Each tablet contains:
(Zidovudine & Lamivudine Tablets)
Zidovudine, a thymidine analogue, is anti-retroviral drug acting against human immunodeficiency virus (HIV). Lamivudine and zidovudine are potent, selective inhibitors of HIV-1 and HIV-2. Lamivudine has been shown to be highly synergistic with zidovudine, inhibiting the replication of HIV in cell culture. Both active substances are metabolised sequentially by intracellular kinases to the 5'-triphosphate (TP). 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.
Absorption: Lamivudine and zidovudine are well absorbed from the gut. The bioavailability of oral lamivudine in adults is normally between 80-85% and for zidovudine 60-70%. A bioequivalence study compared ZVD-PLUS with 3TC 150mg and Retrovir 300mg tablets taken together. The effect of food on the rate and extent of absorption was also studied. ZVD-PLUS was shown to be bioequivalent to 3TC 150mg and Retrovir 300mg given as separate tablets, when administered to fasting subjects. ZVD-PLUS administration, lamivudine and zidovudine Cmax (95% confidence interval) values were 1.5 (1.3- 1.8)mg/mL and 1.8 (1.5-2.2)mg/mL respectively. The median (range) lamivudine and zidovudine tmax values were 0.75 (0.50-2.00) hours and 0.50 (0.25-2.00) hours respectively. The extent (AUC) of lamivudine and zidovudine absorption and estimates of half-life following administration of ZVD-PLUS with food were similar when compared to fasting subjects, although the rate of absorption (Cmax, tmax) was slowed. Based on these data it may be administered with or without food.
Distribution: Intravenous studies with lamivudine and zidovudine showed that the mean apparent volume of distribution is 1.3 and 1.6L/kg respectively. Lamivudine exhibits linear pharmacokinetics over the therapeutic dose range and displays limited binding to the major plasma protein albumin (less than 36% serum albumin in vitro).
Zidovudine plasma protein binding is 34% to 38%. Interactions with medicinal products involving binding site displacement are not anticipated with ZVD-PLUS.
Data show that lamivudine and zidovudine penetrate the central nervous system and reach the cerebrospinal fluid (CSF). The mean ratios of CSF/serum lamivudine and zidovudine concentrations 2-4 hours after oral administration were approximately 0.12 and 0.5 respectively. The true extent of penetration of lamivudine or relationship with any clinical efficacy is unknown.
Metabolism: Metabolism of lamivudine is a minor route of elimination. Lamivudine is predominately cleared by renal excretion of the unchanged active substance. The likelihood of metabolic interactions with lamivudine is low due to the small extent of hepatic metabolism (5-10%) and low plasma binding. The 5'-glucuronide of zidovudine is the major metabolite in both plasma and urine, accounting for approximately 50- 80% of the administered dose eliminated by renal excretion. 3'-amino-3'-deoxythymidine (AMT) has been identified as a metabolite of zidovudine following intravenous dosing.
Elimination: The observed lamivudine half-life of elimination is 5 to 7 hours. The mean systemic clearance of lamivudine is approximately 0.32L/h/kg, with predominantly renal clearance (greater than 70%) via the organic cationic transport system. From studies with intravenous zidovudine, the mean terminal plasma half-life was 1.1 hours and the mean systemic clearance was 1.6L/h/kg. Renal clearance of zidovudine is estimated to be 0.34L/h/kg, indicating glomerular filtration and active tubular secretion by the kidneys.
Renally impaired: Studies in patients with renal impairment show lamivudine elimination is affected by renal dysfunction, due to decreased renal clearance. Dose reduction is required for patients with creatinine clearance of less than 50mL/min. Zidovudine concentrations have also been shown to be increased in patients with advanced renal failure.
Hepatically impaired: Limited data in patients with cirrhosis suggest that accumulation of zidovudine may occur in patients with hepatic impairment because of decreased glucuronidation. Dosage adjustment of zidovudine may be necessary in patients with severe hepatic impairment.
Elderly: The pharmacokinetics of lamivudine and zidovudine have not been studied in patients over 65 years of age. Pregnancy: The pharmacokinetics of lamivudine and zidovudine were similar to that of non-pregnant adults. In humans, consistent with passive transmission of lamivudine across the placenta, lamivudine concentrations in infant serum at birth were similar to those in maternal and cord serum at delivery. Zidovudine was measured in plasma and gave similar results to those observed for lamivudine.
Zidovudine & Lamivudine is indicated for the treatment of HIV infection when antiretroviral therapy is warranted. The duration of clinical benefit from antiretroviral therapy may be limited. Alteration in antiretroviral therapy should be considered if disease progression occurs during treatment.
Maternal Foetal HIV Transmission: Zidovudine is also indicated for the prevention of maternal foetal HIV transmission. The safety of zidovudine for the mother or foetus during the first trimester of pregnancy has not been assessed.
DOSAGE AND DIRECTION OF USE:
The recommended oral dose of Lamivudine & Zidovudine for adults and adolescents ( at least 12 years of age) is one capsule ( containing 150mg of Lamivudine and 300mg of Zidovudine) twice daily with or without food. Dose adjustment: Because it is a fixed dose combination, Lamivudine & Zidovudine 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:
Before combination therapy with Zidovudine is initiated, consult the complete prescribing information for each drug. The safety profile of Zidovudine plus other antiretroviral agents reflects the individual safety profiles of each component.
The incidence of adverse reactions appears to increase with disease progression, and patients should be monitored carefully, especially as disease progression occurs. Current antiretroviral therapy, including Lamivudine, has not been proven to prevent the risk of transmission of HIV to others through sexual contact or blood contamination.
