LAMI PLUS TABLETS
(Zidovudine, Nevirapine & Lamivudine Tablets)
Composition:
Each tablet contains:
Zidovudine BP 300mg
Lamivudine 150mg
Nevirapine 200mg
Presentation:
10x10's
Pharmacology:
It is a combination of three drugs commonly used in the management of Human Immunodeficiency Virus (HIV) infection. Both lamivudine, Nevirapine and zidovudine belong to the nucleoside analogue class of antiretroviral drugs. Both drugs act by inhibiting the reverse transcriptase enzyme of HIV, and by terminating the growth of the DNA chain. Lamivudine in combination with zidovudine & Nevirapine has been shown to have synergistic antiretroviral activity.
Pharmacokinetics:
Lamivudine:
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, Lamivudine 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/hrkg (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/hrkg (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.
Zidovudine:
The pharmacokinetics of zidovudine has been evaluated in 22 adult HIV-infected patients in a Phase 1 dose-escalation study. After oral dosing (capsules), 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-?-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 capsule 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.
Nevirapine
Rash, usually within first six weeks of therapy. D/C drug for severe rash or rash accompanied by other symptoms; Stevens-Johnson syndrome has occurred. Fever, headache, nausea, diarrhea, abdominal pain, thrombocytopenia, anemia, leukopenia, ulcerative stomatitis, hepatitis, peripheral neuropathy, paresthesia, or myalgia may also occur.
Grenulocytopenia has been more commonly observed in children. The safety profile of nevirapine in neonates has not been established.
Indications:
Lamivudine + Zidovudine +Nevirapine indicated for the treatment of HIV infection.
Contra-indications:
Lamivudine + Zidovudine + Nevirapine Tablets is contraindicated in patients with clinically significant hypersensitivity to the active substance or to any of the excipients.
Dosage and directions for use:
The recommended oral dose of Lamivudine + Zidovudine + Nevirapine for adults and adolescents (at least 12 years of age) is one capsule (containing 150 mg of lamivudine, 200mg of Nevirapine and 300 mg of zidovudine) twice daily with or without food.
Dose Adjustment:
Because it is a fixed dose combination, Lamivudine + Zidovudine + Nevirapine should not be prescribed for patients requiring dosage adjustment such as those with reduced renal function (creatinine clearance < 50 mL/min), those with low body weight (< 50 kg or II 0 lb), or those experiencing dose-limiting adverse events.
Warning:
Since it is a fixed-dose combination of lamivudine, Nevirapine and zidovudine, it should ordinarily not be administered concomitantly with either lamivudine or zidovudine.
The complete prescribing information for all agents being considered for use with Lamivudine + Zidovudine + Nevirapine should be consulted before combination therapy with Lamivudine + Zidovudine + Nevirapine is initiated.
Bone marrow suppression
Lamivudine + Zidovudine + Nevirapine should be used with caution in patients who have bone marrow compromise evidenced by granulocyte count <1,000 cells/ mm3 or hemoglobin < 9.5 g/dl (See Side Effects).
Frequent blood counts are strongly recommended in patients with advanced HIV disease who are treated with Lamivudine + Zidovudine + Nevirapine. For HIVinfected individuals and patients with asymptomatic or early HIV disease, periodic blood counts are recommended.
Lactic acidosis/severe hepatomegaly with steatosis
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of antiretroviral nucleoside analogues alone or in combination, including zidovudine and lamivudine. A majority of these cases have been in women. Caution should be exercised when administering Lamivudine + Zidovudine + Nevirapine to any patient, and particularly to those with known risk factors for liver disease. Treatment with Lamivudine + Zidovudine + Nevirapine should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or hepatotoxicity.
Myopathy
Myopathy and myositis, with pathological changes similar to that produced by HIV disease, have been associated with prolonged use of zidovudine and therefore may occur with therapy with Lamivudine + Zidovudine + Nevirapine. .
Patients with hiv and hepatitis b virus coinfection
In clinical trials and postmarketing experience, some patients with HIV infection who have chronic liver disease due to hepatitis B virus infection experienced clinical or laboratory evidence of recur-rent hepatitis upon discontinuation of lamivudine. Consequences may be more severe in patients with decompensated liver disease.
Side-effects & special precautions:
The most commonly observed side effects during clinical trials were headache, malaise and fatigue, nausea, vomiting, diarrhoea, anorexia, fever/chills, neuropathy, insomnia, dizziness, nasal signs and symptoms, cough, musculoskeletal pain and neutropenia.
Special precautions:
Impaired Renal Function
Reduction of the dosages of lamivudine, Nevirapine and zidovudine is recommended for patients with impaired renal function. Patients with creatinine clearance < 50 ml/min should not receive Lamivudine + Zidovudine + Nevirapine.
Pregnancy
Category C. There are no adequate and well-controlled studies of this combination in pregnant women. Lamivudine + Zidovudine + Nevirapine should be used during pregnancy only if the potential benefits outweigh the risks.
Lactation
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. Therefore, there is a potential for adverse effects in nursing infants. Mothers should be instructed not to breast-feed if they are receiving Lamivudine + Zidovudine + Nevirapine.
Paediatric Use
Lamivudine + Zidovudine + 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.
Others
Reduction of doses of lamivudine is recommended for patients with low body weight (less than 50 kg or 110 lb). Therefore patients with low body weight should not receive Lamivudine + Zidovudine + Nevirapine.
Drug Interaction:
Coadministration of ganciclovir, interferon-cc, and other bone marrow suppressive or cytotoxic agents may increase the hematologic toxicity of zidovudine.
Known symptoms of overdosage and particulars of its treatment:
There is no known antidote for Lamivudine + Zidovudine + Nevirapine.
Lamivudine:
One case of an adult ingesting 6 gms of lamivudine has been reported. There were no clinical signs or symptoms noted and hematologic tests remained normal. It is not known whether lamivudine can be removed by peritoneal dialysis or hemodialysis.
Zidovudine:
Acute overdoses of zidovudine have been reported in paediatric patients and adults. These involved exposures up to 50 grams. The only consistent findings were nausea and vomiting. Other reported occurrences included headache, dizziness, drowsiness, lethargy, confusion, and one report of a grand mal seizure. Hematologic changes were transient. All patients recovered. Hemodialysis and peritoneal dialysis appear to have a negligible effect on the removal of zidovudine, while elimination of its primary metabolite is enhanced.
Nevirapine
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.
Storage conditions and period.
Store in cool, dry & dark place, preferably below 25°C. Shelf life is 2 years.
Package: 10 tablets packed in blister strip, 10 such blisters packed in a carton.
