Zidovudine dosage

Fixed-dose combination Lamivudine/zidovudine tablets are a fixed-dose combination doseform that does not allow for dose reduction. Avoid use in patients requiring lamivudine or zidovudine dosage reduction including children under 12 years of age, renally impaired patients with Ccr less than 50 mL/min, or those experiencing dose-limiting adverse effects. 

In one pharmacokinetic study in eight HIV-infected subjects, the renal clearance of zidovudine was significantly reduced by trimethoprim (201). The authors concluded that zidovudine dosages may need to be reduced if trimethoprim is given to patients with impairment of liver function or glucuronidation. Zidovudine, on the other hand, did not alter the pharmacokinetics of trimethoprim. 

Various nervous system adverse effects of zidovudine have been reported, which may or may not be directly related to the drug. These include seizures, confusion, and acute encephalopathy occurring after zidovudine dosage reduction (10). 

The concurrent use of zidovudine and probenecid should be well monitored to ensure that zidovudine levels do not rise excessively. Reduce the zidovudine dosage as necessary. However, the apparent increase in adverse effects during concurrent use seen by one group of researchers should be borne in mind. 

Renal/Hepatic function impairment Zidovudine is eliminated from the body primarily by renal excretion following metabolism in the liver (glucuronidation). In patients with severely impaired renal function (Ccr less than 15 mL/min), dosage reduction is recommended. Although very little data are available, patients with severely impaired hepatic function may be at greater risk of toxicity. 

Trimethoprim has been reported to decrease the therapeutic effect of cyclosporine with a concomitant increased risk of nephrotoxicity. Increased levels of dapsone, warfarin, methotrexate, zidovudine, and sul-fonylureas may occur when given together with trimethoprim dosages of these drugs should be modified and the patient monitored accordingly. 

Caution should be exercised when zidovudine is administered to patients with preexisting anemia or neutropenia and to those with advanced cases of AIDS. Dosage adjustment is required for patients with significant renal impairment and may also be necessary in those with hepatic impairment. 

Zidovudine should be used cautiously with any other agent that causes bone marrow suppression, such as interferon-a, trimethoprim-sulfamethoxazole, dap-sone, foscarnet, flucytosine, ganciclovir, and valganci-clovir. Probenecid and interferon-p inhibit the elimination of zidovudine therefore, a dosage reduction of zidovudine is necessary when the drugs are administered concurrently. Ribavirin inhibits the phosphorylation reactions that activate zidovudine, and zidovudine similarly inhibits the activation of stavudine thus, the coadministration of zidovudine with ribavirin or stavudine is contraindicated. 

Mentre, F. Mallet, A. Experiences with NPML—appU-cation to dosage individualization of cyclosporine, gentamicin and zidovudine. In The Population Approach Rowland, M., Aarons, L., Eds. Commission of European Communities Luxembourg, 1992 75-90. 

Extensive serial audiological studies in an HIV-infected child showed high-frequency hearing loss after 19 months of combined treatment with zidovudine and didanosine (dosages unknown), which were started at 24 months of age (9). Normal tympanograms indicated that this hearing loss was sensorineural. 

The main dose-hmiting adverse reactions of zidovudine therapy in HIV-infected adults and children are hematological comphcations (12). When zidovudine was introduced it was given in about twice the dosage used today. Consequently, hematological adverse effects occur at a much lower frequency than previously reported (13,14). 

In 13 HIV-infected patients with cancer, the mean pharmacokinetics of zidovudine (AUC, half-life, oral clearance, and oral apparent volume of distribution) were no different with or without chemotherapy (42). However, there was a 57% reduction in and a 66% increase in tmax after chemotherapy. There were no differences in the urinary excretion of zidovudine or zidovudine glucuronide. The authors concluded that these minor changes did not warrant any change in the dosage of zidovudine during concurrent chemotherapy. 

F. Mentre and A. Mallet, Experiences with NPML—application to dosage individualisation of cyclosporine, gentamicin and zidovudine, in The Population Approach, M. Rowland and L. Aarons (Eds.). Commission of European Communities, Luxembourg, 1992, pp. 75-90. 

Pharmacokinetics Zidovudine is active orally (with 60% bioavailability) and is distributed to most tissues, including the CNS. Elimination of the drug involves both hepatic metabolism to glucuronides and renal excretion. Dosage reduction is necessary in uremic patients and those with cirrhosis. The half-life of zidovudine is 1-3 hours. 

Methadone effects reduced or unaffected. A drug abuser with AIDS needed an increase in his levomethadone (7 -methadone) dosage from 40 to 60 mg daily, within a month of starting to take zidovudine 1 g daily. ... 

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