Drug Interaction Report

MONITOR: Coadministration with weak inhibitors of CYP450 3A4 may increase the plasma concentrations and adverse effects of palovarotene, which is primarily metabolized by the isoenzyme. Pharmacokinetic modeling simulations suggest that coadministration of palovarotene with cimetidine, a weak CYP450 3A4 inhibitor, resulted in a slight increase in the Cmax and AUC of palovarotene of approximately 10%; however, the clinical significance is unknown. Increased concentrations of palovarotene may increase the risk of adverse effects such as dry skin, dry lips, alopecia, pruritus, erythema, paronychia, cellulitis, decubitus ulcer, xerophthalmia, night blindness, depression, mood alterations, and pseudotumour cerebri (benign intracranial hypertension).

MANAGEMENT: Caution and clinical monitoring are recommended if palovarotene is coadministered with weak CYP450 3A4 inhibitors. The benefits versus risks of coadministration should be assessed. Patients should be advised to notify their health care professional if they experience increased effects of palovarotene such as dry skin, dry lips, alopecia, pruritus, erythema, paronychia, cellulitis, decubitus ulcer, xerophthalmia, night blindness, depression, mood alterations, and pseudotumor cerebri.

GENERALLY AVOID: Grapefruit, pomelo, grapefruit hybrids, and juices or supplements containing these fruits may increase the plasma concentrations of palovarotene. 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 these fruits. Concomitant use of erythromycin, a moderate CYP450 3A4 inhibitor, with palovarotene at steady-state plasma levels increased its peak plasma concentration (Cmax) and systemic exposure (AUC) by 1.6 and 2.5-fold, 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. Increased concentrations of palovarotene may increase the risk of adverse effects such as dry skin, dry lips, alopecia, pruritus, erythema, paronychia, cellulitis, decubitus ulcer, xerophthalmia, night blindness, depression, mood alterations, and pseudotumour cerebri (benign intracranial hypertension).

ADJUST DOSE: Food increases oral absorption of palovarotene.

MANAGEMENT: The manufacturer advises that concomitant use of palovarotene with grapefruit, pomelo, grapefruit hybrids and juices or supplements containing these fruits should be avoided. To ensure maximal absorption, palovarotene should be administered with food.