CRINECERFONT: 57 Adverse Event Reports & Safety Profile

CRENESSITY contains crinecerfont, a selective corticotropin-releasing factor type 1 receptor antagonist, present as crinecerfont free base, with the chemical name, 2-thiazolamine, 4-(2-chloro-4-methoxy-5-methylphenyl)- N -[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl- N -2-propyn-1-yl. Crinecerfont free base is the S-enantiomer with an enantiomeric excess of at least 99.7%. Its molecular formula is C 27 H 28 ClFN 2 OS, and its molecular weight is 483.04 g/mol with the following structure: CRENESSITY Capsules CRENESSITY capsules are intended for oral administration only. Each capsule contains 25 mg, 50 mg, or 100 mg of crinecerfont free base. Inactive ingredients include lauroyl polyoxyl-32 glycerides, medium chain triglycerides, propylene glycol dicaprylate/dicaprate, and Vitamin E polyethylene glycol succinate. The capsule shell contains gelatin, glycerin, red iron oxide, Sorbitol glycerin blend, titanium dioxide, and yellow iron oxide.

Crenessity

Oral Solution The oral solution formulation contains 50 mg/mL of crinecerfont free base. Inactive ingredients include butylated hydroxytoluene, medium-chain triglycerides, oleoyl polyoxyl glycerides, orange flavor, and saccharin. Its molecular formula is C27H28ClFN2OS, and its molecular weight is 483.04 g/mol with the following structure

AND USAGE CRENESSITY is indicated as adjunctive treatment to glucocorticoid replacement to control androgens in adults and pediatric patients 4 years of age and older with classic congenital adrenal hyperplasia (CAH) . CRENESSITY is a corticotropin-releasing factor type 1 receptor antagonist indicated as adjunctive treatment to glucocorticoid replacement to control androgens in adults and pediatric patients 4 years of age and older with classic congenital adrenal hyperplasia (CAH).

AND ADMINISTRATION Continue glucocorticoid replacement therapy for adrenal insufficiency associated with CAH. ( 2.1 ) Adults : 100 mg orally, twice daily with a meal in the morning and evening. ( 2.2 )

Pediatric

Patients (4 years of age and older ) : Weight-based dosage orally, twice daily with a meal in the morning and evening. ( 2.2 )

See Full Prescribing

Information for complete dosage and administration information.

2.1 Important Administration Information Patients receiving CRENESSITY should continue glucocorticoid replacement therapy for the adrenal insufficiency associated with congenital adrenal hyperplasia (see Warning and Precautions ( 5.2 ) . Androstenedione levels can be assessed beginning four weeks after CRENESSITY initiation to inform reduction in glucocorticoid dosage as clinically indicated. Do not reduce the glucocorticoid dosage below that required for replacement therapy.

2.2 Recommended Dosage and Administration Recommended Dosage for Adults The recommended CRENESSITY dosage for adults is 100 mg orally, twice daily with a meal in the morning and evening <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> .

Recommended

Dosage for Pediatric Patients 4 Years of Age and Older The recommended CRENESSITY dosage for pediatric patients 4 years of age and older is weight-based and administered orally, twice daily with a meal in the morning and evening (see Table 1 ) [see Clinical Pharmacology ( 12.3 )] .

Table

1 : Recommended CRENESSITY Weight-Based Dosage for Pediatric Patients 4 Years of Age and Older Weight Dosage Regimen with a Meal 10 kg to less than 20 kg 25 mg orally twice daily 20 kg to less than 55 kg 50 mg orally twice daily Greater than or equal to 55 kg 100 mg orally twice daily

2.3 Dosage Modifications for Concomitant Use with Strong CYP3A4 Inducers Adults In adults, increase the CRENESSITY dosage to 200 mg orally, twice daily with a meal in the morning and evening when used concomitantly with strong CYP3A4 inducers <span class="opacity-50 text-xs">[see Drug Interactions ( 7.1 )]</span> .

