Drug Interactions between aspirin / caffeine / dihydrocodeine and diroximel fumarate

GENERALLY AVOID: Food does not significantly affect the oral bioavailability of diroximel fumarate. Administration of diroximel fumarate with a high-fat, high-calorie (900 to 1000 calories; 50% from fat) meal did not affect the systemic exposure (AUC) of its active metabolite, monomethyl fumarate (MMF), but decreased its peak plasma concentration (Cmax) by 44% and prolonged the time to reach peak concentration (Tmax) from 2.5 to 7.0 hours relative to administration in the fasted state. In comparison, administration of diroximel fumarate with low-fat, low-calorie (350 to 400 calories; 10 to 15 g fat) and medium-fat, medium-calorie (650 to 700 calories; 25 to 30 g fat) meals decreased the MMF Cmax by approximately 12% and 25%, respectively, while also leaving the AUC unaffected.

GENERALLY AVOID: Coadministration of diroximel fumarate with ethanol may reduce the plasma concentrations of monomethyl fumarate (MMF). The mechanism has not been reported. Following coadministration with 240 mL of 5% v/v and 40% v/v ethanol, the mean Cmax of MMF was reduced by 9% and 21%, respectively, relative to coadministration with water. The AUC of MMF was not significantly altered, indicating that ethanol did not induce dose dumping.

MANAGEMENT: Diroximel fumarate may be taken with or without food; however, high-fat, high-calorie meals or snacks should be avoided. The manufacturer recommends meals or snacks containing no more than 700 calories and no more than 30 grams of fat. Taking diroximel fumarate with food may improve tolerability for patients experiencing flushing or gastrointestinal adverse reactions. The manufacturer also recommends avoiding concomitant use of diroximel fumarate with ethanol.

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.