Suzetrigine

The most common adverse reactions (greater incidence in JOURNAVX-treated patients compared to placebo-treated patients) were pruritus, muscle spasms, increased creatine phosphokinase, and rash. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Vertex Pharmaceuticals Incorporated at 1-877-634-8789 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety profile of JOURNAVX is primarily based on data from the pooled, double-blind, placebo- and active-controlled trials in 874 adult patients with moderate to severe acute pain following full abdominoplasty (Trial 1) and bunionectomy (Trial 2) [see Clinical Studies (14) ] , with supportive safety data from one single arm trial in 256 adult patients with moderate to severe acute pain in a broad range of acute pain conditions (Trial 3). In Trials 1 and 2, 874 patients received at least one dose of JOURNAVX. The proportion of patients in Trials 1 and 2 who discontinued study drug prematurely due to adverse events was: 0.6% in JOURNAVX-treated patients (postprocedural hematoma [0.2%], hypotension [0.2%], syncope [0.1%]), 0.6% in hydrocodone bitartrate/acetaminophen (HB/APAP)-treated patients (hypotension/orthostatic hypotension [0.2%], migraine [0.1%], intra-abdominal hematoma [0.1%], nausea [0.1%], pyrexia [0.1%]), and 0.2% in placebo-treated patients (hypotension [0.2%], tachycardia [0.2%]). The safety profile of JOURNAVX was also evaluated by the following subgroup analyses: age (≥ 18 to < 65 years and ≥ 65 years), sex, and race. Since most patients enrolled in the clinical trials were ≥ 18 to < 65 years of age, female, and white, there was insufficient data to detect differences in safety signals between these subgroups. Table 2 displays adverse reactions that occurred more frequently in JOURNAVX-treated patients than placebo-treated patients in the pooled Trials 1 and 2. Table 2: Adverse Reactions Reported in ≥1% of JOURNAVX-Treated Patients and Greater than Rate of Placebo in Two 48-hour Trials in Moderate to Severe Acute Pain (Trials 1 and 2, Pooled) Adverse Reactions (Preferred Term) Placebo (N = 438) n (%) JOURNAVX (N = 874) n (%) HB/APAP Patients received 5 mg/325 mg of oral hydrocodone bitartrate/acetaminophen (HB/APAP) every 6 hours. (N = 879) n (%) Pruritus 7 (1.6) 18 (2.1) 30 (3.4) Muscle spasms 2 (0.5) 11 (1.3) 6 (0.7) Increased blood creatine phosphokinase 2 (0.5) 10 (1.1) 7 (0.8) Rash 2 (0.5) 10 (1.1) 6 (0.7) Nausea and Vomiting In Trial 1, the incidence of patients who experienced either nausea or vomiting was 20% in JOURNAVX-treated patients, 33% in HB/APAP-treated patients, and 25% in placebo-treated patients. In Trial 2, the incidence of patients who experienced either nausea or vomiting was 9% in JOURNAVX-treated patients, 16% in HB/APAP-treated patients, and 12% in placebo-treated patients. Laboratory Abnormalities Creatine Phosphokinase Elevations: In Trials 1 and 2, 2.9% of JOURNAVX-treated patients and 1.2% of placebo-treated patients had a creatine phosphokinase (CPK) level > 3 times the upper limit of normal. The incidence of increased blood CPK was 1.1% in JOURNAVX-treated patients and 0.5% in placebo-treated patients. All reports of CPK elevations occurred in the post-surgical setting. There were no associated signs or symptoms, no serious adverse reactions, and no patients required treatment discontinuation or interruption. Decreased Estimated Glomerular Filtration Rate: In Trials 1 and 2, 2.5% of JOURNAVX-treated patients and 0.9% of placebo-treated patients had a decrease in estimated glomerular filtration rate (eGFR) of ≥ 25% but < 50%. Follow-up eGFR data for these controlled trials was not available after treatment discontinuation. Similar decreases in eGFR also occurred in Trial 3 (the open-label Phase 3 study) and appeared to resolve to baseline by the final safety follow-up visit. There was no control arm for comparison. There were no adverse reactions of eGFR decrease in JOURNAVX-treated patients. Adverse Reactions from the Open-Label Study (Trial 3) In an open-label study of patients with moderate to severe acute pain following a surgical procedure or nonsurgical condition [NCT05661734], a total of 256 adult patients received at least one dose of JOURNAVX. Patients received 100 mg as a first dose, then 50 mg every 12 hours and continued to receive JOURNAVX for up to 14 days or until their pain resolved. Rescue medication of 650 mg of acetaminophen and 400 mg of ibuprofen together every 6 hours was permitted as needed for pain relief. The patients' perceptions of pain control was captured by patient global assessment (PGA). The mean duration of treatment with JOURNAVX was 9.6 days. The majority of patients were female (68%), and the median age was 43 years (range: 18 to 78). In Trial 3, a total of 222 (87%) patients received JOURNAVX for post-surgical pain; orthopedic surgery was the most common (e.g., ligament operation, arthrodesis), followed by plastic surgery (e.g., liposuction, mammoplasty), otorhinolaryngologic surgery (e.g., nasal septal operation, turbinoplasty), and general and urologic surgery (e.g., inguinal hernia repair). Thirty-four (13%) patients received JOURNAVX for non-surgical pain (e.g., arthralgias, limb pain, and sprains/strains). The proportion of patients who discontinued study drug prematurely was 2% due to adverse events (arrhythmia [0.4%], nausea [0.4%], somnolence [0.4%], rash [0.4%]) and 1.6% due to lack of efficacy. The safety profile of JOURNAVX in Trial 3 was consistent with that observed in Trials 1 and 2.

