Drug Interactions between aspirin / caffeine / dihydrocodeine and ibrutinib

GENERALLY AVOID: Coadministration with grapefruit, grapefruit juice, or Seville oranges may significantly increase the plasma concentrations of ibrutinib. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Pharmacokinetic modeling suggests that other moderate CYP450 3A4 inhibitors such as diltiazem and erythromycin may increase ibrutinib systemic exposure (AUC) by 6- to 9-fold under fasting condition. The safety and efficacy of these exposures are unknown. The highest ibrutinib dose evaluated in clinical trials was 12.5 mg/kg (actual doses of 840 to 1400 mg) given for 28 days, which yielded single dose AUC values that were approximately 50% greater than steady-state exposures seen at the highest indicated dose of 560 mg.

ADJUST DOSING INTERVAL: Food increases the oral bioavailability of ibrutinib. The mechanism of interaction is unknown. According to the product labeling, administration with food increases ibrutinib exposure approximately 2-fold compared to administration after overnight fasting.

MANAGEMENT: Patients treated with ibrutinib should avoid consumption of Seville oranges, grapefruit, grapefruit juice, and any supplement containing grapefruit extract. Ibrutinib should be taken once daily at approximately the same time each day.

GENERALLY AVOID: The concurrent use of aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs) and ethanol may lead to gastrointestinal (GI) blood loss. The mechanism may be due to a combined local effect as well as inhibition of prostaglandins leading to decreased integrity of the GI lining.

MANAGEMENT: Patients should be counseled on this potential interaction and advised to refrain from alcohol consumption while taking aspirin or NSAIDs.

The effect of grapefruit juice on the pharmacologic activity of caffeine is controversial. One report suggests that grapefruit juice increases the effect of caffeine. The proposed mechanism is inhibition of cytochrome P-450 metabolism of caffeine. However, a well-conducted pharmacokinetic/pharmacodynamic study did not demonstrate this effect. The clinical significance of this potential interaction is unknown.

One study has reported that coadministration of caffeine and aspirin lead to a 25% increase in the rate of appearance and 17% increase in maximum concentration of salicylate in the plasma. A significantly higher area under the plasma concentration time curve of salicylate was also reported when both drugs were administered together. The exact mechanism of this interaction has not been specified. Physicians and patients should be aware that coadministration of aspirin and caffeine may lead to higher salicylate levels faster.