Crinecerfont (Monograph)

Brand name: Crenessity
Drug class: Pituitary

Introduction

Selective corticotropin-releasing factor (CRF) type 1 receptor antagonist.

Uses for Crinecerfont

Congenital Adrenal Hyperplasia

Adjunctive therapy to glucocorticoid replacement to control androgens in adults and pediatric patients ≥4 years of age with classic congenital adrenal hyperplasia (CAH). Designated an orphan drug by FDA for treatment of CAH.

The Endocrine Society provides clinical practice guidelines for treatment of CAH. Current standard of care in pediatric patients with CAH is hydrocortisone. In adults with CAH, treatment includes daily hydrocortisone and/or long-acting glucocorticoids plus mineralocorticoids, as clinically indicated. Crinecerfont is not discussed in the guidelines because the drug was approved after the guidelines were published.

Crinecerfont Dosage and Administration

General

Patient Monitoring

• Androstenedione levels can be assessed beginning 4 weeks after crinecerfont initiation to inform reduction in glucocorticoid dosage as clinically indicated. Glucocorticoid dosage should not be reduced below the dose required for replacement therapy.

Other General Considerations

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

Administration

Oral Administration

Administer orally as a capsule or suspension.

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

Swallow capsules whole with liquid.

Administer solution using oral syringe provided by pharmacist. When using oral solution for the first time, place press-in bottle adapter into the bottle and keep in place after insertion.

Dosage

Pediatric Patients

Congenital Adrenal Hyperplasia

Oral

Recommended dosage in pediatric patients ≥4 years of age is based on body weight as follows:

10 to <20 kg: 25 mg twice daily.

20 to <55 kg: 50 mg twice daily.

≥55 kg: 100 mg twice daily.

Dosage Modifications for Concomitant Use with Strong CYP3A4 Inducers

Oral

When used concomitantly with a strong CYP3A4 inducer in pediatric patients, the recommended dosage of crinecerfont is as follows:

10 to <20 kg: 50 mg twice daily.

20 to <55 kg: 100 mg twice daily.

≥55 kg: 200 mg twice daily.

Dosage Modifications for Concomitant Use with Moderate CYP3A4 Inducers

Oral

When used concomitantly with a moderate CYP3A4 inducer in pediatric patients, the recommended dosage of crinecerfont is as follows:

10 to <20 kg: morning dose of 25 mg and evening dose of 50 mg.

20 to <55 kg: morning dose of 50 mg and evening dose of 100 mg.

≥55 kg: morning dose of 100 mg and evening dose of 200 mg.

Adults

Congenital Adrenal Hyperplasia

Oral

100 mg twice daily in the morning and evening.

Dosage Modifications for Concomitant Use with Strong CYP3A4 Inducers

Oral

When used concomitantly with a strong CYP3A4 inducer, increase crinecerfont dosage to 200 mg twice daily.

Dosage Modifications for Concomitant Use with Moderate CYP3A4 Inducers

Oral

When used concomitantly with a moderate CYP3A4 inducer, increase crinecerfont dosage to a morning dose of 100 mg and an evening dose of 200 mg.

Special Populations

Hepatic Impairment

No specific dosage recommendations.

Renal Impairment

No specific dosage recommendations for mild or moderate renal impairment. Not recommended in patients with severe renal impairment or end-stage renal disease.

Geriatric Patients

No specific dosage recommendations.

Cautions for Crinecerfont

Contraindications

• Hypersensitivity to crinecerfont or any excipients in the formulation.

Warnings/Precautions

Hypersensitivity Reactions

Hypersensitivity reactions, including throat tightness, angioedema, and generalized rash may occur.

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

Acute Adrenal Insufficiency

Acute adrenal insufficiency or adrenal crisis can occur in patients with underlying adrenal insufficiency who are on inadequate daily glucocorticoid doses.

Continue glucocorticoids upon initiation of and during treatment with crinecerfont. Do not reduce the glucocorticoid dose below the dose required for cortisol replacement.

Any adjustment of daily glucocorticoid dosage after initiation of crinecerfont should be performed under the supervision of a healthcare provider. Administer glucocorticoid stress doses in case of increased cortisol need (e.g., acute intercurrent illness, serious trauma, surgical procedures).

Specific Populations

Pregnancy

Data are insufficient to identify a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes.

If crinecerfont is administered during pregnancy or if a patient becomes pregnant while receiving the drug, report the exposure to 1-855-CRNSITY (1-855-276-7489).

