Kedu

Uses

Kedu, 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 Kedu 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 initiatingKedu in pregnant women for the prevention of maternal-fetal HIV-1 transmission include:

• In most cases,Kedu 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 receivedKedu 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 withKedu 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.

Kedu is also used to associated treatment for these conditions: HIV Transmission, Human Immunodeficiency Virus (HIV) Infections, Perinatal HIV transmission

How Kedu works

Kedu, 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

Kedu dosage

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

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

Symptoms of overdose include fatigue, headache, nausea, and vomiting. LD₅₀ is 3084 mg/kg (orally in mice).

Precaution

Severe renal and hepatic impairment. Childn. Pregnancy.

Interaction

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.

Food Interaction

• Take with or without food. The administration of zidovudine with food causes a 28% reduction in the Cmax but does not affect the AUC.

[Minor] Food may have variable effects on the oral bioavailability of zidovudine.

Fatty foods have been reported to decrease the rate and extent of zidovudine absorption following oral administration.

In a study of 13 AIDS patients, mean peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of zidovudine were 2.8 and 1.4 times higher, respectively, in fasting patients than in those administered the medication with breakfast.

In addition, variations in plasma zidovudine concentrations were increased when administered in the fed state.

In another study of eight patients, the time to reach peak concentration (Tmax) was increased from 0.68 to 1.95 hours, and Cmax was reduced by 50% when zidovudine was administered with a liquid high-fat meal relative to fasting.

Protein meals can also delay the absorption and reduce the Cmax of zidovudine, although the extent of absorption is not significantly affected.

The clinical significance of these alterations, if any, is unknown.

The product labeling states that zidovudine may be taken with or without food.

Kedu Drug Interaction

Moderate: rosuvastatin, valproic acidMinor: sulfamethoxazole / trimethoprim, sulfamethoxazole / trimethoprim, lopinavir / ritonavir, ritonavir, acetaminophen, phenytoinUnknown: ciprofloxacin, ubiquinone, lamivudine / zidovudine, copper gluconate, lamivudine, epoetin alfa, glycerin, raltegravir, darunavir, emtricitabine / tenofovir, cyanocobalamin, cholecalciferol

Kedu Disease Interaction

Major: bone marrow suppression, myopathy, hepatotoxicity, renal dysfunction

Volume of Distribution

Apparent volume of distribution, HIV-infected patients, IV administration = 1.6 ± 0.6 L/kg

Elimination Route

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

Elimination half life, HIV-infected patients, IV administration = 1.1 hours (range of 0.5 - 2.9 hours)

Clearance

• 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

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

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

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

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

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.

Interaction with other Medicine

Store between 15-25° C.

Innovators Monograph

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