2.1 Recommended Dosage and Administration Instructions

Swallow JOURNAVX tablets whole and do not chew or crush.

The recommended starting dose of JOURNAVX is 100 mg orally. Take the starting dose on an empty stomach at least 1 hour before or 2 hours after food to avoid delay in onset of action [see Clinical Pharmacology (12.3)]. Clear liquids may be consumed during this time (e.g., water, apple juice, vegetable broth, tea, black coffee).

Starting 12 hours after the initial dose, take 50 mg of JOURNAVX orally every 12 hours. Take these doses with or without food [see Clinical Pharmacology (12.3)].

Avoid food or drink containing grapefruit during treatment with JOURNAVX [see Dosage and Administration (2.3)].

Use JOURNAVX for the shortest duration, consistent with individual patient treatment goals. Use of JOURNAVX for the treatment of moderate to severe acute pain has not been studied beyond 14 days.

2.2 Recommended Dosage in Patients with Hepatic Impairment

The recommended dosage of JOURNAVX in patients with hepatic impairment is described in Table 1.

2.3 Dosage Modifications for CYP3A Inhibitors

JOURNAVX is contraindicated in patients taking strong CYP3A inhibitors. When JOURNAVX is administered to patients taking moderate CYP3A inhibitors reduce the JOURNAVX dose, as described below:

2.4 Recommendations Regarding Missed Dose(s)

For patients on the standard recommended dosing schedule [see Dosage and Administration (2.1)]:

• If a dose is missed, take the missed dose as soon as possible and then take the next scheduled dose at the recommended time.
• If two or more doses are missed, take 100 mg and then take the next scheduled dose at the recommended time.

For patients with moderate hepatic impairment or patients taking moderate CYP3A inhibitors [see Dosage and Administration (2.2, 2.3)], if a dose is missed, take the missed dose as soon as possible. If the next scheduled dose is within 6 hours, skip the next scheduled dose, and take the subsequent doses at the recommended time.

5.1 Increased Risk of Adverse Reactions with Concomitant Use with Strong or Moderate CYP3A Inhibitors

Strong and moderate CYP3A inhibitors increase suzetrigine and M6-SUZ (active metabolite) exposures which may cause JOURNAVX adverse reactions. Concomitant use of JOURNAVX with strong CYP3A inhibitors is contraindicated [see Drug Interactions (7.1), Clinical Pharmacology (12.3)]. Reduce the JOURNAVX dosage with moderate CYP3A inhibitors [see Dosage and Administration (2.3)].

5.2 Risk of Drug Interactions with Certain CYP3A Substrates

Suzetrigine is an inducer of CYP3A. 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 adjustment of the concomitant CYP3A substrates may be required when initiating or discontinuing JOURNAVX [see Drug Interactions (7.2), Clinical Pharmacology (12.3)].

5.3 Risk of Drug Interactions with Certain Hormonal Contraceptives

JOURNAVX-treated patients taking concomitant hormonal contraceptives containing progestins other than levonorgestrel and norethindrone should use additional nonhormonal contraceptives (such as condoms) or use alternative contraceptives (e.g., a combined oral contraceptive containing ethinyl estradiol as the estrogen and levonorgestrel or norethindrone as the progestin, an intrauterine system) during JOURNAVX treatment and for 28 days after discontinuation of JOURNAVX [see Drug Interactions (7.2), Clinical Pharmacology (12.3)].

5.4 Risk of Adverse Reactions in Patients with Moderate and Severe Hepatic Impairment

Patients with moderate hepatic impairment have higher systemic exposures of suzetrigine and M6-SUZ (active metabolite) than those with normal hepatic function which may increase the risk of JOURNAVX related adverse reactions [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].

Avoid use of JOURNAVX in patients with severe hepatic impairment (Child-Pugh Class C). The recommended JOURNAVX dosage is lower in patients with moderate hepatic impairment (Child-Pugh Class B) than those with normal hepatic function [see Dosage and Administration (2.2)].

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.

