Suzetrigine

Strong and Moderate CYP3A inhibitors : Concomitant use with strong CYP3A inhibitors is contraindicated. Reduce the JOURNAVX dose when used concomitantly with moderate CYP3A inhibitors. Avoid food or drink containing grapefruit. ( 2.3 , 7.1 , 12.3 ) Strong and Moderate CYP3A inducers : Avoid JOURNAVX use with strong or moderate CYP3A inducers. ( 7.1 , 12.3 ) CYP3A substrates : If JOURNAVX is used concomitantly with sensitive CYP3A substrates or CYP3A substrates where minimal concentration changes may lead to loss of efficacy, refer to the Prescribing Information for the CYP3A substrates for dosing instructions.

Dosage modification of the concomitant CYP3A substrates may be required when initiating or discontinuing JOURNAVX. ( 7.2 , 12.3 ) Hormonal contraceptives : JOURNAVX-treated patients using hormonal contraceptives containing progestins other than levonorgestrel and norethindrone should use an additional nonhormonal contraceptive method or an alternative hormonal contraceptive during concomitant use and for 28 days after JOURNAVX discontinuation. ( 7.2 )

7.1 Effect of Other Drugs on JOURNAVX Table 3 describes drug interactions where concomitant use of another drug affects the use of JOURNAVX. Table 3: Drug Interactions: Concomitant Use of Other Drugs that Affect the Use of JOURNAVX Strong and Moderate Food or drink containing grapefruit should be avoided during treatment with JOURNAVX. CYP3A Inhibitors Prevention or Management Strong CYP3A inhibitors: Concomitant use of JOURNAVX with strong CYP3A inhibitors is contraindicated [see Warnings and Precautions (5.1) ] . Moderate CYP3A inhibitors: Reduce the JOURNAVX dosage [see Dosage and Administration (2.3) , Warnings and Precautions (5.1) ] .

Mechanism and Clinical Effect(s) Suzetrigine and M6-SUZ are CYP3A substrates. Strong and moderate CYP3A inhibitors increase suzetrigine and M6-SUZ (active metabolite of suzetrigine) exposures [see Clinical Pharmacology (12.3) ], which may cause JOURNAVX adverse reactions . Strong and Moderate CYP3A Inducers Prevention or Management Avoid concomitant use of JOURNAVX with strong and moderate CYP3A inducers. Mechanism and Clinical Effect(s) Suzetrigine and M6-SUZ are CYP3A substrates. Concomitant use of strong or moderate CYP3A inducers results in reduced exposures of suzetrigine and M6-SUZ, which may result in reduced JOURNAVX efficacy [see Clinical Pharmacology (12.3) ] .

7.2 Effect of JOURNAVX on Other Drugs CYP3A Substrates If JOURNAVX is used concomitantly with sensitive CYP3A substrates or CYP3A substrates where minimal concentration changes may lead to loss of efficacy, refer to the Prescribing Information for the CYP3A substrates for dosing instructions. Dosage modification of the concomitant CYP3A substrates may be required when initiating or discontinuing JOURNAVX [see Warnings and Precautions (5.2) ] . Suzetrigine is an inducer of CYP3A. Concomitant use with JOURNAVX may reduce the exposure of sensitive CYP3A substrates which may decrease the efficacy of these substrates.

Discontinuation of JOURNAVX may increase the exposure of sensitive CYP3A substrates [see Warnings and Precautions (5.2) , Clinical Pharmacology (12.3) ] . Hormonal Contraceptives JOURNAVX-treated patients using hormonal contraceptives containing progestins other than levonorgestrel and norethindrone should use additional nonhormonal contraceptives (such as condoms), or use alternative contraceptives (such as a combined oral contraceptive containing ethinyl estradiol as the estrogen and levonorgestrel or norethindrone as the progestin, or an intrauterine system) during treatment with JOURNAVX and for 28 days after discontinuation of JOURNAVX [see Warnings and Precautions (5.3) ] .

JOURNAVX did not result in clinically significant changes in the pharmacokinetics of ethinyl estradiol and levonorgestrel when used concomitantly with an oral contraceptive containing ethinyl estradiol and levonorgestrel [see Clinical Pharmacology (12.3) ] .

8.1 Pregnancy Risk Summary There are no available data on the use of JOURNAVX during pregnancy to evaluate for a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. In animal reproduction studies in rats, effects on implantation and maintenance of pregnancy occurred at oral suzetrigine doses of ≥ 2.2-times the maximum recommended human dose (MRHD) when administered during early embryonic development or throughout organogenesis.

In a pre- and postnatal development study, reduced mean gestation length and increased postnatal pup mortality were observed at maternal rat exposures of 1.6-times the MRHD and decreased rat pup body weights were observed during the period of birth to weaning at maternal exposures of 2.2-times the MRHD. No malformations were observed when suzetrigine was administered orally to rats and rabbits during the period of organogenesis at doses up to 2.2- and 5.9-times, respectively, the MRHD. The clinical relevance of these findings is unclear. The background risk of major birth defects and miscarriage in patients with moderate to severe acute pain is unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data Suzetrigine was administered orally to pregnant rabbits during the period of organogenesis at 50, 100, and 200 mg/kg/day (approximately 1.6-, 3.1-, and 5.9-times, respectively, the steady state MRHD exposure based on AUC). Increased post-implantation loss and lower fetal body weight were observed at 200 mg/kg/day, which is a dose that also caused maternal toxicity.

No adverse embryofetal effects were observed at doses up to 100 mg/kg. Suzetrigine was administered orally to pregnant rats during the period of organogenesis at 5, 10, and 15 mg/kg/day (approximately 0.57-, 1.6-, and 2.2-times, respectively, the steady state MRHD exposure based on AUC). Increased post-implantation loss and lower number of live fetuses were observed at 15 mg/kg/day. No adverse embryofetal effects were observed at doses up to 10 mg/kg. Placental transfer of suzetrigine was observed in pregnant rats.

In a pre- and postnatal development study, suzetrigine was administered orally to pregnant rats at doses of 5, 10, and 15 mg/kg/day (approximately 0.57-, 1.6-, and 2.2-times, respectively, the steady state MRHD exposure based on AUC) from Gestation Day 6 through Lactation Day 20.…