Crenessity

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 [see Clinical Pharmacology ( 12.3)].

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

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 [see Drug Interactions ( 7.1)].

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

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 [see Drug Interactions ( 7.1)].

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

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.

8.1  Pregnancy 

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 (see Data).

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).

Data

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.

8.2  Lactation 

Risk Summary 

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. (see Data). 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.

8.4  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 subjects (Study 2), evidence from an adequate and well-controlled study in adults with CAH (Study 1), and pharmacokinetic data from adults and pediatric subjects [see Dosage and Administration ( 2.2), Warnings and Precautions ( 5.2), Adverse Reactions ( 6.1), Clinical Pharmacology ( 12.3), and Clinical Studies ( 14.2)].

The safety and effectiveness of CRENESSITY in pediatric patients less than 4 years of age have not been established.

8.5  Geriatric 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.

8.6 Renal Impairment

CRENESSITY is not recommended in patients with severe renal impairment or end-stage renal disease [see Clinical Pharmacology ( 12.3)].

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 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.