Crinecerfont

Crinecerfont
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Parth Vikram Singh

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Overview

Crinecerfont is a corticotropin-releasing factor type 1 receptor antagonist that is FDA approved for the treatment of CRENESSITY is a corticotropin-releasing factor type 1 receptor antagonist that is FDA approved 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).. Common adverse reactions include 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.

Pediatric Patients: Most common adverse reactions (at least 4% for CRENESSITY and greater than placebo) are headache, abdominal pain, fatigue, nasal congestion, and epistaxis..

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

• 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).

• Important Administration Information
  • Patients receiving CRENESSITY should continue glucocorticoid replacement therapy for the adrenal insufficiency associated with congenital adrenal hyperplasia.
  • 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.

• Recommended Dosage for Adults
  • The recommended CRENESSITY dosage for adults is 100 mg orally, twice daily with a meal in the morning and evening.

• 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. The recommended CRENESSITY weight-based dosage for pediatric patients aged 4 years and older is as follows: For patients weighing between 10 kg and less than 20 kg, the dosage is 25 mg orally twice daily with a meal. For patients weighing between 20 kg and less than 55 kg, the dosage increases to 50 mg orally twice daily with a meal. For patients who weigh 55 kg or more, the recommended dosage is 100 mg orally twice daily with a meal.

    

    Recommended CRENESSITY Weight-Based Dosage for Pediatric Patients 4 Years of Age and Older

• 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.
  • 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. For patients weighing between 10 kg and less than 20 kg, the recommended dosage is 50 mg orally twice daily with a meal. For those weighing between 20 kg and less than 55 kg, the dosage increases to 100 mg orally twice daily with a meal. For patients weighing 55 kg or more, the dosage is 200 mg orally twice daily with a meal.

      

      Dosage Increase of CRENESSITY for Use with Strong CYP3A4 Inducers in Pediatric Patients 4 Years of Age and Older

• 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.
  • 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. The dosage regimen with a meal for pediatric patients is outlined as follows: For patients weighing between 10 kg and less than 20 kg, the morning dose is 25 mg orally, and the evening dose is 50 mg orally. For those weighing between 20 kg and less than 55 kg, the morning dose is 50 mg orally, and the evening dose is 100 mg orally. For patients weighing 55 kg or more, the morning dose is 100 mg orally, and the evening dose is 200 mg orally.

      

      Dosage Increase of CRENESSITY for Use with Moderate CYP3A4 Inducers in Pediatric Patients 4 Years of Age and Older

• Administration Instructions
  • Administer CRENESSITY orally, twice daily, with a meal in the morning and evening.
  • 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.

• 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.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Crinecerfont in adult patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Crinecerfont in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

• 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. The recommended CRENESSITY weight-based dosage for pediatric patients aged 4 years and older is as follows: For patients weighing between 10 kg and less than 20 kg, the dosage is 25 mg orally twice daily with a meal. For patients weighing between 20 kg and less than 55 kg, the dosage increases to 50 mg orally twice daily with a meal. For patients who weigh 55 kg or more, the recommended dosage is 100 mg orally twice daily with a meal.

• Dosage Modifications for Concomitant Use with Strong CYP3A4 Inducers
  • In pediatric patients, increase the CRENESSITY dosage with a meal in the morning and evening when used concomitantly with strong CYP3A4 inducers. For patients weighing between 10 kg and less than 20 kg, the recommended dosage is 50 mg orally twice daily with a meal. For those weighing between 20 kg and less than 55 kg, the dosage increases to 100 mg orally twice daily with a meal. For patients weighing 55 kg or more, the dosage is 200 mg orally twice daily with a meal.

• Dosage Modifications for Concomitant Use with Moderate CYP3A4 Inducers
  • In pediatric patients, increase the CRENESSITY dosage with the evening meal when used concomitantly with moderate CYP3A4 inducers. The dosage regimen with a meal for pediatric patients is outlined as follows: For patients weighing between 10 kg and less than 20 kg, the morning dose is 25 mg orally, and the evening dose is 50 mg orally. For those weighing between 20 kg and less than 55 kg, the morning dose is 50 mg orally, and the evening dose is 100 mg orally. For patients weighing 55 kg or more, the morning dose is 100 mg orally, and the evening dose is 200 mg orally.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Crinecerfont in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Crinecerfont in pediatric patients.