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. Reduced mean gestation length and increased postnatal pup mortality between birth and Postnatal Day 4 were observed at ≥ 10 mg/kg and increased incidences of fully resorbed litters, lower live newborn pups, and reductions in pup body weights were observed at 15 mg/kg. No effects on learning and memory or sexual maturation were observed at dose up to 15 mg/kg/day. The effects on implantation, maintenance of pregnancy, reduced mean gestation length, and increased postnatal pup mortality in rats are of uncertain relevance to humans.

8.2 Lactation Risk Summary There are no data on the presence of suzetrigine or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. Suzetrigine is present in animal milk. When a drug is present in animal milk, it is likely that the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for JOURNAVX and any potential adverse effects on the breastfed child from JOURNAVX or from the underlying maternal condition.

8.3 Females and Males of Reproductive Potential Contraception Advise patients using hormonal contraceptives containing progestins other than levonorgestrel and norethindrone to use an additional nonhormonal contraceptive or to use alternative contraceptives during JOURNAVX treatment and for 28 days after discontinuation of JOURNAVX [see Drug Interactions (7.2) ]. Infertility In a female fertility study in rats, increased pre-implantation loss was observed at oral suzetrigine doses of ≥ 2.2-times the MRHD when administered prior to mating and through Gestation Day 7. Following discontinuation of suzetrigine for 4 weeks, the increased pre-implantation loss in rats was not observed. The finding in rats may be explained by the effect of suzetrigine on the rat progesterone receptor, which was more sensitive to suzetrigine than the human progesterone receptor based on in vitro studies. The finding in the rat study is of uncertain relevance to humans. JOURNAVX may reversibly impact the likelihood of females of reproductive potential to become pregnant while on treatment. Patients using contraceptives should continue to use contraceptives [see Nonclinical Toxicology (13.1) ].

8.4 Pediatric Use The safety and effectiveness of JOURNAVX has not been established in pediatric patients.

8.5 Geriatric Use Of the total 1130 patients with moderate to severe acute pain who received JOURNAVX in the Phase 3 studies [see Clinical Studies (14) ] , 71 patients (6.3%) were 65 years of age and older. Clinical studies of JOURNAVX did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients. However, based on population pharmacokinetic analyses in patients with ages ranging from 18 to 75 years, age does not have a clinically relevant impact on suzetrigine exposure [see Clinical Pharmacology (12.3) ] .

8.6 Hepatic Impairment JOURNAVX has not been studied in patients with severe hepatic impairment. Avoid use of JOURNAVX in patients with severe hepatic impairment (Child-Pugh Class C) [see Warnings and Precautions (5.4) ]. The recommended JOURNAVX dosage is lower in patients with moderate hepatic impairment (Child-Pugh Class B) [see Dosage and Administration (2.2) ] than those with normal hepatic function. The recommended dosage in patients with mild hepatic impairment (Child-Pugh Class A) is the same as those with normal hepatic function. Patients with moderate hepatic impairment had greater suzetrigine and M6-SUZ (the active metabolite) exposure than those with normal hepatic function [see Clinical Pharmacology (12.3) ] , which may increase the risk of suzetrigine adverse reactions.