Lactation

No data on presence of crinecerfont in human milk, effects on the breastfed infant, or effects on milk production. Crinecerfont is present in animal milk thus, it is likely that the drug will be present in human milk.

Monitor for signs of adrenal insufficiency when an infant is exposed to crinecerfont through breast milk.

Consider developmental and health benefits of breastfeeding 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

Safety and effectiveness in the treatment of CAH have been established in pediatric patients ≥4 years of age.

Safety and effectiveness in pediatric patients <4 years of age not established.

Geriatric Use

It is unknown if patients ≥65 years of age respond differently from younger patients.

Hepatic Impairment

Hepatic impairment has no clinically significant effect on the pharmacokinetics of crinecerfont.

Renal Impairment

Not recommended in patients with severe renal impairment or end-stage renal disease.

Common Adverse Effects

Most common adverse reactions (≥4%) in adults: fatigue, headache, dizziness, arthralgia, back pain, decreased appetite, myalgia.

Most common adverse reactions (≥4%) in pediatric patients: headache, abdominal pain, fatigue, nasal congestion, epistaxis.

Drug Interactions

Metabolized primarily by CYP3A4 and to a lesser extent by CYP2B6.

Not likely to induce CYP3A, CYP1A2, CYP2C8, CYP2C9, CYP2B6 or inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP2E1 at clinically relevant doses. Not an inhibitor of P-glycoprotein (P-gp), breast cancer resistant protein (BCRP), bile salt export pump (BSEP), organic anion transporting polypeptide (OATP)1B1, or OATP1B3, organic anion transporter (OAT)1, OAT3, organic cation transporter (OCT) 2, multidrug and toxin extrusion transporter (MATE)1, or MATE2-K. Not a substrate for P-gp, BCRP, BSEP, OATP1B1, or OATP1B3.

Weak CYP3A inhibitor.

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

CYP3A4 inducers:concomitant use of crinecerfont with a strong or moderate CYP3A4 inducer decreases crinecerfont exposure, which may reduce efficacy of crinecerfont. Increase crinecerfont morning and evening dosages 2-fold when crinecerfont is used concomitantly with a strong CYP3A4 inducer. When used with a moderate CYP3A4 inducer, increase crinecerfont evening dosage 2-fold; do not increase morning dosage.

Inhibitors of CYP2B6, CYP2C9, CYP2C19, CYP1A2, CYP2C8, or CYP2D6: Crinecerfont dosage adjustment not necessary.

Specific Drugs

Crinecerfont Pharmacokinetics

Absorption

Onset

Steady state is achieved in approximately 7 days.

Time to peak concentration is 4 hours after oral administration.

Food

Administration of capsules and oral solution with high fat meal increased maximum concentration by 4.9- and 8.6-fold, respectively. Administration of capsules and oral solution with high fat meal increased AUC by 3.3- and 8.3-fold, respectively.

Distribution

Extent

Widely distributed into liver, adrenal gland, lung, spleen, myocardium, fat, and the lymphatic system.

Plasma Protein Binding

≥99.9%

Elimination

Metabolism

CYP3A4 and to a lesser extent by CYP2B6. CYP2C8 and CYP2C19 have minor contributions to metabolism.

Single active metabolite, M6, has similar affinity for CRF1 receptor but is not expected to significantly contribute to pharmacological activity.

Elimination Route

Approximately 47.3% (2.7% as unchanged) of the dose was recovered in feces and 2% (amount as unchanged is undetectable) in urine.

Half-life

14 hours.

Stability

Storage

Oral

Capsules

Store at 15–25°C. Do not freeze.

Solution

Store and dispense in original container. Store in an upright position.

Store unopened bottles under refrigeration at 2–8°C. Do not freeze. Once bottle is opened, may store under refrigeration at 2–8°C or at room temperature (15–25°C) for up to 30 days. Discard any unused solution after 30 days of first opening bottle.

Actions

• Selective CRF type 1 receptor antagonist.

• 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 patients that if a dose or doses are missed, to take one dose of crinecerfont as soon as possible (even if it is soon before the next scheduled dose) and then to resume the regular dosing schedule.

• Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.

• Advise patients to inform their clinician if they are or plan to become pregnant or plan to breast-feed. Advise patients who are exposed to crinecerfont during pregnancy that there is a pregnancy safety study.

• Inform patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

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.

Crinecerfont is obtained through designated distributors. Contact manufacturer or consult crinecerfont website ([Web]) for specific availability information.

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