CRENESSITY Capsule / Oral solution Ref.[115529] Active ingredients: Crinecerfont

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.

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)]

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 [see Clinical Studies (14.1)].

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:

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) [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:

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 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.

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 [see Dosage and Administration (2.3)].

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 [see Dosage and Administration (2.4)].

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 [see Clinical Pharmacology (12.3)], which may reduce CRENESSITY efficacy.

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.

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.

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.

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.

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