Drug Interactions between nirmatrelvir / ritonavir 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.

ADJUST DOSING INTERVAL: Administration with food may modestly affect the bioavailability of ritonavir from the various available formulations. When the oral solution was given under nonfasting conditions, peak ritonavir concentrations decreased 23% and the extent of absorption decreased 7% relative to fasting conditions. Dilution of the oral solution (within one hour of dosing) with 240 mL of chocolate milk or a nutritional supplement (Advera or Ensure) did not significantly affect the extent and rate of ritonavir absorption. When a single 100 mg dose of the tablet was administered with a high-fat meal (907 kcal; 52% fat, 15% protein, 33% carbohydrates), approximately 20% decreases in mean peak concentration (Cmax) and systemic exposure (AUC) were observed relative to administration after fasting. Similar decreases in Cmax and AUC were reported when the tablet was administered with a moderate-fat meal. In contrast, the extent of absorption of ritonavir from the soft gelatin capsule formulation was 13% higher when administered with a meal (615 KCal; 14.5% fat, 9% protein, and 76% carbohydrate) relative to fasting.

MANAGEMENT: Ritonavir should be taken with meals to enhance gastrointestinal tolerability.