8.7 Renal Impairment JOURNAVX has not been studied in patients with renal impairment of eGFR < 15 mL/min. Avoid use of JOURNAVX in patients with renal impairment of eGFR < 15 mL/min [see Clinical Pharmacology (12.3) ] . The recommended dosage in patients with eGFR > 15 mL/min is the same as those with normal kidney function.

12.1 Mechanism of Action Suzetrigine is a selective blocker of the Na V 1.8 voltage-gated sodium channel, compared to other known voltage-gated sodium channels (Na V 1.1 through 1.9). Na V 1.8 is expressed in peripheral sensory neurons including dorsal root ganglion neurons, where its role is to transmit pain signals (action potentials). By selectively inhibiting Na V 1.8 channels, suzetrigine inhibits transmission of pain signals to the spinal cord and brain. M6-SUZ, a major active metabolite, is a less potent inhibitor of Na V 1.8 than suzetrigine by 3.7-fold.

12.2 Pharmacodynamics Cardiac Electrophysiology At 2 times the exposure of the maximum recommended JOURNAVX dose, clinically significant QTc prolongation was not observed.

12.3 Pharmacokinetics The pharmacokinetic parameters for suzetrigine and its major active metabolite, M6-SUZ, are shown in Table 4. Table 4: Pharmacokinetic Parameters of Suzetrigine and M6-SUZ Suzetrigine M6-SUZ (Active Metabolite) Based on an in vitro electrophysiology assay in human dorsal root ganglion neurons, M6-SUZ is a less potent inhibitor of Na V1.8 than suzetrigine by 3.7-fold. AUC: area under the concentration versus time curve; CV: coefficient of variation; C max : maximum observed concentration; T max : time of maximum concentration; NA: not applicable General Information Steady State AUC 0-24h (CV%), µg*h/mL 11.5 (25.6%) 34.7 (25.6%) Steady State C max (CV%), µg/mL 0.62 (27.7%) 1.5 (24.5%) Time to 90% Steady State, days 3 5 Mean (CV%) Accumulation Ratio Based on simulations of a dose of 50 mg every 12 hours (q12h). 3.4 (30.2%) 4.5 (30.6%) Absorption Median T max (range), hours 3.0 hours (1.50, 5.03) 10.0 hours (4.0, 48.1) Distribution Suzetrigine and M6-SUZ do not partition preferentially into human red blood cells. Mean (CV%) Apparent Volume of Distribution, L 495 (25.0%) NA Protein Binding 99% 96% Elimination Mean (CV%) Effective Half-Life, hours 23.6 (36.2%) 33.0 (34.9%) Steady State Mean (CV%) Apparent Oral Clearance, L/hours 13.9 (37.5%) NA Metabolism Primary Pathway CYP3A CYP3A Excretion Primary Pathway Feces: 49.9% (9.1% SUZ and rest as metabolites) Urine: 44.0% (primarily as metabolites) Effect of Food Administration of 100 mg of JOURNAVX (the first dose) with a high-fat meal (800 to 1000 calories, 50% derived from fat), a moderate-fat meal (600 calories, 30% derived from fat), and a low-fat meal (up to 500 calories with no more than 25% derived from fat) resulted in decreased initial concentrations of suzetrigine and M6-SUZ in comparison to a fasted state. The median T max of suzetrigine and M6-SUZ in the fasted state was 3 hours and 8 to 10 hours, respectively. When administered in the fed state (high-fat meal or moderate-fat meal) the median T max of suzetrigine was delayed to 5 hours and the median T max of M6-SUZ was delayed to 24 hours. The C max 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 JOURNAVX administration. Administration of the second JOURNAVX dose of 50 mg with or without regard to meals is predicted to not affect the systemic exposures of suzetrigine and M6-SUZ. Specific Populations No clinically significant differences in pharmacokinetics of suzetrigine and M6-SUZ were observed based on age (18-75 years), sex, body weight (44-126 kg), race, and renal impairment (eGFR ≥ 15 mL/min by CKD-EPI equation with adjustment for the body surface area). The effect of renal impairment with eGFR < 15 mL/min on suzetrigine and M6-SUZ pharmacokinetics is unknown. Patients with Hepatic Impairment In patients with mild hepatic impairment (Child-Pugh Class A), no clinically significant differences in pharmacokinetics of suzetrigine and M6-SUZ were observed. In patients with moderate hepatic impairment (Child-Pugh Class B), at steady state, suzetrigine AUC 