SUZETRIGINE: 407 Adverse Event Reports & Safety Profile

The active ingredient in JOURNAVX (suzetrigine) tablets is suzetrigine, a sodium channel blocker, which has the following chemical name: 4-[(2 R ,3 S ,4 S ,5 R )-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)oxolane-2-amido]pyridine-2-carboxamide. Its molecular formula is C 21 H 20 F 5 N 3 O 4 . Suzetrigine's molecular weight is 473.39 g/mol. Suzetrigine has the following structural formula: Suzetrigine is a white to off-white solid and is practically insoluble in water. JOURNAVX is available as a blue, film-coated tablet for oral administration containing 50 mg of suzetrigine and the following inactive ingredients: croscarmellose sodium, hypromellose acetate succinate, magnesium stearate, and microcrystalline cellulose. The tablet film coat contains FD&C Blue #2 aluminum lake, polyethylene glycol, polyvinyl alcohol-partially hydrolyzed, talc, and titanium dioxide.

Chemical

Structure

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. ( 1 )

AND ADMINISTRATION Swallow JOURNAVX tablets whole and do not chew or crush. ( 2.1 ) Recommended starting JOURNAVX oral dose is 100 mg. Take the starting dose on an empty stomach at least 1 hour before or 2 hours after food. Clear liquids may be consumed during this time (e.g., water, apple juice, vegetable broth, tea, black coffee). ( 2.1 )

Starting

12 hours after the starting dose, take 50 mg of JOURNAVX orally every 12 hours. Take these doses with or without food. ( 2.1 ) Use JOURNAVX for the shortest duration, consistent with individual patient treatment goals. Use of JOURNAVX for the treatment of acute pain has not been studied beyond 14 days. ( 2.1 ) See the full prescribing information for the recommended dosage in patients with hepatic impairment ( 2.2 ), for JOURNAVX dosage modifications with concomitant use of CYP3A inhibitors ( 2.3 ), and recommendations regarding missed dose(s). ( 2.4 ) Avoid food or drink containing grapefruit during treatment with JOURNAVX. ( 2.3 )

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 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span>. 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.

Table

1: Recommended JOURNAVX Dosage in Patients with Hepatic Impairment Degree of Hepatic Impairment (HI)

Recommended Dosage

Severe HI (Child-Pugh Class C) Avoid use [see Use in Specific Populations (8.6) ]. Moderate HI (Child-Pugh Class B)

Dose

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

Doses

2, 3, and 4 : 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) ].

Dose

5 and Subsequent Doses : Starting 12 hours after Dose 4, take 50 mg of JOURNAVX orally every 24 hours. Take these dose(s) with or without food [see Clinical Pharmacology (12.3) ]. Mild HI (Child-Pugh Class A) The recommended dosage is the same as in those with normal hepatic function [see Dosage and Administration (2.1) ].

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: Dose 1 : 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 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span>. Clear liquids may be consumed during this time (e.g., water, apple juice, vegetable broth, tea, black coffee).

Doses

2, 3, and 4 : 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) ].

Dose

5 and Subsequent Doses : Starting 12 hours after Dose 4, take 50 mg of JOURNAVX orally every 24 hours. Take these dose(s) with or without food [see Clinical Pharmacology (12.3) ]. Avoid food or drink containing grapefruit during treatment with JOURNAVX [see Drug Interactions (7.1) , Clinical Pharmacology (12.3) ].

2.4 Recommendations Regarding Missed Dose(s) For patients on the standard recommended dosing schedule <span class="opacity-50 text-xs">[see Dosage and Administration (2.1) ]</span> : 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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.2 , 2.3) ]</span> , 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.

Concomitant use of JOURNAVX with strong CYP3A inhibitors is contraindicated [see Warnings and Precautions (5.1) , Drug Interactions (7.1) ] . Concomitant use with strong CYP3A inhibitors is contraindicated. ( 4 )

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) <span class="opacity-50 text-xs">[see Clinical Studies (14) ]</span> , 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.

AND PRECAUTIONS Moderate and Severe Hepatic Impairment : Avoid use in patients with severe hepatic impairment (Child-Pugh Class C). Use in patients with moderate hepatic impairment may increase the risk of adverse reactions. The recommended dosage is lower in patients with moderate hepatic impairment (Child-Pugh Class B) than those with normal hepatic function. ( 5.4 )

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 <span class="opacity-50 text-xs">[see Drug Interactions (7.1) , Clinical Pharmacology (12.3) ]</span> . Reduce the JOURNAVX dosage with moderate CYP3A inhibitors <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) ]</span> .

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 <span class="opacity-50 text-xs">[see Drug Interactions (7.2) , Clinical Pharmacology (12.3) ]</span>.

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 <span class="opacity-50 text-xs">[see Drug Interactions (7.2) , Clinical Pharmacology (12.3) ]</span>.

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 <span class="opacity-50 text-xs">[see Use in Specific Populations (8.6) , Clinical Pharmacology (12.3) ]</span> . 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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.2) ]</span>.

INTERACTIONS 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 <span class="opacity-50 text-xs">[see Warnings and Precautions (5.2) ]</span> . 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 <span class="opacity-50 text-xs">[see Warnings and Precautions (5.2) , Clinical Pharmacology (12.3) ]</span> .

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) ] .