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Product
Antiretroviral products (Zidovir )
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Antiretroviral products (Zidovir )
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Zidovir
Zidovudine 100 mg capsules
Zidovudine 300 mg tablets
Zidovudine Oral Solution
COMPOSITION
Zidovir -100
Each capsule contains
Zidovudine …100mg
ZIDOVIR-300
Each tablet contains
Zidovudine…300mg
ZIDOVIR Oral Solution
Each 5 ml contains Zidovudine 50 mg
PHARMACOLOGY
Pharmacodynamics
Zidovudine is a synthetic nucleoside analogue of the naturally occurring nucleoside, thymidine, in which the 3`-hydroxy (-OH) group is replaced by an azido (-N 3 ) group. Within cells, zidovudine is converted to the active metabolite, zidovudine 5`-triphosphate (AztTP), by the sequential action of the cellular enzymes. Zidovudine 5`-triphosphate inhibits the activity of the HIV reverse transcriptase both by competing for utilization with the natural substrate, deoxythymidine 5`-triphosphate (dTTP), and by its incorporation into viral DNA. The lack of a 3`-OH group in the incorporated nucleoside analogue prevents the formation of the 5` to 3` phosphodiester linkage essential for DNA chain elongation and, therefore, the viral DNA growth is terminated. The active metabolite AztTP is also a weak inhibitor of the cellular DNA polymerase-alpha and mitochondrial polymerase-gamma and has been reported to be incorporated into the DNA of cells in culture.
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Pharmacokinetics
Adults
The pharmacokinetic properties of zidovudine in fasting patients are summarized in Table 1. Following oral administration, zidovudine is rapidly absorbed and extensively distributed, with peak serum concentrations occurring within 0.5 to 1.5 hours. Binding to plasma protein is low. Zidovudine is primarily eliminated by hepatic metabolism. The major metabolite of zidovudine is 3`-azido-3`-deoxy-5`- O -(beta)- D -glucopyranuronosylthymidine (GZDV). GZDV area under the curve (AUC) is about three-fold greater than the zidovudine AUC. Urinary recovery of zidovudine and GZDV accounts for 14% and 74%, respectively, of the dose following oral administration. A second metabolite, 3`-amino-3`-deoxythymidine (AMT), has been identified in the plasma following single-dose intravenous (IV) administration of zidovudine. The AMT AUC was one fifth of the zidovudine AUC. Pharmacokinetics of zidovudine were dose independent at oral dosing regimens ranging from 2 mg/kg every 8 hours to 10 mg/kg every 4 hours.
Table 1. Zidovudine Pharmacokinetic Parameters in Fasting Adult Patients
Pediatrics
Zidovudine pharmacokinetics has been evaluated in HIV-infected pediatric patients (Table 2).
Patients from 3 Months to 12 Years of Age : Overall, zidovudine pharmacokinetics in pediatric patients greater than 3 months of age are similar to those in adult patients. Proportional increases in plasma zidovudine concentrations were observed following administration of oral solution from 90 to 240 mg/m 2 every 6 hours. Oral bioavailability, terminal half-life, and oral clearance were comparable to adult values. 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 (see DOSAGE AND ADMINISTRATION: Neonatal Dosing ).
Patients Younger Than 3 Months of Age : Zidovudine pharmacokinetics has been evaluated in pediatric patients from birth to 3 months of life. Zidovudine elimination was determined immediately following birth in 8 neonates who were exposed to zidovudine in utero. The half-life was 13.0 ± 5.8 hours. In neonates £ 14 days old, bioavailability was greater, total body clearance was slower, and half-life was longer than in pediatric patients >14 days old. For dose recommendations for neonates, see Dosage and administration: Neonatal Dosing.
Table 2. Zidovudine Pharmacokinetic Parameters in Pediatric Patients *
INDICATIONS
ZIDOVIR in combination with other antiretroviral agents is indicated the treatment of HIV infection. It is also indicated for the prevention of maternal-foetal HIV transmission.
DOSAGE AND ADMINISTRATION
Adults
The recommended oral dose of ZIDOVIR is 600 mg/day in divided doses in combination with other antiretrovirals.
Pediatrics
The recommended dose in pediatric patients 6 weeks to 12 years of age is 160 mg/m 2 every 8 hours (480 mg/m 2 /day up to a maximum of 200 mg every 8 hours) in combination with other antiretrovirals.