Contraindications

• CRENESSITY is contraindicated in patients with hypersensitivity to crinecerfont or any excipients of CRENESSITY.
• Reactions have included throat tightness, angioedema, and generalized rash.

Warnings

• 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.

• 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.
  • 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.

Adverse Reactions

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.

• 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. In adults with congenital adrenal hyperplasia treated with CRENESSITY, the following adverse reactions occurred at a frequency of 4% or greater and more frequently than in placebo-treated subjects: Fatigue was reported in 25% of CRENESSITY-treated patients compared to 15% in the placebo group. Headache occurred in 16% of CRENESSITY patients versus 15% in those receiving placebo. Dizziness was observed in 8% of CRENESSITY patients, compared to 3% in the placebo group. Arthralgia (joint pain) was reported by 7% of CRENESSITY patients, with none in the placebo group. Back pain occurred in 6% of patients on CRENESSITY, compared to 3% in the placebo group. Decreased appetite and myalgia (muscle pain) were both reported in 4% of CRENESSITY patients, while 2% and 3% of placebo patients experienced these respectively.

    

    Adverse Reactions (≥4%) in Adults with Congenital Adrenal Hyperplasia Treated with CRENESSITY and Occurring More Frequently Than in Placebo-Treated Subjects

• 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 103 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 103 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).

• 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. In pediatric subjects with congenital adrenal hyperplasia treated with CRENESSITY, the following adverse reactions occurred at a frequency of 4% or greater and more frequently than in placebo-treated subjects: Headache was reported in 25% of CRENESSITY-treated patients compared to 6% in the placebo group. Abdominal pain was experienced by 13% of CRENESSITY patients, with none in the placebo group. Fatigue occurred in 7% of those receiving CRENESSITY, while none in the placebo group reported it. Nasal congestion was observed in 7% of CRENESSITY patients, compared to 3% in the placebo group. Epistaxis (nosebleeds) was reported by 4% of CRENESSITY patients, with no occurrences in the placebo group.

    

    Adverse Reactions (≥ 4%) in Pediatric Subjects with Congenital Adrenal Hyperplasia Treated with CRENESSITY and Occurring More Frequently Than in Placebo-Treated Subjects

• 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 103 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 103 cells/mcL occurred in 4% (3 of 68) of CRENESSITY-treated subjects, compared to no subjects (0 of 32) in the placebo group.

Postmarketing Experience

There is limited information regarding Crinecerfont Postmarketing Experience in the drug label.

Drug Interactions

• Strong CYP3A4 Inducers
  • Increase CRENESSITY morning and evening dosages 2-fold when CRENESSITY is used concomitantly with a strong CYP3A4 inducer.

• 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.

• 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.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA):

• Risk Summary
  • Available data from reports of pregnancy in clinical trials with CRENESSITY are insufficient to identify a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes.
  • No developmental toxicity was observed in rats at 4-fold higher than human exposure at the maximum recommended human dose (MRHD) based on area under the concentration-time curve (AUC). Crinecerfont was associated with a low incidence of poly-malformations (craniofacial defects) in rabbits at 2-fold higher than human exposure at the MRHD. In a pre- and postnatal developmental toxicity study, no developmental toxicity was observed in rats at 4-fold higher than human exposure at the MRHD.
  • The background risk of major birth defects and miscarriage for the indicated population 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.
  • If CRENESSITY is administered during pregnancy, or if a patient becomes pregnant while receiving CRENESSITY, health care providers should report exposure to CRENESSITY by calling 1-855-CRNSITY (1-855-276-7489).

