Drug Interactions between pralsetinib and Propoxyphene Compound 65

GENERALLY AVOID: Alcohol may have additive CNS- and/or respiratory-depressant effects with propoxyphene. Misuse of propoxyphene, either alone or in combination with other CNS depressants, has been a major cause of drug-related deaths, particularly in patients with a history of emotional disturbances, suicidal ideation, or alcohol and drug abuse.

MANAGEMENT: The use of alcohol during propoxyphene therapy should be avoided. Patients should be warned not to exceed the recommended dosage of propoxyphene and to avoid activities requiring mental alertness until they know how these agents affect them.

ADJUST DOSING INTERVAL: Food significantly increases the oral bioavailability of pralsetinib. According to the product labeling, administration of pralsetinib (200 mg) with a high-fat meal (approximately 800 to 1000 calories; 50% to 60% from fat) increased mean pralsetinib peak plasma concentration (Cmax) and systemic exposure (AUC) by 104% and 122%, respectively. The median time to maximum concentration (Tmax) was delayed from 4 hours to 8.5 hours, when compared to the fasted state.

GENERALLY AVOID: The juice of grapefruit and/or Seville oranges may increase the plasma concentrations of pralsetinib. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit and Seville oranges. In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands. Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition. Increased exposure to pralsetinib may increase the risk of adverse effects such as interstitial lung disease/pneumonitis, liver transaminase elevations, hypertension, and hemorrhage. Some clinical trials have also observed prolongation of the QT interval in patients on pralsetinib, though this was not observed in a study of 34 patients with rearranged during transfection (RET)-altered solid tumors on pralsetinib at the recommended dosage.

MANAGEMENT: Pralsetinib should be administered on an empty stomach, with no food intake recommended for at least 2 hours before and at least 1 hour after taking the medication. Patients should avoid consumption of grapefruit, grapefruit juice, Seville oranges, or Seville orange juice during treatment with pralsetinib.

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.