Pediatric Patients

4 Years of Age and Older In pediatric patients, increase the CRENESSITY dosage with a meal in the morning and evening when used concomitantly with strong CYP3A4 inducers as shown in Table 2 [see Drug Interactions ( 7.1 ) ].

Table

2 : Dosage Increase of CRENESSITY for Use with Strong CYP3A4 Inducers in Pediatric Patients 4 Years of Age and Older Weight Dosage Regimen with a Meal 10 kg to less than 20 kg 50 mg orally twice daily 20 kg to less than 55 kg 100 mg orally twice daily Greater than or equal to <55 kg 200 mg orally twice daily

2.4 Dosage Modifications for Concomitant Use with Moderate CYP3A4 Inducers Adults In adults, increase the CRENESSITY dosage to 200 mg orally with the evening meal when used concomitantly with moderate CYP3A4 inducers. The CRENESSITY dosage of 100 mg with the morning meal remains unchanged <span class="opacity-50 text-xs">[see Drug Interactions ( 7.1 )]</span> .

Pediatric Patients

4 Years of Age and Older In pediatric patients, increase the CRENESSITY dosage with the evening meal when used concomitantly with moderate CYP3A4 inducers as shown in Table 3 [see Drug Interactions ( 7.1 )] .

Table

3 .

Dosage

Increase of CRENESSITY for Use with Moderate CYP3A4 Inducers in Pediatric Patients 4 Years of Age and Older Dosage Regimen with a Meal Weight Morning Dose Evening Dose 10 kg to less than 20 kg 25 mg orally 50 mg orally 20 kg to less than 55 kg 50 mg orally 100 mg orally Greater than or equal to 55 kg 100 mg orally 200 mg orally 2. 5 Administration Instructions Administer CRENESSITY orally, twice daily, with a meal in the morning and evening [see Clinical Pharmacology ( 12.3 )].

Crenessity

Capsules Take CRENESSITY capsules orally and swallow whole with liquid.

Crenessity

Oral Solution Refer patients and/or caregivers to the Instructions for Use (IFU) for complete administration instructions. Discard any unused CRENESSITY oral solution after 30 days of first opening the bottle [see How Supplied/Storage and Handling ( 16.2 )]. 2. 6 Missed Doses If a dose or doses are missed, advise the patient to take one dose of CRENESSITY as soon as possible (even if it is soon before the next scheduled dose) and then to resume the regular dosing schedule.

CRENESSITY is contraindicated in patients with hypersensitivity to crinecerfont or any excipients of CRENESSITY. Reactions have included throat tightness, angioedema, and generalized rash [see Warnings and Precautions ( 5.1 )] . Hypersensitivity to crinecerfont or any excipients of CRENESSITY. ( 4 )

REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Hypersensitivity Reactions [see Warnings and Precautions ( 5.1 )] Risk of Acute Adrenal Insufficiency or Adrenal Crisis with Inadequate Concomitant Glucocorticoid Therapy [see Warnings and Precautions ( 5.2 )] Adults: Most common adverse reactions (at least 4% for CRENESSITY and greater than placebo) are fatigue, headache, dizziness, arthralgia, back pain, decreased appetite, and myalgia. ( 6.1 )

Pediatric

Patients: Most common adverse reactions (at least 4% for CRENESSITY and greater than placebo) are headache, abdominal pain, fatigue, nasal congestion, and epistaxis. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Neurocrine Biosciences, Inc. at 877-641-3461 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. Adults with Congenital Adrenal Hyperplasia ( CAH) The safety of CRENESSITY in adults was assessed in Study 1, a randomized, double-blind, placebo-controlled study of 182 adults aged 18 to 58 years with classic CAH due to 21-hydroxylase deficiency. A total of 122 subjects received CRENESSITY 100 mg twice daily and 59 subjects received placebo twice daily for up to 24 weeks <span class="opacity-50 text-xs">[see Clinical Studies ( 14.1 )]</span> .