• Animal Data
  • Crinecerfont was administered orally to pregnant rabbits at doses of 100, 500, and 1000 mg/kg/day, and to pregnant rats at doses of 150, 500, and 2000 mg/kg/day during the period of organogenesis. No crinecerfont-related malformations were observed in rats at 4-fold higher than human exposure at the MRHD based on AUC. Low incidence of poly-malformations (craniofacial defects) and slightly lower mean fetal weights were observed in rabbits treated with crinecerfont at 2-fold higher than human exposure at the MRHD based on AUC.
  • In a pre- and postnatal developmental toxicity study, crinecerfont was administered orally to pregnant rats at doses of 15, 50, and 250 mg/kg/day during the period of organogenesis and lactation through Day 20 postpartum. No changes in pup mortality, growth, sexual maturation, behavior, mating and fertility, or ovarian and uterine parameters were observed. The exposure in dams at the No Observed Adverse Effect Level (NOAEL) of 250 mg/kg/day was approximately 4-fold higher than human exposure at the MRHD based on AUC.

Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Crinecerfont in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Crinecerfont during labor and delivery.

Nursing Mothers

• There are no data on the presence of crinecerfont in human milk, the effects on the breastfed infant, or the effects on milk production. Crinecerfont 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. Infants exposed to CRENESSITY through breast milk should be monitored for signs of adrenal insufficiency such as weakness, decreased feeding and weight loss.
• The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for CRENESSITY and any potential adverse effects on the breastfed child from CRENESSITY or from the underlying maternal condition.
• Data
  • Crinecerfont was excreted in the milk of rats, with milk-to-plasma concentration ratios ranging from 1.5 to 12. No effects on postnatal development were observed in a pre- and postnatal development study, in which female rats were treated orally with up to 250 mg/kg/day (4-fold higher than human exposure at the MRHD based on AUC) during organogenesis through lactation.

Pediatric Use

• The safety and effectiveness of CRENESSITY as adjunctive treatment to glucocorticoid replacement to control androgens have been established in pediatric patients 4 years of age and older with classic CAH.
• Use of CRENESSITY for this indication is supported by evidence from an adequate and well-controlled study of 103 pediatric subject. evidence from an adequate and well-controlled study in adults with CAH and pharmacokinetic data from adults and pediatric subjects.
• The safety and effectiveness of CRENESSITY in pediatric patients less than 4 years of age have not been established.

Geriatic Use

The clinical trial of CRENESSITY in adults with classic CAH did not enroll subjects 65 years of age and older to determine whether they respond differently from younger subjects.

Gender

There is no FDA guidance on the use of Crinecerfont with respect to specific gender populations.

Race

There is no FDA guidance on the use of Crinecerfont with respect to specific racial populations.

Renal Impairment

CRENESSITY is not recommended in patients with severe renal impairment or end-stage renal disease

Hepatic Impairment

There is no FDA guidance on the use of Crinecerfont in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Crinecerfont in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Crinecerfont in patients who are immunocompromised.

Administration and Monitoring

Administration

Important Administration Information

Patients receiving CRENESSITY should continue glucocorticoid replacement therapy for the adrenal insufficiency associated with congenital adrenal hyperplasia. 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.

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.

• 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.

The dosage regimen with a meal for pediatric patients is based on their weight as follows: For patients weighing between 10 kg and less than 20 kg, the recommended dosage is 25 mg orally twice daily. For those weighing between 20 kg and less than 55 kg, the dosage increases to 50 mg orally twice daily. For patients who weigh 55 kg or more, the recommended dosage is 100 mg orally twice daily.

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.
• 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.

The dosage regimen with a meal for pediatric patients using CRENESSITY, when considering strong CYP3A4 inducers, is as follows: For patients weighing between 10 kg and less than 20 kg, the recommended dosage is 50 mg orally twice daily. For those weighing between 20 kg and less than 55 kg, the dosage increases to 100 mg orally twice daily. For patients weighing 55 kg or more, the recommended dosage is 200 mg orally twice daily.

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.
• 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. The dosage regimen with a meal for pediatric patients is structured based on weight, with specific morning and evening doses. For patients weighing between 10 kg and less than 20 kg, the morning dose is 25 mg orally, and the evening dose is 50 mg orally. For those weighing between 20 kg and less than 55 kg, the morning dose is 50 mg orally, and the evening dose is 100 mg orally. For patients weighing 55 kg or more, the morning dose is 100 mg orally, and the evening dose is 200 mg orally.

