Combivir Drug Interactions

As COMBIVIR contains lamivudine and zidovudine, any interactions that have been identified with these agents individually may occur with COMBIVIR. The interactions listed as follows should not be considered exhaustive but are representative of the classes of medicinal products where caution should be exercised.
Effect of lamivudine on the pharmacokinetics of other agents: In vitro, lamivudine demonstrates no or weak inhibition of the drug transporters organic anion transporter 1B1 (OATP1B1), OATP1B3, breast cancer resistance protein (BCRP) or P-glycoprotein (Pgp), multidrug and toxin extrusion protein 1 (MATE1), MATE2-K or organic cation transporter 3 (OCT3). Lamivudine is therefore not expected to affect the plasma concentrations of drugs that are substrates of these drug transporters.
Lamivudine is an inhibitor of OCT1 and OCT2 in vitro with IC50 values of 17 and 33 uM, respectively, however lamivudine has low potential to affect the plasma concentrations of OCT1 and OCT2 substrates at therapeutic drug exposures (up to 300 mg).
Effect of other agents on the pharmacokinetics of lamivudine: Lamivudine is a substrate of MATE1, MATE2-K and OCT2 in vitro. Trimethoprim (an inhibitor of these drug transporters) has been shown to increase lamivudine plasma concentrations, however this interaction is not considered clinically significant as no dose adjustment of lamivudine is needed.
Lamivudine is a substrate of the hepatic uptake transporter OCT1. As hepatic elimination plays a minor role in the clearance of lamivudine, drug interactions due to inhibition of OCT1 are unlikely to be of clinical significance.
Lamivudine is a substrate of Pgp and BCRP, however due to its high bioavailability it is unlikely that these transporters play a significant role in the absorption of lamivudine. Therefore co-administration of drugs that are inhibitors of these efflux transporters is unlikely to affect the disposition and elimination of lamivudine.
Interactions relevant to lamivudine: The likelihood of metabolic interactions with lamivudine is low due to limited metabolism and plasma protein binding, and almost complete renal elimination of unchanged lamivudine.
Lamivudine is predominantly eliminated by active organic cationic secretion. The possibility of interactions with other medicinal products administered concurrently should be considered, particularly when their main route of elimination is active renal secretion via the organic cationic transport system e.g. trimethoprim. Other active substances (e.g. ranitidine, cimetidine) are eliminated only in part by this mechanism and were shown not to interact with lamivudine.
Active substances shown to be predominantly excreted either via the active organic anionic pathway, or by glomerular filtration are unlikely to yield clinically significant interactions with lamivudine.
Sorbitol: Coadministration of sorbitol solution (3.2 g, 10.2 g, 13.4 g) with a single 300 mg dose of lamivudine oral solution resulted in dose-dependent decreases of 14%, 32%, and 36% in lamivudine exposure (AUC∞) and 28%, 52%, and 55% in the Cmax of lamivudine in adults. When possible, avoid chronic coadministration of sorbitol-containing medicines with COMBIVIR. Consider more frequent monitoring of HIV-1 viral load when chronic coadministration cannot be avoided.
Trimethoprim: Administration of trimethoprim/sulphamethoxazole 160 mg/800 mg (co-trimoxazole) causes a 40% increase in lamivudine exposure because of the trimethoprim component. However, unless the patient has renal impairment, no dosage adjustment of lamivudine is necessary. Lamivudine has no effect on the pharmacokinetics of trimethoprim or sulphamethoxazole. The effect of co-administration of lamivudine with higher doses of co-trimoxazole used for the treatment of Pneumocystis jiroveci pneumonia and toxoplasmosis has not been studied.
Emtricitabine: Lamivudine may inhibit the intracellular phosphorylation of emtricitabine when the two medicinal products are used concurrently. Additionally, the mechanism of viral resistance for both lamivudine and emtricitabine is mediated via mutation of the same viral reverse transcriptase gene (M184V) and therefore the therapeutic efficacy of these drugs in combination therapy may be limited. COMBIVIR is not recommended for use in combination with emtricitabine or emtricitabine-containing fixed dose combinations.
Interactions relevant to zidovudine: 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.
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 Pneumocystis jiroveci pneumonia 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: Co-administration of zidovudine with lamivudine results in a 13% increase in zidovudine exposure and a 28% increase in peak plasma levels. However overall exposure (AUC) is 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 zidovudine, while in one patient a high level was noted. These observations suggest that phenytoin concentrations should be carefully monitored in patients receiving COMBIVIR and phenytoin.
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 COMBIVIR.
Miscellaneous: Other medicinal products, 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 COMBIVIR.
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 zidovudine. If concomitant therapy with COMBIVIR and 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 COMBIVIR 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 zidovudine with these medicinal products.