxemia, and severe hepatomegaly with steatosis have been reported with the use of certain antiretroviral nucleoside analogues. Therapy with Zidovudine, Lamivudine & Nevirapine should be Pended until the diagnosis of lactic acidosis has been excluded. Caution should be exercised when administering Zidovudine & Lamivudine to any patient, particularly obese women, with hepatomegaly, hepatitis, or other known risk factors for liver disease. Treatment with Zidovudine, Lamivudine & Nevirapine should be spender in the setting of rapidly elevating aminotransferase levels, progressive hepatomegaly, or metabolic/lactic acidosis of unknown aetiology.
OTHER SERIOUS ADVERSE REACTIONS
Reports of pancreatitis, sensitization reactions, vasculitis and seizures have been rare. These adverse events, except for sensitization, have also been associated with HIV disease. Changes in skin and nail pigmentation have been associated with the use of Zidovudine, Lamivudine & Nevirapine.
Category C. Congenital abnormalities were found to occur with similar frequency between infants born to mothers who received Zidovudine, Lamivudine & Nevirapine and infants born to mothers who received placebo. Abnormalities were either problems in embryogenesis (prior to 14 weeks) or were recognised on ultrasound before or immediately after initiation of study drugs.
HIV infected women are advised not to breast feed to avoid postnatal transmission of HIV to a child who may not yet be infected. Zidovudine, Lamivudine & Nevirapine is excreted in human milk.
IMPAIRED RENAL AND HEPATIC FUNCTION
Zidovudine, Lamivudine & Nevirapine is eliminated from the body primarily by renal excretion following metabolism in the liver. In patients with severely impaired renal function, dosage reduction is recommended. Although very little data are available, patients with severely impaired hepatic function may be at greater risk of toxicity.
Impaired Renal Function:
Reduction of the dosages of lamivudine, Neviraoine and Zidovudine is recommended for patients with impaired renal function. Patients with creatinine clearance< 50ml/min should not receive Zidovudine, Lamivudine & Nevirapine.
Category C. There are no adequate and well-controlled studies of this combination in pregnant women. Zidovudine, Lamivudine & Nevirapine should be used during pregnancy only if the potential benefits outweigh risks.
It is recommended that HIV-infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV infection Zidovudine is excreted in breast milk. No data are available on this combination or lamivudine. Mothers should be instructed not to breast- feed if they are receiving Zidovudine, Lamivudine & Nevirapine.
Zidovudine, Lamivudine & Nevirapine should not be administered to paediatric patients less than 12 years of age because it is a fixed dose combination that cannot be adjusted for this patient population.
Reduction of doses of lamivudine is recommended for patients with low body weight (less than 50kg or 110 lb). Therefore patients with low body weight should not receive Zidovudine, Lamivudine & Nevirapine.
Adults: The frequency and severity of adverse events associated with the use of Zidovudine, Lamivudine & Nevirapine in adults are greater in patients with more advanced infection at the time of initiation of therapy.
The anaemia reported in patients with advanced HIV disease receiving Zidovudine, Lamivudine & Nevirapine appeared to be the result of impaired erythrocyte maturation. Thrombocytopenia has also been reported in patients with advanced disease. Mild drug-associated elevations in total bilirubin levels have been reported as an uncommon occurrence in
patients treated for asymptomatic HIV infection.
Clinical adverse events or symptoms which occurred in at least 5% of all patients with advanced HIV disease treated with 1,500 mg/day of Zidovudine, Lamivudine & Nevirapine were: fever, headache, nausea, vomiting, anorexia, myalgia, insomnia, dizziness, paraesthesia, dyspnoea and rash. Malaise, gastrointestinal pain, dyspepsia, and taste perversion were also reported.
Paediatrics: Anaemia and granulocytopenia among paediatric patients with advanced HIV disease receiving zidovudine occurred with similar incidence to that reported for adults with AIDS or advanced AIDS-Related complex.
Macrocytosis was frequently observed.
The most commonly observed side effects during clinical trials were Headache, malaise and fatigue, nausea, vomiting ,diarrhea,anorexia,fever/chills,neuropathy,insomnia,dizziness,nasal signs and symptoms. Cough,muscloskeletal pain and neutropenia.
Ganciclovir, interferon alpha: Use of Zidovudine, Lamivudine & Nevirapine in combination with either ganciclovir or interferon alpha increases the risk of hematologic toxicities in some patients with advanced HIV disease. Hematologic parameters should be monitored frequently in all patients receiving either of these combinations.
Bone Marrow Suppressive Agents/Cytotoxic Agents: Co administration of Zidovudine, Lamivudine & Nevirapine with drugs that are cytotoxic or which interfere with RBC/WBC number or function (e.g. dapsone, flucytosine, vincristine, vinblastine or adriamycin) may increase the risk of hematologic toxicity.
Probenecid: Limited data suggests that probenecid may increase Zidovudine, Lamivudine & Nevirapine levels by inhibiting glucuronidation and/or by reducing renal excretion of Zidovudine, Lamivudine & Nevirapine Phenytoin: Phenytoin plasma levels have been reported to be low in some patients receiving Zidovudine & Lamivudine. In one study, a 30% decrease in oral Zidovudine & Lamivudine clearance was observed with phenytoin.
Methadone: No adjustments in methadone maintenance requirements were reported in a study of nine HIV positive patients receiving methadone maintenance. Fluconazole: The co administration of fluconazole with Zidovudine, Lamivudine & Nevirapine has been reported to interfere with the oral clearance and metabolism of Zidovudine, Lamivudine & Nevirapine.
Atovaquone: A decrease in Zidovudine, Lamivudine & Nevirapine oral clearance was observed. Valproic Acid: Data suggests that valproic acid increases the oral bioavailability of Zidovudine, Lamivudine & Nevirapine through inhibition of first pass hepatic metabolism. Patients should be monitored for a possible increase in Zidovudine, Lamivudine & Nevirapine related adverse events.
Lamivudine: Co-administration of zidovudine with lamivudine resulted in an increase in the maximum concentration (Cmax) of zidovudine.
Store in a cool & dry place, protected from light.
Keep out of reach of children.
1X60’s HDPE Bottles.