Crinecerfont (Monograph)

Brand name: Crenessity
Drug class: Pituitary

Introduction

Crinecerfont is a selective corticotropin-releasing factor (CRF) type 1 receptor antagonist.

Uses for Crinecerfont

Crinecerfont has the following uses:

Crinecerfont 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).

Crinecerfont Dosage and Administration

General

Crinecerfont is available in the following dosage form(s) and strength(s):

• Capsules: 25 mg, 50 mg, 100 mg

• Oral Solution: 50 mg/mL

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Dosage and Administration in Adults and Pediatric Patients

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

• Continue glucocorticoid replacement therapy for adrenal insufficiency associated with congenital adrenal hyperplasia.

• Recommended Dosage in Adults: 100 mg orally twice daily.

• Recommended Dosage in Pediatric Patients (4 years of age and older): Dosage in pediatric patients is weight-based. In patients 10 kg to <20 kg, the recommended dosage is 25 mg twice daily. In patients 20 kg to <55 kg, the recommended dosage is 50 mg twice daily. In patients ≥55 kg, the recommended dosage is 100 mg twice daily.

• Dosage modifications are required in patients receiving concomitant therapy with moderate or strong cytochrome P-450 (CYP) 3A4 inducers.

• See Full Prescribing Information for complete dosage and administration information.

Cautions for Crinecerfont

Contraindications

Hypersensitivity to crinecerfont or any excipients in the formulation.

Warnings/Precautions

Hypersensitivity Reactions

A hypersensitivity reaction, including throat tightness, angioedema, and generalized rash, occurred in a subject after 3 days of treatment with crinecerfont.

If a clinically significant hypersensitivity reaction occurs, initiate appropriate therapy and discontinue crinecerfont.

Risk of Acute Adrenal Insufficiency or Adrenal Crisis with Inadequate Concomitant Glucocorticoid Therapy

Continue glucocorticoids upon initiation of and during treatment with crinecerfont. 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 crinecerfont should be performed under the supervision of a healthcare 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 patients treated with crinecerfont and 0% in patients treated with placebo. In the placebo-controlled clinical study of pediatric subjects with classic CAH, there were no events of adrenal crisis.

Specific Populations

Pregnancy

Available data from reports of pregnancy in clinical trials with crinecerfont 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 crinecerfont is administered during pregnancy, or if a patient becomes pregnant while receiving the drug, healthcare providers should report the exposure by calling 1-855-CRNSITY (1-855-276-7489).

Lactation

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 crinecerfont 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 crinecerfont and any potential adverse effects on the breastfed child from the drug or underlying maternal condition.

Pediatric Use

The safety and effectiveness of crinecerfont 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 crinecerfont for this indication is supported by evidence from an adequate and well-controlled study of 103 pediatric subjects, 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 crinecerfont in pediatric patients less than 4 years of age have not been established.

Geriatric Use

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

Renal Impairment

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

Common Adverse Effects

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

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

Strong CYP3A4Inducers: Increase crinecerfont morning and evening dosage 2-fold.

ModerateCYP3A4Inducers: Increase crinecerfont evening dosage 2-fold.

Actions

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.

Advice to Patients

• Advise patients and/or caregivers to read the FDA-approved patient labeling.

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

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

• 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 crinecerfont that they should not receive the drug.

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

• Advise women who are exposed to crinecerfont during pregnancy that there is a pregnancy safety study.

Additional Information

AHFSfirstRelease^™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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