Administration Instructions

Administer CRENESSITY orally, twice daily, with a meal in the morning and evening.

• 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.

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.

Monitoring

• 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.

• 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.

IV Compatibility

There is limited information regarding the compatibility of Crinecerfont and IV administrations.

Overdosage

There is limited information regarding Crinecerfont overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.

Pharmacology

There is limited information regarding Crinecerfont Pharmacology in the drug label.

Mechanism of Action

Crinecerfont is a selective corticotropin-releasing factor (CRF) type 1 receptor antagonist. Crinecerfont blocks the binding of CRF to CRF type 1 receptors in the pituitary but not CRF type 2 receptors. Crinecerfont binding to CRF type 1 receptors inhibits adrenocorticotropic hormone (ACTH) secretion from the pituitary, thereby reducing ACTH-mediated adrenal androgen production.

Structure

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 C27H28ClFN2OS, and its molecular weight is 483.04 g/mol with the following structure:

CRENESSITY 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.

Pharmacodynamics

• Exposure-Response Relationships
  • Model based exposure-response analyses for adults and pediatric patients with CAH demonstrated that, within the studied exposures of CRENESSITY in Phase 3 trials, relatively flat exposure-response relationships were observed for androstenedione reduction from baseline to Week 4 for both adults and pediatric patients and percent glucocorticoid daily dose reduction from baseline to Week 24 for adults and to Week 28 for pediatric patients.
• Adrenocorticotropic Hormone (ACTH) Reduction
  • In 8 adults with classic CAH (NCT0352886) who received the recommended CRENESSITY dosage for 2 weeks, the median percent reduction from baseline in ACTH was 62%.
  • In the Phase 3 clinical trials of adults and pediatric patients with classic CAH, administration of the recommended CRENESSITY dosage for 4 weeks during the initial glucocorticoid stable period led to a reduction in ACTH levels.
  • In Study 1, the median percent reduction from baseline to Week 4 in ACTH was 65%.
  • In Study 2, the median percent reduction from baseline to Week 4 in ACTH was 72%.
• Cardiac Electrophysiology
  • At a dose 4 times the maximum approved recommended dosage, CRENESSITY does not prolong the QT interval to any clinically relevant extent.

Pharmacokinetics

Crinecerfont maximum plasma concentration (Cmax) and area under the time concentration curve (AUC0-24 hours) increases dose-proportionally over the approved recommended dosage range. Upon twice daily dosing, steady state conditions are achieved in approximately 7 days with an accumulation ratio of 1.4.

• Absorption
  • Crinecerfont median time to reach Cmax (Tmax) is 4 hours following oral administration of CRENESSITY.
  • No clinically significant differences in crinecerfont Cmax or AUC were observed following administration of CRENESSITY oral capsules and oral solution.
  • Steady state exposures for crinecerfont in adults and pediatric patients following oral administration of CRENESSITY.
  • In Study 1 (adults) and Study 2 (pediatrics), the pharmacokinetic parameters AUC24hr,ss and Cmax were measured for CRENESSITY. In Study 1, for the 100 mg twice daily (bid) dose, the geometric mean AUC24hr,ss was 72,846 ngh/mL with a coefficient of variation (CV%) of 51%. In Study 2, the AUC24hr,ss for the pediatric doses was 74,693 ngh/mL (CV% 48%) for the 100 mg bid dose in patients weighing 55 kg or more, and 47,062 ng*h/mL (CV% 51%) for the 50 mg bid dose in patients weighing between 20 kg and less than 55 kg. For Cmax, in Study 1, the 100 mg bid dose resulted in a geometric mean of 4,231 ng/mL (CV% 46%). In Study 2, the 100 mg bid dose in patients weighing 55 kg or more yielded a Cmax of 4,555 ng/mL (CV% 43%), and the 50 mg bid dose in patients weighing between 20 kg and less than 55 kg had a Cmax of 2,887 ng/mL (CV% 48%).
  • CV%, coefficient of variation expressed as a percentage; bid, twice daily; steady-state exposure parameters are generated from simulation of 500 subjects based on population pharmacokinetic modeling and weight band appropriate formulation.

