Zidovudine is primarily eliminated by hepatic conjugation to an inactive glucuronidated metabolite. Active substances which are primarily eliminated by hepatic metabolism especially via glucuronidation may have the potential to inhibit metabolism of zidovudine. The interactions listed as follows should not be considered exhaustive but are representative of the classes of medicinal products where caution should be exercised.
Atovaquone: zidovudine does not appear to affect the pharmacokinetics of atovaquone. However, pharmacokinetic data have shown that atovaquone appears to decrease the rate of metabolism of zidovudine to its glucuronide metabolite (steady state AUC of zidovudine was increased by 33% and peak plasma concentration of the glucuronide was decreased by 19%). At zidovudine dosages of 500 or 600 mg/day it would seem unlikely that a three week, concomitant course of atovaquone for the treatment of acute PCP would result in an increased incidence of adverse reactions attributable to higher plasma concentrations of zidovudine. Extra care should be taken in monitoring patients receiving prolonged atovaquone therapy.
Clarithromycin: clarithromycin tablets reduce the absorption of zidovudine. This can be avoided by separating the administration of zidovudine and clarithromycin by at least two hours.
Lamivudine: A modest increase in Cmax (28%) was observed for zidovudine when administered with lamivudine, however overall exposure (AUC) was not significantly altered. Zidovudine has no effect on the pharmacokinetics of lamivudine.
Phenytoin: Phenytoin blood levels have been reported to be low in some patients receiving RETROVIR, while in one patient a high level was noted. These observations suggest that phenytoin levels should be carefully monitored in patients receiving both medicinal products.
Probenecid: Limited data suggest that probenecid increases the mean half-life and AUC of zidovudine by decreasing glucuronidation. Renal excretion of the glucuronide (and possibly zidovudine itself) is reduced in the presence of probenecid.
Rifampicin: Limited data suggests that co-administration of zidovudine and rifampicin decreases AUC of zidovudine by 48% ± 34%. However the clinical significance of this is unknown.
Stavudine: Zidovudine may inhibit the intracellular phosphorylation of stavudine when the two medicinal products are used concurrently. Stavudine is therefore not recommended to be used in combination with RETROVIR.
Miscellaneous: Other active substances including but not limited to aspirin, codeine, morphine, methadone, indomethacin, ketoprofen, naproxen, oxazepam, lorazepam, cimetidine, clofibrate, dapsone and isoprinosine may alter the metabolism of zidovudine by competitively inhibiting glucuronidation or directly inhibiting hepatic microsomal metabolism. Careful thought should be given to the possibilities of interactions before using such medicinal products, particularly for chronic therapy, in combination with RETROVIR.
Concomitant treatment, especially acute therapy, with potentially nephrotoxic or myelosuppressive medicinal products (for example systemic pentamidine, dapsone, pyrimethamine, co-trimoxazole, amphotericin, flucytosine, ganciclovir, interferon, vincristine, vinblastine and doxorubicin) may also increase the risk of adverse reactions to RETROVIR. If concomitant therapy with any of these medicinal products is necessary then extra care should be taken in monitoring renal function and haematological parameters and, if required, the dosage of one or more agents should be reduced.
Since some patients receiving RETROVIR may continue to experience opportunistic infections, concomitant use of prophylactic antimicrobial therapy may have to be considered. Such prophylaxis has included co-trimoxazole, aerosolised pentamidine, pyrimethamine and aciclovir. Limited data from clinical trials do not indicate a significantly increased risk of adverse reactions to RETROVIR with these medicinal products.