Drug Interactions between cimetidine and upadacitinib

GENERALLY AVOID: Grapefruit, grapefruit juice or supplements containing grapefruit may increase the plasma concentrations of upadacitinib. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in these fruits. Inhibition of hepatic CYP450 3A4 may also contribute. The interaction has not been studied with grapefruit. In study subjects, administration with the potent CYP450 3A4 inhibitor ketoconazole increased upadacitinib peak plasma concentration (Cmax) and systemic exposure (AUC) by 70% and 75%, respectively. 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. Upadacitinib side effects including lymphopenia, neutropenia, anemia, serious infections, and hyperlipidemia may be increased.

MONITOR CLOSELY: Smoking during treatment with upadacitinib may increase the risk of major adverse cardiovascular events (MACE) and the risk of developing malignancies. During upadacitinib clinical studies, current or past smokers had an additional increased risk of overall malignancies. Also, upadacitinib may increase patients' risk of MACE, including myocardial infarction, stroke, and cardiovascular death.

MANAGEMENT: The manufacturer advises that concomitant use of upadacitinib with grapefruit, grapefruit juice, or supplements containing grapefruit should be avoided. Caution is advised if upadacitinib is prescribed to current or past smokers. Patients should be informed about the symptoms of serious cardiovascular events and the steps to take if they occur. The manufacturer recommends discontinuing upadacitinib in patients who have experienced a myocardial infarction or stroke.

Concurrent use of cimetidine and ethanol may result in increased ethanol concentrations. The mechanism appears to be due to inhibition of gastric alcohol dehydrogenase by cimetidine, leading to increased bioavailability of the alcohol and inhibition of hepatic metabolism of alcohol. The clinical significance of this interaction is limited. More importantly, patients requiring cimetidine for gastrointestinal disease should be counseled to avoid alcohol to prevent worsening of their disease. The other H-2 receptor antagonists appear to have minimal effects on the concentrations of alcohol.

Caffeine effects may be increased in patients also taking cimetidine. The mechanism may be due to decreased caffeine metabolism induced by cimetidine. Although adequate clinical data are lacking, a reduction in dose or elimination of caffeine may be needed if excess CNS stimulation is observed.

H2 antagonists may reduce the clearance of nicotine. Cimetidine, 600 mg given twice a day for two days, reduced clearance of an intravenous nicotine dose by 30%. Ranitidine, 300 mg given twice a day for two days, reduced clearance by 10%. The clinical significance of this interaction is not known. Patients should be monitored for increased nicotine effects when using the patches or gum for smoking cessation and dosage adjustments should be made as appropriate.