Drug Interaction Report

MONITOR CLOSELY: Concomitant administration of corticosteroids may potentiate the risk of tendinitis and tendon rupture associated with fluoroquinolone treatment. The mechanism is unknown. Tendinitis and tendon rupture have most frequently involved the Achilles tendon, although cases involving the rotator cuff (the shoulder), the hand, the biceps, and the thumb have also been reported. Some have required surgical repair or resulted in prolonged disability. Tendon rupture can occur during or up to several months after completion of fluoroquinolone therapy.

MANAGEMENT: Caution is recommended if fluoroquinolones are prescribed in combination with corticosteroids, particularly in patients with other concomitant risk factors (e.g., age over 60 years; recipient of kidney, heart, and/or lung transplant). Patients should be advised to stop taking the fluoroquinolone, avoid exercise and use of the affected area, and promptly contact their physician if they experience pain, swelling, or inflammation of a tendon. In general, fluoroquinolones should only be used to treat conditions that are proven or strongly suspected to be caused by bacteria and only if the benefits outweigh the risks.

GENERALLY AVOID: Coadministration with potent and moderate inducers of CYP450 3A4 may significantly decrease the plasma concentrations of suzetrigine and M6-SUZ, a major active metabolite whose systemic exposure (AUC) at steady state is approximately 3 times that of the parent drug but exhibits 3.7-fold less potency in blocking the NaV1.8 voltage-gated sodium channels responsible for transmission of pain signals to the spinal cord and brain. Both suzetrigine and M6-SUZ are primarily metabolized by CYP450 3A4. When a single dose of suzetrigine was administered with the potent CYP450 3A4 inducer rifampin at steady state, mean suzetrigine peak plasma concentration (Cmax) and systemic exposure (AUC) decreased by 80% and 93%, respectively, while mean Cmax of M6-SUZ increased by 30% and AUC decreased by 85%. Coadministration with efavirenz, a moderate CYP450 3A4 inducer, is predicted to decrease the mean Cmax and AUC of suzetrigine by 29% and 63%, respectively, while the mean Cmax of M6-SUZ is predicted to increase by 30% and AUC to decrease by 60%. Reduced efficacy of suzetrigine may occur.

MANAGEMENT: Concomitant use of suzetrigine with potent or moderate CYP450 3A4 inducers should generally be avoided.

GENERALLY AVOID: Grapefruit and/or grapefruit juice may increase the plasma concentrations of suzetrigine and M6-SUZ, a major active metabolite whose systemic exposure (AUC) at steady state is approximately 3 times that of the parent drug but exhibits 3.7-fold less potency in blocking the NaV1.8 voltage-gated sodium channels responsible for transmission of pain signals to the spinal cord and brain. The proposed mechanism for the interaction is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Inhibition of hepatic CYP450 3A4 may also contribute. The interaction has not been studied with grapefruit juice but has been reported for other CYP450 3A4 inhibitors. When a single dose of suzetrigine was administered with itraconazole, a potent CYP450 3A4 inhibitor, mean suzetrigine peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 1.5- and 4.8-fold, respectively, while mean Cmax of M6-SUZ decreased by 32% and AUC increased by 4.4-fold. Coadministration of fluconazole, a moderate CYP450 3A4 inhibitor, with suzetrigine dosed according to the manufacturer's recommended dosage modification is predicted to increase the mean Cmax and AUC of suzetrigine by 1.4- and 1.5-fold, respectively, while the mean Cmax and AUC of M6-SUZ are predicted to increase by 1.1- and 1.2-fold, respectively, compared to suzetrigine administered at the regular recommended dosage without fluconazole. In general, the effects of grapefruit products are concentration-, dose- and preparation-dependent, and can vary widely among brands. Certain preparations of grapefruit (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.

ADJUST DOSE INTERVAL: Food may delay the absorption of suzetrigine without impacting the overall systemic exposures to parent drug and M6-SUZ. Administration of suzetrigine 100 mg (the first dose) with a high-fat meal (800 to 1000 calories; 50% from fat), a moderate-fat meal (600 calories; 30% from fat), and a low-fat meal (<=500 calories; <=25% from fat) resulted in decreased initial plasma concentrations of suzetrigine and M6-SUZ compared to administration in a fasted state. The median time to reach peak plasma concentration (Tmax) for suzetrigine and M6-SUZ when administered with either a high-fat or moderate-fat meal was 5 hours and 24 hours, respectively, versus 3 hours and 8 to 10 hours, respectively, when administered in the fasted state. The Cmax and AUC of suzetrigine and M6-SUZ were not affected by any of the meal conditions, including a high-fat meal consumed one hour after suzetrigine. Administration of the second suzetrigine dose of 50 mg with or without regard to meals is also predicted to have no effect on the systemic exposures of suzetrigine and M6-SUZ.

MANAGEMENT: Patients should avoid consumption of foods or drinks containing grapefruit during treatment with suzetrigine. The starting dose of 100 mg should be taken on an empty stomach at least 1 hour before or 2 hours after food, although clear liquids (e.g., water, apple juice, vegetable broth, tea, black coffee) may be consumed during this time. Subsequent doses may be taken with or without food.