    

    Geometric Mean (CV%) for AUC24,ss and Cmax in Adults and Pediatric Patients with Classic Congenital Adrenal Hyperplasia Following Oral Administration of CRENESSITY

• Effect of Food
  • Following administration of CRENESSITY capsule, crinecerfont Cmax increased 4.9-fold and AUC increased 3.3-fold with a high-fat meal (800 to 1000 calories, 50% fat), compared to fasted conditions.
  • Following administration of CRENESSITY oral solution, crinecerfont Cmax increased 8.6-fold and AUC increased 8.3-fold with a high-fat meal, compared to fasted conditions.
• Distribution
  • Mean apparent volume of distribution (CV%) of crinecerfont in adults with CAH is 852 L (31%). Crinecerfont plasma protein binding is greater than or equal to 99.9%.
• Elimination
  • Crinecerfont’s effective half-life is approximately 14 hours with a mean (CV%) apparent clearance of 3.5 L/h (37%).
  • Metabolism
    • Crinecerfont is metabolized primarily by CYP3A4 and to a lesser extent by CYP2B6 in vitro. Additionally, CYP2C8 and CYP2C19 may also have minor contributions to crinecerfont metabolism.
  • Excretion
    • Following a single oral 100 mg dose of radiolabeled crinecerfont, approximately 47.3% (2.7% as unchanged) of the dose was recovered in feces and 2% (amount as unchanged is undetectable) in urine.
• Specific Populations
  • No clinically significant differences in the pharmacokinetics of crinecerfont were observed based on age (range: 5 to 54 years), sex (58.7% male), race (4.8% Asian, 9.7% Black, 77.5% White), mild to severe hepatic impairment (Child Pugh Class A to C), or mild to moderate renal impairment (estimated glomerular filtration rate: equal to or greater than 44 mL/min/1.73 m2; CKD-EPI 2009 formula for adults and bedside Schwartz formula for pediatric patients).
  • Crinecerfont has not been studied in patients with severe renal impairment or end-stage renal disease.

Nonclinical Toxicology

• Carcinogenesis
  • In a 2-year carcinogenicity study, rats were administered daily crinecerfont doses of 5, 15, and 100 mg/kg/day via oral gavage. An increased incidence of thyroid follicular cell combined adenomas and carcinomas was observed in female rats at the 100 mg/kg/day dose level (approximately 4-fold higher than human exposure at the MRHD based on AUC). Thyroid follicular cell tumors can occur in rats from excessive thyroid stimulating hormone (TSH) secondary to liver enzyme induction, which is not thought to commonly occur in humans. No evidence of increased tumorigenicity was seen in male rats up to approximately 5-fold higher than human exposure at the MRHD based on AUC or in female rats up to approximately 2-fold higher than human exposure at the MRHD based on AUC.
  • In a 6-month study in Tg.rasH2 mice, daily crinecerfont doses of 15, 50, 500, and 1500 mg/kg/day were administered via oral gavage. Crinecerfont did not increase the incidence of tumors in male or female transgenic mice (approximately 4-fold higher than human exposure at the MRHD based on AUC).

• Mutagenesis
  • Crinecerfont was not mutagenic in the in vitro bacterial reverse mutation test (Ames) or clastogenic in the in vitro mammalian chromosomal aberrations assay in human peripheral blood lymphocytes or in the in vivo rat bone marrow micronucleus assay.

• Impairment of Fertility
  • There were no crinecerfont-related effects on male or female fertility or female reproductive performance in rats treated orally with up to 1000 mg/kg/day crinecerfont at 2-fold higher than human exposure at the MRHD by AUC exposure.

