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Drug interactions with valganciclovir: In-vivo drug interaction studies with Valganciclovir have not been performed. Since valganciclovir is extensively and rapidly metabolised to ganciclovir; drug interactions associated with ganciclovir will be expected for valganciclovir.
Effects of other medicinal products on ganciclovir: Imipenem-cilastatin: Convulsions have been reported in patients taking ganciclovir and imipenem-cilastatin concomitantly. These drugs should not be used concomitantly unless the potential benefits outweigh the potential risks.
Probenecid: Probenecid given with oral ganciclovir resulted in statistically significantly decreased renal clearance of ganciclovir (20 %) leading to statistically significantly increased exposure (40 %). These changes were consistent with a mechanism of interaction involving competition for renal tubular secretion. Therefore, patients taking probenecid and Valganciclovir should be closely monitored for ganciclovir toxicity.
Effects of ganciclovir on other medicinal products: Zidovudine: When zidovudine was given in the presence of oral ganciclovir there was a small (17 %), but statistically significant increase in the AUC of zidovudine. There was also a trend towards lower ganciclovir concentrations when administered with zidovudine, although this was not statistically significant. However, since both zidovudine and ganciclovir have the potential to cause neutropenia and anaemia, some patients may not tolerate concomitant therapy at full dosage.
Didanosine: Didanosine plasma concentrations were found to be consistently raised when given with ganciclovir (both intravenous and oral). At ganciclovir oral doses of 3 and 6 g/day, an increase in the AUC of didanosine ranging from 84 to 124 % has been observed, and likewise at intravenous doses of 5 and 10 mg/kg/day, an increase in the AUC of didanosine ranging from 38 to 67 % has been observed. There was no clinically significant effect on ganciclovir concentrations. Patients should be closely monitored for didanosine toxicity.
Mycophenolate Mofetil: Based on the results of a single dose administration study of recommended doses of oral mycophenolate mofetil (MMF) and intravenous ganciclovir and the known effects of renal impairment on the pharmacokinetics of MMF and ganciclovir, it is anticipated that co-administration of these agents (which have the potential to compete for renal tubular secretion) will result in increases in phenolic glucuronide of mycophenolic acid (MPAG) and ganciclovir concentration. No substantial alteration of mycophenolic acid (MPA) pharmacokinetics is anticipated and MMF dose adjustment is not required. In patients with renal impairment to whom MMF and ganciclovir are co-administered, the dose recommendation of ganciclovir should be observed and the patients monitored carefully. Since both MMF and ganciclovir have the potential to cause neutropenia and leucopenia, patients should be monitored for additive toxicity.
Zalcitabine: No clinically significant pharmacokinetic changes were observed after concomitant administration of ganciclovir and zalcitabine. Both valganciclovir and zalcitabine have the potential to cause peripheral neuropathy and patients should be monitored for such events.
Stavudine: No clinically significant interactions were observed when stavudine and oral ganciclovir were given in combination.
Trimethoprim: No clinically significant pharmacokinetic interaction was observed when trimethoprim and oral ganciclovir were given in combination. However, there is a potential for toxicity to be enhanced since both drugs are known to be myelosuppressive and therefore both drugs should be used concomitantly only if the potential benefits outweigh the risks.
Other antiretrovirals: At clinically relevant concentrations, there is unlikely to be either a synergistic or antagonistic effect on the inhibition of either HIV in the presence of ganciclovir or CMV in the presence of a variety of antiretroviral drugs. Metabolic interactions with, for example, protease inhibitors and non-nucleoside reverse transcriptase inhibitors (NNRTIs) are unlikely due to the lack of P450 involvement in the metabolism of either valganciclovir or ganciclovir.
Other potential drug interactions: Toxicity may be enhanced when valganciclovir is co-administered with, or is given immediately before or after, other drugs that inhibit replication of rapidly dividing cell populations such as occur in the bone marrow, testes and germinal layers of the skin and gastrointestinal mucosa. Examples of these types of drugs are dapsone, pentamidine, flucytosine, vincristine, vinblastine, adriamycin, amphotericin B, trimethoprim/sulpha combinations, nucleoside analogues and hydroxyurea.
Since ganciclovir is excreted through the kidney, toxicity may also be enhanced during co-administration of valganciclovir with drugs that might reduce the renal clearance of ganciclovir and hence increase its exposure. The renal clearance of ganciclovir might be inhibited by two mechanisms: (a) nephrotoxicity, caused by drugs such as cidofovir and foscarnet, and (b) competitive inhibition of active tubular secretion in the kidney by, for example, other nucleoside analogues.
Therefore, all of these drugs should be considered for concomitant use with valganciclovir only if the potential benefits outweigh the potential risks.
