1 INDICATIONS AND USAGE JOURNAVX is indicated for the treatment of moderate to severe acute pain, including postoperative pain, in adults.

JOURNAVX is a sodium channel blocker indicated for the treatment of moderate to severe acute pain, including postoperative pain, in adults.

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6 ADVERSE REACTIONS 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.