0-12h increased by 1.5-fold (90% CI: 1.1-2.1) and C max increased by 1.3-fold (90% CI: 1.0-1.7) and M6-SUZ AUC 0-12h and C max both increased by 1.2-fold (AUC 90% CI: 0.83-1.6; C max 90% CI: 0.84-1.6). The effect of severe hepatic impairment (Child-Pugh Class C) on suzetrigine and M6-SUZ pharmacokinetics is unknown. Drug Interaction Studies Clinical Studies and Model-Informed Approaches Strong CYP3A Inhibitors: Concomitant administration of itraconazole (a strong CYP3A inhibitor) with a single dose of JOURNAVX increased the geometric mean (90% CI) AUC 0-inf of suzetrigine and M6-SUZ by 4.8-fold (4.3-5.4) and 4.4-fold (3.6-5.4), respectively, while the geometric mean (90% CI) C max of suzetrigine increased by 1.5-fold (1.3-1.6) and C max of M6-SUZ decreased by 32% (24-39%) [see Drug Interactions (7.1) ] . Moderate CYP3A Inhibitors: Concomitant administration of fluconazole (a moderate CYP3A inhibitor) with JOURNAVX with the recommended dosage modification [see Dosage and Administration (2.3) ] is predicted to increase the geometric mean (90% CI) AUC tau of suzetrigine and M6-SUZ by 1.5-fold (1.4-1.5) and 1.2-fold (1.2-1.3), respectively, while the geometric mean (90% CI) C max of suzetrigine and M6-SUZ is predicted to increase by 1.4-fold (1.4-1.5) and 1.1-fold (1.1-1.2), respectively, when compared to the regular recommended dosage in the absence of fluconazole [see Dosage and Administration (2.3) , Drug Interactions (7.1) ] . Strong CYP3A Inducers: Concomitant administration of rifampin (strong CYP3A inducer) at steady state with a single dose of JOURNAVX decreased the geometric mean (90% CI) AUC 0-inf of suzetrigine and M6-SUZ by 93% (91-94%) and 85% (83-86%), respectively, while the geometric mean (90% CI) C max of suzetrigine decreased by 80% (75-83%) and the C max of M6-SUZ increased by 1.3-fold (1.1-1.5) [see Drug Interactions (7.1) ] . Moderate CYP3A Inducers: Concomitant administration of efavirenz (moderate CYP3A inducer) with a single dose of JOURNAVX is predicted to decrease the geometric mean (90% CI) AUC 0-t of suzetrigine and M6-SUZ by 63% (61-65%) and 60% (58-62%), respectively, while the geometric mean (90% CI) C max of suzetrigine is predicted to decrease by 29% (27-32%) and M6-SUZ is predicted to increase by 1.3-fold (1.3-1.4), respectively [see Drug Interactions (7.1) ] . Sensitive CYP3A Substrates: JOURNAVX administered 50 mg every 12 hours, at steady state decreased the geometric mean (90% CI) AUC 0-inf of midazolam (sensitive CYP3A substrate) by 48% (43-53%) and C max by 37% (27-45%) [see Drug Interactions (7.2) ]. Proton Pump Inhibitors: No clinically significant differences in suzetrigine and M6-SUZ pharmacokinetics were observed when JOURNAVX was used concomitantly with omeprazole. Other Drugs: No clinically significant differences in the pharmacokinetics of the following drugs were observed when used concomitantly with JOURNAVX: oral digoxin (P-gp substrate), ethinyl estradiol (hormonal contraceptive), or levonorgestrel (hormonal contraceptive). In Vitro Studies Cytochrome P450 (CYP450) Enzymes: Suzetrigine inhibits CYP2C8, CYP2C9, and CYP2C19, but is not expected to result in clinically significant drug interactions. Suzetrigine does not inhibit CYP1A2, CYP2B6, CYP2D6, and CYP3A enzymes, and M6-SUZ does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A enzymes. Suzetrigine induces CYP3A and to a lesser extent CYP2B6, CYP2C8, CYP2C9, and CYP2C19. Suzetrigine does not induce CYP1A2. UDP-Glucuronosyltransferase (UGT): Suzetrigine does not inhibit UGT1A1 . Transporter Systems: Suzetrigine and M6-SUZ are not substrates of BCRP, OATP1B1 or OATP1B3. Suzetrigine is not a P-gp substrate, but M6-SUZ is a P-gp substrate. Suzetrigine inhibits OATP1B1, OATP1B3 and OAT3 but is not expected to result in clinically significant drug interactions. Suzetrigine does not inhibit BCRP, OAT1, OCT2, MATE1, and MATE2/K transporters. M6-SUZ inhibits OATP1B1, OATP1B3, OAT1, and OAT3 but is not expected to result in clinically significant drug interactions. M6-SUZ does not inhibit P-gp, BCRP, OCT2, MATE1 and MATE2/K transporters.