Maternal-fetal HIV transmission
The recommended dosing regimen for administration to pregnant women (>14 weeks of pregnancy) and their neonates is:
Maternal dosing: 100 mg orally 5 times per day until the start of labor. During labor and delivery, intravenous zidovudine should be administered at 2 mg/kg (total body weight) over 1 hour followed by a continuous intravenous infusion of 1mg/kg/hour (total body weight) until clamping of the umbilical cord.
Neonatal dosing: 2 mg/kg orally every 6 hours starting within 12 hours after birth and continuing through 6 weeks of age. Neonates unable to receive oral dosing may be administered zidovudine intravenously at 1.5 mg/kg, infused over 30 minutes, every 6 hours.
Patient Monitoring
Hematologic toxicities appear to be related to pre-treatment bone marrow reserve and to dose and duration of therapy. In patients with poor bone marrow reserve, particularly in patients with advanced symptomatic HIV disease, frequent monitoring of hematologic indices is recommended to detect serious anaemia or neutropenia (see Warnings and Precautions ). In patients who experience hematologic toxicity, reduction in hemoglobin may occur as early as 2 to 4 weeks, and neutropenia usually occurs after 6 to 8 weeks.
Dose adjustment
Anemia: Significant anemia (hemoglobin of <7.5 g/dL or reduction of >25% of baseline) and/or significant neutropenia (granulocyte count of <750 cells/mm 3 or reduction of >50% from baseline) may require a dose interruption until evidence of marrow recovery is observed (see Warnings and Precautions ). In patients who develop significant anemia, dose modification does not necessarily eliminate the need for transfusion. If marrow recovery occurs following dose interruption, resumption in dose may be appropriate using adjunctive measures such as epoetin alfa at recommended doses, depending on hematologic indices such as serum erythropoetin level and patient tolerance.
For patients experiencing pronounced anemia while receiving chronic co-administration of zidovudine and drugs such as fluconazole and valproic acid, zidovudine dose reduction may be considered.
CONTRAINDICATIONS
ZIDOVIR tablets, capsules and solution are contraindicated for patients who exhibit potentially life-threatening allergic reactions to any of the components of the formulation.
WARNINGS AND PRECAUTIONS
General
Duovir and Duovir-N are combination product tablets that contain zidovudine as one of their components. ZIDOVIR should not be administered concomitantly with Duovir and Duovir-N .
The incidence of adverse reactions appears to increase with disease progression, and patients should be monitored carefully, especially as disease progression occurs.
Bone Marrow Suppression
ZIDOVIR should be used with caution in patients who have bone marrow compromise evidenced by granulocyte count <1000 cells/mm 3 or hemoglobin <9.5 g/dL. In patients with advanced symptomatic HIV disease, anemia and neutropenia were the most significant adverse effects observed. There have been reports of pancytopenia associated with the use of zidovudine, which was reversible in most instances after discontinuance of the drug. However, significant anaemia, in many cases requiring dose adjustment, discontinuation of zidovudine, and/or blood transfusions, has occurred during treatment with zidovudine alone or in combination with other antiretrovirals.
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 (see Dosage and Administration ).
Myopathy
Myopathy and myositis with pathological changes, similar to that produced by HIV disease, have been associated with prolonged use of zidovudine.
Lactic Acidosis/Severe Hepatomegaly with Steatosis
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including zidovudine and other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged exposure to antiretroviral nucleoside analogues may be risk factors. Particular caution should be exercised when administering ZIDOVIR to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with ZIDOVIR should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).
Use With Interferon- and Ribavirin-Based Regimens
In vitro studies have shown ribavirin can reduce the phosphorylation of pyrimidine nucleoside analogues such as zidovudine. Although no evidence of a pharmacokinetic or pharmacodynamic interaction (e.g., loss of HIV/HCV virologic suppression) was seen when ribavirin was co-administered with zidovudine in HIV/HCV co-infected patients, hepatic decompensation (some fatal) has occurred in HIV/HCV co-infected patients receiving combination antiretroviral therapy for HIV and interferon alfa with or without ribavirin. Patients receiving interferon alfa with or without ribavirin and zidovudine should be closely monitored for treatment-associated toxicities, especially hepatic decompensation, neutropenia, and anemia. Discontinuation of zidovudine should be considered as medically appropriate. Dose reduction or discontinuation of interferon alfa, ribavirin, or both should also be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Childs Pugh >6)
Presentaion
Zidovir 100/300 ….1 strip = 10 CAPS
Zidovir oral solution…..1 bot=100ml
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