Clinical Studies

Adults with Classic Congenital Adrenal Hyperplasia

• The efficacy of CRENESSITY to reduce androgen levels and enable a reduced glucocorticoid dose while maintaining androgen control in adults with classic CAH was evaluated in a randomized, double-blind, placebo-controlled study (Study 1; NCT#04490915). This study enrolled 182 adults with classic CAH due to 21- hydroxylase deficiency on supraphysiological glucocorticoid doses and with androgen concentrations in the normal range or with inadequate androgen control.
• Subjects were randomized to receive CRENESSITY 100 mg twice daily (N=122) or placebo (N=60) for 24 weeks. During the first 4 weeks of CRENESSITY treatment, subjects maintained a stable glucocorticoid regimen except for stress dosing as needed. During Weeks 4 to 12, the glucocorticoid dose was reduced as frequently as every 2 weeks without regard to androstenedione levels, with the goal to achieve a glucocorticoid dose of 8 to 10 mg/m2/day in hydrocortisone dose equivalents adjusted for body surface area by Week 12. From Weeks 12 to 20, the glucocorticoid dose was further adjusted, if needed, to achieve androstenedione control by Week 24.
• The mean (range) age was 31 (18 to 58) years, 51% were male, 90% were White, and 8% were Hispanic or Latino. At baseline, the mean (SD) glucocorticoid total daily dose in hydrocortisone equivalents was 32 (9) mg/day (18 [5] mg/m2/day), with mean (SD) androstenedione levels of 620 (729) ng/dL prior to the morning glucocorticoid dose.
• The efficacy of CRENESSITY was assessed by the least-squares (LS) mean (SEM) percent change from baseline in the total glucocorticoid daily dose while androstenedione was controlled (≤120% of baseline or ≤upper limit of normal [ULN]) after 24 weeks. The LS mean percent change from baseline in daily glucocorticoid dose was statistically significantly greater in the CRENESSITY group at -27% compared to -10% in the placeboIn the treatment group, the baseline glucocorticoid daily dose for CRENESSITY was 18 mg/m²/day (mean ± SD: 5), and the least squares (LS) mean percent change from baseline was -27% (SEM: 2). The placebo-subtracted LS mean difference was -17% with a 95% confidence interval of -24% to -10%, and the result was statistically significant with a p-value of <0.0001. In comparison, the baseline glucocorticoid daily dose for the placebo group was also 18 mg/m²/day (mean ± SD: 6), with an LS mean percent change from baseline of -10% (SEM: 3).In hydrocortisone equivalents (4x equivalency factor for (methyl)predniso(lo)ne, 60x for dexamethasone) adjusted for body surface area.

  

  Primary Change From Baseline in Glucocorticoid Daily Dose While Maintaining Androstenedione Control at Week 24 in Adults with Classic Congenital Adrenal Hyperplasia (Study 1)

• At Week 24, there was a statistically significantly greater percentage of subjects achieving a reduction to a physiologic glucocorticoid daily dose (≤11 mg/m2/day hydrocortisone equivalents) while androstenedione was controlled (≤120% of baseline or ≤ULN) with CRENESSITY compared to placebo (63% vs 18%, p<0.0001).
• At Week 4, following a treatment period at a stable glucocorticoid dose regimen, the LS mean change from baseline in serum androstenedione in the CRENESSITY group was statistically significantly different at -299 ng/dL compared to the LS mean increase from baseline in the placebo group of 46 ng/dL.

In Study 1, which assessed the change from baseline in serum androstenedione levels at Week 4 in adults with classic congenital adrenal hyperplasia, the treatment group receiving CRENESSITY showed a baseline mean serum androstenedione level of 634 ng/dL (SD: 796). The least squares (LS) mean change from baseline was -299 ng/dL (SEM: 38), and the placebo-subtracted LS mean difference was -345 ng/dL, with a 95% confidence interval of -457 ng/dL to -232 ng/dL, which was statistically significant (p<0.0001). In contrast, the placebo group had a baseline mean serum androstenedione level of 590 ng/dL (SD: 572), with an LS mean change from baseline of 46 ng/dL (SEM: 51).

