Drug Interactions between aminophylline / ephedrine / guaifenesin / phenobarbital and irinotecan

GENERALLY AVOID: Coadministration with potent inducers of CYP450 3A4 may significantly decrease the plasma concentrations of irinotecan and its pharmacologically active metabolite, SN-38. Irinotecan is partially metabolized by CYP450 3A4 to inactive substances, and induction of this process results in less of the drug available for conversion to SN-38 via hepatic carboxylesterases. Available data also suggest induction of other enzymatic pathways (e.g., UGT1A1; carboxylesterases) and drug transporters (e.g., multispecific organic anion transporter, or MRP2; mitoxantrone-resistance half transporter protein, or MXR) that may be involved in the clearance of irinotecan and/or SN-38, although the extent to which they contribute to the interaction is unknown. In a study of patients with malignant glioma, irinotecan clearance was 61% greater in the group receiving enzyme-inducing anticonvulsants (n=34) than in the group receiving other anticonvulsants (n=22). In a study of pediatric high-grade glioma patients, a 1.5-fold increase in the median clearance of irinotecan and a 20-fold decrease in the median systemic exposure to SN-38 were observed in patients receiving enzyme-inducing anticonvulsants compared to those not receiving the anticonvulsants. Patients receiving enzyme-inducing anticonvulsants in these studies also experienced milder toxicities or tolerated higher dosages of irinotecan. In a phase II clinical trial, patients receiving irinotecan for malignant glioma had an unusually low incidence of toxicity, and AUCs of irinotecan and SN-38 were 40% and 25%, respectively, of those determined previously in patients with metastatic colorectal cancer. A pharmacokinetic interaction was suspected, as more than 90% of the glioma patients received concomitant enzyme-inducing anticonvulsants and/or dexamethasone, while the colorectal cancer patients did not. In a pediatric case study, irinotecan pharmacokinetics were determined in a 15-year-old boy on day 1 of two treatment cycles (50 mg/m2 daily for 5 days every 21 days)--one before and one after the addition of phenytoin. Irinotecan clearance increased by 168% and the AUC of irinotecan and SN-38 decreased by 63% and 60%, respectively, in the presence of phenytoin. Similarly, in a 14-year-old girl receiving irinotecan daily for 5 days on two consecutive weeks every 21 days for two cycles, pharmacokinetic studies on day 8 of each cycle showed that irinotecan clearance decreased by 42% and the AUC of irinotecan and SN-38 increased by 76% and 138%, respectively, following discontinuation of phenytoin just prior to cycle 2.

MANAGEMENT: Concomitant use of irinotecan with potent CYP450 3A4 inducers should generally be avoided. Consideration should be given to substituting nonenzyme-inducing agents at least one to two weeks prior to initiation of irinotecan therapy whenever possible.

MONITOR: Barbiturates may decrease serum levels and therapeutic effects of the methylxanthines. The mechanism is barbiturate induction of CYP450 3A4 and 1A2 hepatic metabolism of methylxanthines.

MANAGEMENT: Close observation for clinical and laboratory evidence of decreased methylxanthine effect is indicated if these drugs must be used together. Patients should be advised to notify their physician if they experience a worsening of their respiratory symptoms.

Ephedrine-methylxanthine combinations are used for the treatment of asthma but the efficacy of the combination has been questioned. This combination may lead to increased xanthine side effects. The mechanism is unknown, but may be related to synergistic pharmacologic effects. Patients using this combination should be closely monitored for side effects such as nausea, vomiting, tachycardia, nervousness, or insomnia. If side effects are noted, the dosage of the xanthine may need to be decreased.