Drug Interactions between acitretin and palovarotene

CONTRAINDICATED: Ethanol consumption with acitretin leads to the formation of etretinate, which has a much longer half-life than acitretin. Major human fetal abnormalities have been associated with the administration of acitretin, etretinate, and other retinoids. The longer elimination half-life of etretinate relative to acitretin increases the duration of teratogenic potential for female patients. In one case report of a patient with apparent sporadic ethanol intake, etretinate was present in plasma and fat for 52 months after acitretin was discontinued.

MANAGEMENT: Female patients should be warned that ethanol is contraindicated during active treatment with acitretin and for two months after cessation of therapy.

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.