Change From Baseline in Serum Androstenedione (ng/dL) at Week 4* in Adults with Classic Congenital Adrenal Hyperplasia(Study 1)

Pediatric Patients with Classic Congenital Adrenal Hyperplasia

• The efficacy of CRENESSITY to improve androgen control and enable a reduced glucocorticoid dose while maintaining androgen control in pediatric patients with classic CAH was evaluated in a Phase 3 randomized, double-blind, placebo-controlled study (Study 2; NCT#04806451). This study enrolled 103 pediatric subjects 4 to 17 years of age with classic CAH due to 21-hydroxylase deficiency and inadequate androgen control on supraphysiological glucocorticoid doses.
• Subjects were randomized to receive either 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 [CRENESSITY N=37; placebo N=14 ], or 100 mg twice daily via oral capsules for subjects ≥55 kg [CRENESSITY N=32; placebo N=20]).
• During the first 4 weeks of CRENESSITY treatment, subjects were maintained on a stable glucocorticoid regimen except for stress dosing, as needed. The primary efficacy endpoint was the change from baseline in serum androstenedione at Week 4. From Weeks 4 to 20, the glucocorticoid dose could be reduced as frequently as every 4 weeks provided androstenedione levels were controlled. The goal was to achieve a glucocorticoid dose of 8 to 10 mg/m2/day (hydrocortisone dose equivalents adjusted for body surface area) by Week 28 while maintaining androstenedione control.
• The mean (range) age was 12 (4 to 17) years, 41% were Tanner Stage 1 or 2, 52% were male, 63% were White, and 11% were Hispanic or Latino. With respect to concurrent glucocorticoid use at baseline, 92% of patients were receiving hydrocortisone alone and 8% were receiving prednisone [or equivalent] (with or without hydrocortisone). At baseline, subjects were receiving a mean (SD) glucocorticoid total daily dose in hydrocortisone equivalents of 16 (4) mg/m2/day, and had a mean (SD) androstenedione level of 431 (461) ng/dL and mean (SD) serum 17-hydroxyprogesterone level of 8682 (6847) ng/dL prior to the morning glucocorticoid dose.
• t Week 4, following a treatment period at a stable glucocorticoid dose regimen, the LS mean reduction from baseline in serum androstenedione in the CRENESSITY group was statistically significantly different at -197 ng/dL compared to the increase of 71 ng/dL in the placebo group.

  

  Change From Baseline in Serum Androstenedione (ng/dL) at Week 4* in Pediatric Subjects with Classic Congenital Adrenal Hyperplasia (Study 2)

• In Study 2, which evaluated the change from baseline in serum androstenedione levels at Week 4 in pediatric subjects with classic congenital adrenal hyperplasia, the treatment group receiving CRENESSITY had a baseline mean serum androstenedione level of 405 ng/dL (SD: 464). The least squares (LS) mean change from baseline was -197 ng/dL (SEM: 40), and the placebo-subtracted LS mean difference was -268 ng/dL, with a 95% confidence interval of -403 ng/dL to -132 ng/dL, which was statistically significant (p=0.0002). In comparison, the placebo group had a baseline mean serum androstenedione level of 483 ng/dL (SD: 456), with an LS mean change from baseline of 71 ng/dL (SEM: 56).
• At Week 4, following a treatment period at a stable glucocorticoid regimen, the LS mean reduction (SEM) from baseline in serum 17-hydroxyprogesterone in the CRENESSITY group was statistically significantly different at -5865 (572) ng/dL compared to the increase of 556 (818) ng/dL in the placebo group (LS Mean Treatment Difference -6421, 95% CI -8387, -4454, p<0.0001).
• The LS mean percent change from baseline in the total glucocorticoid daily dose while androstenedione was controlled (≤120% of baseline or ≤ULN) at Week 28 in the CRENESSITY group was statistically significantly different at -18% compared to the increase of 6% in the placebo group.
• In Study 2, which assessed the percent change from baseline in glucocorticoid daily dose while maintaining androstenedione control at Week 28 in pediatric subjects with classic congenital adrenal hyperplasia, the treatment group receiving CRENESSITY had a baseline mean glucocorticoid daily dose of 17 mg/m²/day (SD: 4). The least squares (LS) mean percent change from baseline was -18% (SEM: 2), and the placebo-subtracted LS mean difference was -24%, with a 95% confidence interval of -30% to -17%, which was statistically significant (p<0.0001). In comparison, the placebo group had a baseline mean glucocorticoid daily dose of 16 mg/m²/day (SD: 3), with an LS mean percent change from baseline of 6% (SEM: 3).

