Drug-Drug Interaction

SELECTED ANTICONVULSANTS/IRINOTECAN

MECHANISM OF ACTION
Phenytoin, phenobarbital, and carbamazepine may induce the metabolism of irinotecan(1-4) by CYP P-450-3A4.

DISCUSSION
In a clinical trial, irinotecan clearance values were 65.4% higher in patients receiving phenytoin when compared to patients who were not taking enzyme-inducing anticonvulsants.(2) In another clinical trial, irinotecan clearance was 117% higher in patients receiving anticonvulsants that included phenytoin.(5) Data from another clinical trial also suggested that phenytoin increases irinotecan clearance.(6)

CLINICAL EFFECTS
Concurrent use of phenytoin, phenobarbital, or carbamazepine with irinotecan may result in decreased levels of irinotecan, as well as its active metabolites, and decreased clinical effectiveness.

SEVERITY LEVEL
2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

PATIENT MANAGEMENT
Consideration should be given to substituting non-enzyme inducing anticonvulsants at least 2 weeks prior to irinotecan therapy.(1)

PREDISPOSING FACTORS
None determined.

REFERENCES

1. Camptosar (irinotecan hydrochloride) US prescribing information. Pharmacia .Camptosar (irinotecan hydrochloride) US prescribing information. Pharmacia & Upjohn Company May, 2010.
2. Kuhn JG. Influence of anticonvulsants on the metabolism and elimination of .Kuhn JG. Influence of anticonvulsants on the metabolism and elimination of irinotecan. A North American Brain Tumor Consortium preliminary report. Oncology (Huntingt) 2002 Aug;16(8 Suppl 7):33-40.
3. Mathijssen RH, Sparreboom A, Dumez H, van Oosterom AT, de Bruijn EA. .Mathijssen RH, Sparreboom A, Dumez H, van Oosterom AT, de Bruijn EA. Altered irinotecan metabolism in a patient receiving phenytoin. Anticancer Drugs 2002 Feb;13(2):139-40.
4. Murry DJ, Cherrick I, Salama V, Berg S, Bernstein M, Kuttesch N, Blaney .Murry DJ, Cherrick I, Salama V, Berg S, Bernstein M, Kuttesch N, Blaney SM. Influence of phenytoin on the disposition of irinotecan: a case report. J Pediatr Hematol Oncol 2002 Feb;24(2):130-3.
5. Gajjar A, Radomski K, Bowers D, Chintagumpala M, Thompson S, Houghton P, .Gajjar A, Radomski K, Bowers D, Chintagumpala M, Thompson S, Houghton P, Stewart C. Pharmacokinetics of Irinotecan (IRN) and metabolites in pediatric high-grade giloma patients with and without co-administration of enzyme-inducing anticonvulsants. 2000.
6. Reid J, Buckner L, Schaaf L, Cha S, Wright K, Marks R, Wiesenfeld M, .Reid J, Buckner L, Schaaf L, Cha S, Wright K, Marks R, Wiesenfeld M, Pfeifle D, Harfield A, Krook J, Duncan B, Miller L. Anticonvulsants alter the pharmacokinetics of Irinotecan (CPT-11) in patients with recurrent glioma. 2000.