Adverse Reactions

Leading to Discontinuation of Treatment A total of 3% of CRENESSITY-treated subjects and no placebo-treated subjects discontinued treatment because of adverse reactions of restlessness, apathy, dyspepsia, nausea, and vomiting.

Commonly Observed Adverse Reactions

Adverse reactions that occurred in ≥4% of CRENESSITY-treated subjects and more frequently than in placebo-treated subjects are presented in Table 4 .

Table

4 : Adverse Reactions (≥4%) in Adults with Congenital Adrenal Hyperplasia Treated with CRENESSITY and Occurring More Frequently Than in Placebo-Treated Subjects Adverse Reactions CRENESSITY (N=122) % Placebo (N=59) % Fatigue 25 15 Headache 16 15 Dizziness 8 3 Arthralgia 7 0 Back pain 6 3 Decreased appetite 4 2 Myalgia 4 3 Suicidal Ideation and Behavior Study 1 excluded subjects with active suicidal ideation with intent or plan within the six months prior to screening and those with a history of suicidal behavior within the past year, based on the Columbia-Suicide Severity Rating Scale (C-SSRS) administered at screening. The C-SSRS was administered to subjects at regular intervals during the study. Three of 122 (2.5%) CRENESSITY-treated subjects reported suicidal ideation without method, intent or plan on the C-SSRS during the 24-week double-blind treatment period compared to 1 of 59 (1.7%) placebo-treated subjects. One of the three subjects receiving CRENESSITY and the placebo-treated subject reported a lifetime history of suicidal ideation. One CRENESSITY-treated subject without a history of suicidal ideation or behavior attempted suicide during the open-label period after 320 days of treatment.

Laboratory Findings

Neutrophil count less than 2 x 10 3 cells/mcL occurred in 14% (17 of 120) of CRENESSITY-treated subjects, compared to 5% (3 of 58) of subjects in the placebo group. Neutrophil count less than 1 x 10 3 cells/mcL occurred in 0.8% (1 of 120) of CRENESSITY-treated subjects, compared to 1.7% subjects (1 of 58) in the placebo group.

Pediatric

Patients with Congenital Adrenal Hyperplasia The safety of CRENESSITY in pediatric patients was evaluated in Study 2, a randomized, double-blind placebo-controlled study of 103 pediatric subjects aged 4 to 17 years with classic CAH due to 21-hydroxylase deficiency. Pediatric subjects were randomized to receive CRENESSITY twice daily (N=69) or placebo (N=34) for 28 weeks, using weight-based dosing (50 mg twice daily via oral solution for subjects 20 to <55 kg, or 100 mg twice daily via oral capsules for subjects ≥55 kg) [see Clinical Studies ( 14.2 )] .

Adverse Reactions

Leading to Discontinuation of Treatment A total of 3% of CRENESSITY-treated subjects and no placebo-treated subjects discontinued treatment because of adverse reactions of abdominal pain, myalgia, and dizziness.

Commonly Observed Adverse Reactions

Adverse reactions that occurred at an incidence of ≥4% in CRENESSITY-treated pediatric subjects (50 mg twice daily or 100 mg twice daily) and greater than placebo are presented in Table 5 .

Table

5 : Adverse Reactions (≥ 4%) in Pediatric Subjects with Congenital Adrenal Hyperplasia Treated with CRENESSITY and Occurring More Frequently Than in Placebo-Treated Subjects Adverse Reactions CRENESSITY (N=69) % Placebo (N=33) % Headache 25 6 Abdominal pain 1 13 0 Fatigue 7 0 Nasal congestion 7 3 Epistaxis 4 0 1 Abdominal pain includes: abdominal pain, abdominal pain upper and abdominal pain lower Suicidal Ideation and Behavior Study 2 excluded subjects with active suicidal ideation with intent or plan within six months prior to screening or those with a lifetime history of suicidal behavior based on the C-SSRS administered at screening. Four of 67 (6%) CRENESSITY-treated subjects and 0 of the 31 (0%) placebo-treated subjects reported suicidal ideation without method, intent or plan on the C-SSRS during the 28-week double-blind treatment period. Two of the four CRENESSITY-treated subjects reported a lifetime history of suicidal ideation. There were no completed suicides or suicide attempts.