  

  Percent Change From Baseline in Glucocorticoid Daily Dose While Maintaining Androstenedione Control at Week 28 in Pediatric Subjects with Classic Congenital Adrenal Hyperplasia (Study 2)

How Supplied

• CRENESSITY Capsules

The CRENESSITY capsules are available in different strengths, each with its distinct appearance and packaging. The 25 mg strength comes in oval, orange soft gelatin capsules marked with "WWV 25" in black ink, and is supplied in bottles containing 60 capsules with the NDC number 70370-5025-1. The 50 mg strength is in oval, two-toned orange and gold soft gelatin capsules, marked with "WWV 50" in black ink, and also comes in bottles of 60 capsules, with the NDC number 70370-5050-1. The 100 mg strength is in oblong, gold soft gelatin capsules, printed with "WWV 100" in black ink, and is provided in bottles containing 30 capsules, with the NDC number 70370-5100-1.

CRENESSITY Capsule Information

• CRENESSITY Oral Solution

50 mg/mL is a light yellow to orange, orange-flavored liquid. The amber polyethylene terephthalate (PET) bottle contains 30 mL oral solution.

Storage

Store at 15°C to 25°C (59°F to 77°F).

Packaged in child-resistant HDPE bottles. Do not freeze.

CRENESSITY Oral Solution

Store and dispense in original container. Store CRENESSITY Oral Solution in an upright position.

Store unopened bottles under refrigeration at 2°C to 8°C (36°F to 46°F). Do not freeze.

Once a bottle is opened for use, it may be stored under refrigeration at 2°C to 8°C (36°F to 46°F) or at room temperature (15°C to 25°C [59°F to 77°F]) for up to 30 days. Discard any unused oral solution after 30 days of first opening the bottle.

Packaged in child-resistant PET bottles.

Images

Drug Images

{{#ask: Page Name::Crinecerfont |?Pill Name |?Drug Name |?Pill Ingred |?Pill Imprint |?Pill Dosage |?Pill Color |?Pill Shape |?Pill Size (mm) |?Pill Scoring |?NDC |?Drug Author |format=template |template=DrugPageImages |mainlabel=- |sort=Pill Name }}

Package and Label Display Panel

• PRINCIPAL DISPLAY PANEL

NDC 70370-5025-1 Crenessity (crinecerfont) capsules 25 mg 60 Capsules Rx only

• PRINCIPAL DISPLAY PANEL

NDC 70370-5050-1 Crenessity (crinecerfont) capsules 50 mg 60 Capsules Rx only

• PRINCIPAL DISPLAY PANEL

NDC 70370-5100-1 Crenessity (crinecerfont) capsules 100 mg 30 Capsules Rx only

• PRINCIPAL DISPLAY PANEL

NDC 70370-5250-1 Crenessity (crinecerfont) oral solution 50 mg/mL 30 mL Rx only

{{#ask: Label Page::Crinecerfont |?Label Name |format=template |template=DrugLabelImages |mainlabel=- |sort=Label Page }}

Patient Counseling Information

• Administration Information

Counsel patients that CRENESSITY must be taken with a meal, without regard to fat or caloric content

• Drug Interactions

Inform patients that the CRENESSITY dosage will need to be increased if they are taking strong or moderate CYP3A4 inducers

• Hypersensitivity Reactions

Advise patients to seek prompt medical attention if signs or symptoms of hypersensitivity reactions occur. Advise patients who have had signs or symptoms of systemic hypersensitivity reactions to CRENESSITY that they should not receive CRENESSITY

• Acute Adrenal Insufficiency or Adrenal Crisis with Inadequate Concomitant Glucocorticoid Therapy

Inform patients that they should continue glucocorticoids when taking CRENESSITY. Counsel patients that any adjustment of glucocorticoid doses should be done under the guidance of their health care provider. Counsel patients about the continued need for stress dose glucocorticoids during times of increased cortisol need (e.g., during illness).

• Pregnancy

Advise women who are exposed to CRENESSITY during pregnancy that there is a pregnancy safety study. CRENESSITY is a trademark of Neurocrine Biosciences, Inc.

Precautions with Alcohol

Alcohol-Crinecerfont interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

Crenessity

Look-Alike Drug Names

There is limited information regarding Crinecerfont Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.