CYP3A4 and/or UGT1A1 inhibitors: Irinotecan and active metabolite SN-38 are metabolized via the human cytochrome P450 3A4 isoenzyme (CYP3A4) and uridine diphosphate-glucuronosyl transferase 1A1 (UGT1A1) (see Pharmacology: Pharmacokinetics under Actions). Co-administration of irinotecan with inhibitors of CYP3A4 and/or UGT1A1 may result in increased systemic exposure to irinotecan and the active metabolite SN-38. Physicians should take this into consideration when administering irinotecan with these drugs.
Ketoconazole: Irinotecan clearance is greatly reduced in patients receiving concomitant ketoconazole, leading to increased exposure to SN-38. Ketoconazole should be discontinued at least 1 week prior to starting irinotecan therapy and should not be administered during irinotecan therapy.
Atazanavir sulfate: Co-administration of atazanavir sulfate, a CYP3A4 and UGT1A1 inhibitor has the potential to increase systemic exposure to SN-38, the active metabolite of irinotecan. Physicians should take this into consideration when co-administering these drugs.
CYP3A4 inducers: Anticonvulsants: Concomitant administration of CYP3A-inducing anticonvulsant drugs (e.g., carbamazepine, phenobarbital or phenytoin) leads to reduced exposure to the active metabolite SN-38. Consideration should be given to starting or substituting non-enzyme-inducing anticonvulsants at least one week prior to initiation of irinotecan therapy in patients requiring anticonvulsant treatment.
St. John's Wort (Hypericum perforatum): Exposure to the active metabolite SN-38 is reduced in patients taking concomitant St. John's Wort. St. John's Wort should be discontinued at least 1 week prior to the first cycle of irinotecan, and should not be administered during irinotecan therapy.
Other interactions: Neuromuscular blocking agents: Interaction between irinotecan and neuromuscular blocking agents cannot be ruled out, since irinotecan has anticholinesterase activity. Drugs with anticholinesterase activity may prolong the neuromuscular blocking effects of suxamethonium and the neuromuscular blockade of non-depolarizing drugs may be antagonized.
Antineoplastic agents: The adverse effects of irinotecan, such as myelosuppression and diarrhea, would be expected to be exacerbated by other antineoplastic agents having a similar adverse effect profile.
Dexamethasone: Lymphocytopenia has been reported in patients receiving irinotecan, and it is possible that the administration of dexamethasone as antiemetic prophylaxis may have enhanced the likelihood of lymphocytopenia. However, serious opportunistic infections have not been observed and no complications have specifically been attributed to lymphocytopenia.
Hyperglycemia has been observed in patients with a history of diabetes mellitus or evidence of glucose intolerance prior to administration of irinotecan. It is probable that dexamethasone, given as antiemetic prophylaxis, contributed to hyperglycemia in some patients.
Laxatives: Laxative use during therapy with irinotecan is expected to worsen the incidence or severity of diarrhea.
Diuretics: Dehydration secondary to vomiting and/or diarrhea may be induced by irinotecan. The physician may wish to withhold diuretics during dosing with irinotecan and during periods of active vomiting or diarrhea.
Bevacizumab: Results from a dedicated drug-drug interaction trial demonstrated no significant effect of bevacizumab on the pharmacokinetics of irinotecan and its active metabolite SN-38.