Laboratory Findings

Neutrophil count less than 2 x 10 3 cells/mcL occurred in 37% (25 of 68) of CRENESSITY-treated subjects, compared to 16% (5 of 32) of subjects in the placebo group. Neutrophil count less than 1 x 10 3 cells/mcL occurred in 4% (3 of 68) of CRENESSITY-treated subjects, compared to no subjects (0 of 32) in the placebo group.

AND PRECAUTIONS Hypersensitivity Reactions: Include throat tightness, angioedema, and generalized rash. If clinically significant hypersensitivity occurs, initiate appropriate therapy and discontinue CRENESSITY. ( 5.1 ) Risk of Acute Adrenal Insufficiency or Adrenal Crisis with Inadequate Concomitant Glucocorticoid Therapy: Continue glucocorticoids upon initiation of and during treatment with CRENESSITY. Do not reduce the glucocorticoid dose below the dose required for cortisol replacement. Any adjustment of daily glucocorticoid dosage after initiation of CRENESSITY should be performed under the supervision of a health care provider. Use glucocorticoid stress doses in cases of increased cortisol need (e.g., acute intercurrent illness, serious trauma, surgical procedures). ( 5.2 )

5.1 Hypersensitivity Reactions A hypersensitivity reaction, including throat tightness, angioedema, and generalized rash, occurred in a subject after 3 days of treatment with CRENESSITY. If a clinically significant hypersensitivity reaction occurs, initiate appropriate therapy and discontinue CRENESSITY. 5. 2 Risk of Acute Adrenal Insufficiency or Adrenal Crisis w ith Inadequate Concomitant Glucocorticoid Therapy Continue glucocorticoids upon initiation of and during treatment with CRENESSITY. Do not reduce the glucocorticoid dose below the dose required for cortisol replacement. Acute adrenal insufficiency or adrenal crisis, which can potentially be fatal or life-threatening, can occur in patients with underlying adrenal insufficiency who are on inadequate daily glucocorticoid doses, especially in situations associated with increased cortisol need, such as acute intercurrent illness, serious trauma, or surgical procedures. Any adjustment of daily glucocorticoid dosage after initiation of CRENESSITY should be performed under the supervision of a health care provider. Use glucocorticoid stress doses in case of increased cortisol need (e.g., acute intercurrent illness, serious trauma, surgical procedures ). In the placebo-controlled clinical study of adults with classic CAH, the incidence of adrenal crisis was 1.6% in subjects treated with CRENESSITY and 0% in subjects treated with placebo. In the placebo-controlled clinical study of pediatric subjects with classic CAH, there were no events of adrenal crisis.

INTERACTIONS Strong CYP3A4 I nducers: Increase CRENESSITY morning and evening dosage 2-fold. (Section 2.3 , 7.1 ) Moderate CYP3A4 Inducers: Increase CRENESSITY evening dosage 2-fold. ( 2.4 , 7.1 )

7.1 Effects of Other Drugs on CRENESSITY Strong CYP3A4 Inducers Increase CRENESSITY morning and evening dosages 2-fold when CRENESSITY is used concomitantly with a strong CYP3A4 inducer <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.3 )]</span>. Moderate CYP3A4 Inducers Increase CRENESSITY evening dosage 2-fold when CRENESSITY is used concomitantly with a moderate CYP3A4 inducer. Do not increase the morning dosage <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.4 )]</span>. Mechanism of Drug Interaction and Clinical Effect CRENESSITY is a CYP3A4 substrate. Concomitant use of CRENESSITY with a strong or moderate CYP3A4 inducer decreases crinecerfont exposure <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 ) ]</span>, which may reduce CRENESSITY efficacy.