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of lamivudine alone or in combination, in the treatment of HIV infection.
BONE MARROW SUPPRESSION
Zidovudine & Lamivudine 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.
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 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 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.
Category C. Congenital abnormalities were found to occur with similar frequency between infants born to mothers who received Zidovudine & Lamivudine 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 is excreted in human milk.
IMPAIRED RENAL AND HEPATIC FUNCTION
Zidovudine & Lamivudine 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.
Lamivudine should be used with caution in patients with advanced cirrhotic liver disease due to chronic Hepatitis B infection, as there is a small risk of rebound hepatitis post treatment.
Pancreatitis has been observed in some patients receiving Lamivudine. However it is unclear whether this is due to Lamivudine or to underlying HIV disease. Pancreatitis must be considered whenever a patient develops abdominal pain, nausea, vomiting or elevated biochemical markers. Discontinue use of Lamivudine until diagnosis of pancreatitis is excluded.
Lactic acidosis/severe hepatomegaly with steatosis:
Long-term use of Lamivudine can result in potentially fatal lactic acidosis. Symptomatic hyperlactacaemia and lactic acidosis are uncommon. Clinical features are non-specific, and include nausea, vomiting, abdominal pain, dyspnoea, fatigue and weight loss. Suspicious biochemical features include mild raised transaminases, raised lactate dehydrogenase (LDH) and/or creatine kinase. In patients with suspicious symptoms or biochemistry. measure the venous lactate level (normal <2 mmol/L), and
respond as follows:
Lactate 2 - 5 mmol/L: monitor regularly, and be alert for clinical signs.
Lactate 5 - 10 mmol/L without symptoms: monitor closely.
Lactate 5 - 10 mmol/L with symptoms: STOP all therapy. Exclude other causes (e.g. sepsis, uraemia. diabetic ketoacidosis, thyrotoxicosis, lymphoma).
Lactate 5 - 10 mmol/L: STOP all therapy (80% mortality in case studies).
Diagnosis of lactic acidosis is confirmed by demonstrating metabolic acidosis with an increased anion gap and raised lactate level. Therapy should be stopped in any acidotic patient with raised lactate level.
Blood for lactate assays should be heparinised and stored on ice. After recovery, NRTI's should be avoided. Seek expert advice on medicine selection. The above lactate values may not be applicable to paediatric patients. Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of Lamivudine alone or in combination, in the treatment of HIV infection. Most cases were women. Caution should be exercised when administering Lamivudine to patients with known risk factors for liver disease.
Treatment with Lamivudine should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or hepatotoxicity.
Patients receiving Lamivudine may continue to develop opportunistic infections and other complications of HIV infection, and therefore they should remain under close observation by medical practitioners experienced in the treatment of patients with associated HIV disease.
The risk of HIV transmission to others:
Patients should be advised that current antiretroviral therapy, including Lamivudine, has not been proven to prevent the risk of transmission of HIV to others through sexual contact or blood contamination. Appropriate precautions should continue to be employed.
Patients with moderate to severe renal impairment:
In patients with moderate to severe renal impairment, the terminal half-life of lamivudine is increased due to decreased clearance. The dose should therefore be adjusted.
Adults: The frequency and severity of adverse events associated with the use of Zidovudine & Lamivudine 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 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 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 following side-effects have been reported during therapy of HIV disease with Lamivudine alone, and in combination with other anti-retrovirals.
Pancreatitis, upper abdominal pain, nausea; vomiting and diarrhoea have been reported.
Blood and lymphatic system disorders:
Neutropenia, thrombocytopenia and anaemia have occurred.
Skin and appendages disorders:
Alopecia has been reported.
Central and Peripheral Nervous system disorders:
Peripheral neuropathy, paraesthesia, and headache have been reported.
Musculo-skeletal system disorders:
Arthralgia, muscle disorders including less frequently, rhabdomyolysis have been reported.
Body as a whole:
Malaise, fatigue and fever have occurred.
Other adverse events were similar to that observed in adults.
The most commonly reported adverse experiences were anaemia and neutropenia. The long-term consequences of in vitro and infant exposure to Zidovudine & Lamivudine are unknown.
Ganciclovir, interferon alpha: Use of Zidovudine & Lamivudine 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 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 levels by inhibiting glucuronidation and/or by reducing renal excretion of Zidovudine & Lamivudine.
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 has been reported to interfere with the oral clearance and metabolism of Zidovudine & Lamivudine. Atovaquone: A decrease in Zidovudine & Lamivudine oral clearance was observed.
Valproic Acid: Data suggests that valproic acid increases the oral bioavailability of Zidovudine & Lamivudine through inhibition of first pass hepatic metabolism. Patients should be monitored for a possible increase in Zidovudine & Lamivudine related adverse events. Lamivudine: Co-administration of zidovudine with lamivudine resulted in an increase in the maximum concentration (Cmax) of zidovudine. Other nucleoside analogues: Experimental nucleoside analogues affecting DNA replication such as ribavirin antagonize the in vitro antiviral activity of zidovudine against HIV.
No reported cases of acute overdosage (up to 50 gms) in both children and adults have been fatal. The consistent finding in these cases was spontaneous or induced nausea and vomiting. Hematologic changes were transient and not severe. Hemodialysis and peritoneal dialysis appear to have a negligible effect on the removal of Zidovudine & Lamivudine while elimination of its primary metabolite is enhanced.
Store in a cool & dry place, protected from light.
Keep out of reach of children.
1X60’s HDPE Bottles.