7.1 Effect of Other Drugs on JOURNAVX

Table 3 describes drug interactions where concomitant use of another drug affects the use of JOURNAVX.

7.2 Effect of JOURNAVX on Other Drugs

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

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 NaV1.8 voltage-gated sodium channel, compared to other known voltage-gated sodium channels (NaV1.1 through 1.9). NaV1.8 is expressed in peripheral sensory neurons including dorsal root ganglion neurons, where its role is to transmit pain signals (action potentials). By selectively inhibiting NaV1.8 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 NaV1.8 than suzetrigine by 3.7-fold.

12.2 Pharmacodynamics

12.3 Pharmacokinetics

The pharmacokinetic parameters for suzetrigine and its major active metabolite, M6-SUZ, are shown in Table 4.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14.1 Overview of Clinical Studies

The efficacy of JOURNAVX in the treatment of moderate to severe acute pain in adults was established in two randomized, double-blind, placebo and active-controlled trials of acute pain, one following full abdominoplasty (Trial 1) [see Clinical Studies (14.2)] and the other following bunionectomy (Trial 2) [see Clinical Studies (14.3)]. In each trial, pain intensity was measured using a patient-reported 11-point numeric pain rating scale (NPRS), ranging from 0 to 10, where zero corresponds to no pain and 10 corresponds to the worst pain imaginable.

Patients were eligible for study participation if they had moderate to severe pain on the verbal categorical rating system (VRS) and a pain score of ≥ 4 on the NPRS, within 4 hours of the abdominoplasty completion (Trial 1) or during the 9-hour period after discontinuation of regional anesthesia following bunionectomy (Trial 2). Once eligible, patients were randomized to receive oral JOURNAVX, placebo, or hydrocodone bitartrate/acetaminophen (HB/APAP) for a duration of 48 hours. For the JOURNAVX treatment regimen, patients received an initial loading dose of 100 mg JOURNAVX, followed by 50 mg every 12 hours. For the HB/APAP-control regimen, patients received 5 mg/325 mg every 6 hours. For both studies, 400 mg of ibuprofen every 6 hours, as needed for pain relief, was permitted as a rescue medication.

14.2 Moderate to Severe Acute Pain Following Full Abdominoplasty

Trial 1 [NCT05558410] evaluated the efficacy of JOURNAVX over 48 hours in 1,118 adult patients with moderate to severe acute pain following a full abdominoplasty procedure (JOURNAVX n = 447, placebo n = 223, and hydrocodone bitartrate/acetaminophen (HB/APAP) n = 448). The majority of patients were female (98%), and the mean age was 42 years (range: 18 to 69). The study population consisted of 70% White participants, 27% Black or African American participants, 1% Asian participants, 0.8% Native Hawaiian or other Pacific Islander participants, 0.5% American Indian or Alaska Native participants, and 0.9% Other or Multiracial participants, among which 34% identified as Hispanic or Latino. The mean pain score at baseline was 7.4 (range: 4 to 10). All baseline characteristics, including NPRS, VRS, and BMI were generally balanced across treatment arms.

In Trial 1, 89% of patients in the JOURNAVX group completed the treatment period (compared to 75% of patients in the placebo group and 85% of patients in the HB/APAP group), and 9% of patients in the JOURNAVX group discontinued due to lack of efficacy (compared to 22% of patients in the placebo group and 13% of patients in the HB/APAP group).

Efficacy was evaluated by the time-weighted sum of the pain intensity difference from 0 to 48 hours (SPID48) in the JOURNAVX group compared to the placebo group and then to the HB/APAP group. Treatment with JOURNAVX demonstrated statistically significant superior reduction in pain compared to treatment with placebo (see Table 5).

In an exploratory analysis, the time-weighted sum of the pain intensity difference from 0 to 24 hours (SPID24) reported using the least square mean was 48.0 for the JOURNAVX group and 24.2 for the placebo group. The mean pain intensities over time are depicted for the JOURNAVX, placebo, and HB/APAP groups in Figure 1.