The pharmacokinetic parameters for suzetrigine and its major active metabolite, M6-SUZ, are shown in Table 4. Table 4: Pharmacokinetic Parameters of Suzetrigine and M6-SUZ Suzetrigine M6-SUZ (Active Metabolite) Based on an in vitro electrophysiology assay in human dorsal root ganglion neurons, M6-SUZ is a less potent inhibitor of Na V1.8 than suzetrigine by 3.7-fold. AUC: area under the concentration versus time curve; CV: coefficient of variation; C max : maximum observed concentration; T max : time of maximum concentration; NA: not applicable General Information Steady State AUC 0-24h (CV%), µg*h/mL 11.5 (25.6%) 34.7 (25.6%) Steady State C max (CV%), µg/mL 0.62 (27.7%) 1.5 (24.5%) Time to 90% Steady State, days 3 5 Mean (CV%) Accumulation Ratio Based on simulations of a dose of 50 mg every 12 hours (q12h). 3.4 (30.2%) 4.5 (30.6%) Absorption Median T max (range), hours 3.0 hours (1.50, 5.03) 10.0 hours (4.0, 48.1) Distribution Suzetrigine and M6-SUZ do not partition preferentially into human red blood cells. Mean (CV%) Apparent Volume of Distribution, L 495 (25.0%) NA Protein Binding 99% 96% Elimination Mean (CV%) Effective Half-Life, hours 23.6 (36.2%) 33.0 (34.9%) Steady State Mean (CV%) Apparent Oral Clearance, L/hours 13.9 (37.5%) NA Metabolism Primary Pathway CYP3A CYP3A Excretion Primary Pathway Feces: 49.9% (9.1% SUZ and rest as metabolites) Urine: 44.0% (primarily as metabolites) Effect of Food Administration of 100 mg of JOURNAVX (the first dose) with a high-fat meal (800 to 1000 calories, 50% derived from fat), a moderate-fat meal (600 calories, 30% derived from fat), and a low-fat meal (up to 500 calories with no more than 25% derived from fat) resulted in decreased initial concentrations of suzetrigine and M6-SUZ in comparison to a fasted state. The median T max of suzetrigine and M6-SUZ in the fasted state was 3 hours and 8 to 10 hours, respectively. When administered in the fed state (high-fat meal or moderate-fat meal) the median T max of suzetrigine was delayed to 5 hours and the median T max of M6-SUZ was delayed to 24 hours. The C max 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 JOURNAVX administration. Administration of the second JOURNAVX dose of 50 mg with or without regard to meals is predicted to not affect the systemic exposures of suzetrigine and M6-SUZ. Specific Populations No clinically significant differences in pharmacokinetics of suzetrigine and M6-SUZ were observed based on age (18-75 years), sex, body weight (44-126 kg), race, and renal impairment (eGFR ≥ 15 mL/min by CKD-EPI equation with adjustment for the body surface area). The effect of renal impairment with eGFR < 15 mL/min on suzetrigine and M6-SUZ pharmacokinetics is unknown. Patients with Hepatic Impairment In patients with mild hepatic impairment (Child-Pugh Class A), no clinically significant differences in pharmacokinetics of suzetrigine and M6-SUZ were observed. In patients with moderate hepatic impairment (Child-Pugh Class B), at steady state, suzetrigine AUC 0-12h increased by 1.5-fold (90% CI: 1.1-2.1) and C max increased by 1.3-fold (90% CI: 1.0-1.7) and M6-SUZ AUC 0-12h and C max both increased by 1.2-fold (AUC 90% CI: 0.83-1.6; C max 90% CI: 0.84-1.6). The effect of severe hepatic impairment (Child-Pugh Class C) on suzetrigine and M6-SUZ pharmacokinetics is unknown. Drug Interaction Studies Clinical Studies and Model-Informed Approaches Strong CYP3A Inhibitors: Concomitant administration of itraconazole (a strong CYP3A inhibitor) with a single dose of JOURNAVX increased the geometric mean (90% CI) AUC 0-inf of suzetrigine and M6-SUZ by 4.8-fold (4.3-5.4) and 4.4-fold (3.6-5.4), respectively, while the geometric mean (90% CI) C max of suzetrigine increased by 1.5-fold (1.3-1.6) and C max of M6-SUZ decreased by 32% (24-39%) [see Drug Interactions (7.1) ] . Moderate CYP3A Inhibitors: Concomitant administration of fluconazole (a moderate CYP3A inhibitor) with JOURNAVX with the recommended dosage modification [see Dosage and Administration (2.3) ] is predicted to increase the geometric mean (90% CI) AUC tau of suzetrigine and M6-SUZ by 1.5-fold (1.4-1.5) and 1.2-fold (1.2-1.3), respectively, while the geometric mean (90% CI) C max of suzetrigine and M6-SUZ is predicted to increase by 1.4-fold (1.4-1.5) and 1.1-fold (1.1-1.2), respectively, when compared to the regular recommended dosage in the absence of fluconazole [see Dosage and Administration (2.3) , Drug Interactions (7.1) ] . Strong CYP3A Inducers: Concomitant administration of rifampin (strong CYP3A inducer) at steady state with a single dose of JOURNAVX decreased the geometric mean (90% CI) AUC 0-inf of suzetrigine and M6-SUZ by 93% (91-94%) and 85% (83-86%), respectively, while the geometric mean (90% CI) C max of suzetrigine decreased by 80% (75-83%) and the C max of M6-SUZ increased by 1.3-fold (1.1-1.5) [see Drug Interactions (7.1) ] . Moderate CYP3A Inducers: Concomitant administration of efavirenz (moderate CYP3A inducer) with a single dose of JOURNAVX is predicted to decrease the geometric mean (90% CI) AUC 0-t of suzetrigine and M6-SUZ by 63% (61-65%) and 60% (58-62%), respectively, while the geometric mean (90% CI) C max of suzetrigine is predicted to decrease by 29% (27-32%) and M6-SUZ is predicted to increase by 1.3-fold (1.3-1.4), respectively [see Drug Interactions (7.1) ] . Sensitive CYP3A Substrates: JOURNAVX administered 50 mg every 12 hours, at steady state decreased the geometric mean (90% CI) AUC 0-inf of midazolam (sensitive CYP3A substrate) by 48% (43-53%) and C max by 37% (27-45%) [see Drug Interactions (7.2) ]. Proton Pump Inhibitors: No clinically significant differences in suzetrigine and M6-SUZ pharmacokinetics were observed when JOURNAVX was used concomitantly with omeprazole. Other Drugs: No clinically significant differences in the pharmacokinetics of the following drugs were observed when used concomitantly with JOURNAVX: oral digoxin (P-gp substrate), ethinyl estradiol (hormonal contraceptive), or levonorgestrel (hormonal contraceptive). In Vitro Studies Cytochrome P450 (CYP450) Enzymes: Suzetrigine inhibits CYP2C8, CYP2C9, and CYP2C19, but is not expected to result in clinically significant drug interactions. Suzetrigine does not inhibit CYP1A2, CYP2B6, CYP2D6, and CYP3A enzymes, and M6-SUZ does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A enzymes. Suzetrigine induces CYP3A and to a lesser extent CYP2B6, CYP2C8, CYP2C9, and CYP2C19. Suzetrigine does not induce CYP1A2. UDP-Glucuronosyltransferase (UGT): Suzetrigine does not inhibit UGT1A1 . Transporter Systems: Suzetrigine and M6-SUZ are not substrates of BCRP, OATP1B1 or OATP1B3. Suzetrigine is not a P-gp substrate, but M6-SUZ is a P-gp substrate. Suzetrigine inhibits OATP1B1, OATP1B3 and OAT3 but is not expected to result in clinically significant drug interactions. Suzetrigine does not inhibit BCRP, OAT1, OCT2, MATE1, and MATE2/K transporters. M6-SUZ inhibits OATP1B1, OATP1B3, OAT1, and OAT3 but is not expected to result in clinically significant drug interactions. M6-SUZ does not inhibit P-gp, BCRP, OCT2, MATE1 and MATE2/K transporters.