Figure 1: Mean Pain Intensity Over Time in Adults with Moderate to Severe Acute Pain Following Full Abdominoplasty (Trial 1)

Note: Pre-rescue pain scores were carried forward for 6 hours following the use of rescue medication. HB/APAP = hydrocodone bitartrate/acetaminophen

14.3 Moderate to Severe Acute Pain Following Bunionectomy

Trial 2 [NCT05553366] evaluated the efficacy of JOURNAVX over 48 hours in 1,073 adult patients with moderate to severe acute pain following bunionectomy (JOURNAVX n = 426, placebo n = 216, and HB/APAP n = 431). The majority of patients were female (85%), and the mean age was 48 years (range: 18 to 75). The study population consisted of 71% White participants, 24% Black or African American participants, 2% Asian participants, 0.2% Native Hawaiian or other Pacific Islander participants, 1% American Indian or Alaska Native participants, and 1% Other or Multiracial participants, and 0.3% with race missing, among which 34% identified as Hispanic or Latino. The mean pain score at baseline was 6.8 (range: 4 to 10). All baseline characteristics, including NPRS, VRS, and BMI were generally balanced across treatment arms.

In Trial 2, 87% of patients in the JOURNAVX group completed the treatment period (compared to 82% of patients in the placebo group and 90% of patients in the HB/APAP group), and 12% of patients in the JOURNAVX group discontinued due to lack of efficacy (compared to 16% of patients in the placebo group and 8% of patients in the HB/APAP group).

Efficacy was evaluated by the time-weighted sum of the pain intensity difference from 0 to 48 hours (SPID48) in the JOURNAVX group compared to the placebo group and then to the HB/APAP group. Treatment with JOURNAVX demonstrated statistically significant superior reduction in pain compared to treatment with placebo (see Table 6).

In an exploratory analysis, the time-weighted sum of the pain intensity difference from 0 to 24 hours (SPID24) reported using the least square mean was 30.6 in the JOURNAVX group and 19.8 in the placebo group. The mean pain intensities over time are depicted for the JOURNAVX, placebo, and HB/APAP groups in Figure 2.

Figure 2: Mean Pain Intensity Over Time in Adults with Moderate to Severe Acute Pain Following Bunionectomy (Trial 2)

Note: Pre-rescue pain scores were carried forward for 6 hours following the use of rescue medication. HB/APAP = hydrocodone bitartrate/acetaminophen

Store at 68°F to 77°F (20°C to 25°C); excursions permitted to 59°F to 86°F (15°C to 30°C) [see USP Controlled Room Temperature].

Drug Interactions

Ask patients to tell you all the medications they are taking, including any herbal supplements or vitamins [see Drug Interactions (7)].

Food or drink containing grapefruit should be avoided [see Dosage and Administration (2.3), Drug Interactions (7.1)].

When used concomitantly with hormonal contraceptives containing a progestin other than levonorgestrel or norethindrone, advise patients to use an additional nonhormonal contraceptive (such as condoms) or use alternative contraceptives during JOURNAVX treatment and for 28 days after discontinuation of JOURNAVX [see Drug Interactions (7.2)].

Females of Reproductive Potential

Advise females of reproductive potential that JOURNAVX may reversibly impact the likelihood to become pregnant while on treatment. Patients using contraceptives should continue to use contraceptives [see Use in Specific Populations (8.3)].

Use in Patients with Hepatic Impairment

Inquire and/or assess whether patients have hepatic impairment.

Administration Instructions

Advise patients to take the starting dose of JOURNAVX on an empty stomach at least 1 hour before or 2 hours after food to avoid delay in onset of action. Clear liquids may be consumed (such as water, apple juice, vegetable broth, tea, or black coffee) during this time. Avoid food or drink containing grapefruit during treatment with JOURNAVX [see Dosage and Administration (2.2, 2.3)].

Subsequent doses of JOURNAVX can be taken with or without food.

Patients should be instructed to swallow JOURNAVX tablets whole (do not chew or crush).

Inform patients about what to do in the event they miss a dose of JOURNAVX [see Dosage and Administration (2.4)].