Macimorelin Acetate

MACRILEN is indicated for the diagnosis of adult growth hormone deficiency (AGHD). MACRILEN is a growth hormone (GH) secretagogue receptor agonist indicated for the diagnosis of adult growth hormone deficiency ( 1 ). Limitations of Use : The safety and diagnostic performance has not been established for subjects with BMI > 40kg/m 2 ( 1 ). Limitations of Use The safety and diagnostic performance of MACRILEN have not been established for subjects with a body mass index (BMI) > 40 kg/m 2 .

For oral solution: 60 mg white to off-white granules in a pouch for reconstitution in 120 mL of water, resulting in a solution of 0.5 mg/mL of macimorelin. For oral solution: 60 mg ( 3 )

None None ( 4 )

QT Prolongation: QT prolongation can lead to development of torsade de pointes-type ventricular tachycardia. Avoid the concomitant use of MACRILEN with drugs that are known to prolong QT interval ( 5.1 , 7.1 ). Potential for False Positive Test Results with Use of Strong CYP3A4 Inducers: Discontinue and washout strong CYP3A4 inducers before testing ( 5.2 , 7.2 ). Potential for False Negative Test Results in Recent Onset Hypothalamic Disease: Consider repeat testing if indicated ( 5.3 ). 5.1 QT Prolongation MACRILEN causes an increase of about 11 msec in the corrected QT (QTc) interval [see Clinical Pharmacology ( 12.2 )] . QT prolongation can lead to development of torsade de pointes-type ventricular tachycardia with the risk increasing as the degree of prolongation increases. The concomitant use of MACRILEN with drugs that are known to prolong the QT interval should be avoided [see Dosage and Administration ( 2.2 ) and Drug Interactions ( 7.1 )] .

5.2 Potential for False Positive Test Results with Use of Strong CYP3A4 Inducers Concomitant use of strong CYP3A4 inducers with MACRILEN can decrease macimorelin plasma levels significantly and thereby lead to a false positive result [see Drug Interactions ( 7.2 )] . Strong CYP3A4 inducers should be discontinued and enough time should be given to allow washout of CYP3A4 inducers prior to test administration [see Dosage and Administration ( 2.2 )].

5.3 Potential for False Negative Test Results in Recent Onset Hypothalamic Disease Adult growth hormone (GH) deficiency caused by a hypothalamic lesion may not be detected early in the disease process. Macimorelin acts downstream from the hypothalamus and macimorelin stimulated release of stored GH reserves from the anterior pituitary could produce a false negative result early when the lesion involves the hypothalamus. Repeat testing may be warranted in this situation.

to report suspected adverse reactions 1-800-332-1088 to report suspected adverse reactions , contact Aeterna Zentaris GmbH at 1-843-900-2332, or FDA at 1‑800-332-1088 or www.fda.gov/medwatch. to report suspected adverse reactions 1-800-332-1088 to report suspected adverse reactions , contact Aeterna Zentaris GmbH at 1-843-900-2332, or FDA at 1‑800-332-1088 or www.fda.gov/medwatch. The most common adverse reactions were dysgeusia, dizziness, headache, fatigue, nausea, hunger, diarrhea, upper respiratory tract infection, feeling hot, hyperhidrosis, nasopharyngitis, and sinus bradycardia ( 6.1 ).

6.1 Clinical Studies Experience to report suspected adverse reactions 1-800-332-1088 to report suspected adverse reactions , contact Aeterna Zentaris GmbH at 1-843-900-2332, or FDA at 1‑800-332-1088 or www.fda.gov/medwatch. 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 trial of another drug and may not reflect the rates observed in practice. The data in Table 1 are derived from an open-label, randomized, cross-over study that compared the diagnostic performance of MACRILEN to the insulin tolerance test (ITT) for the diagnosis of adult growth hormone deficiency [see Clinical Studies ( 14 )]. A total of 154 subjects with a high to low pre-test probability of having adult growth hormone deficiency received a single oral dose of 0.5 mg/kg MACRILEN. Out of 154 subjects, 58% were male, 42% female, and 86% of white origin. Median values were for age 41 years (range: 18 – 66 years) and body mass index was 27.5 kg/m 2 (range: 16 – 40 kg/m 2 ). Common adverse reactions presented in Table 1 were adverse reactions that were not present at baseline and occurred during MACRILEN dosing in at least two individuals. Table 1: Common Adverse Reactions Reported in at Least Two Individuals Dosed with MACRILEN in an Open-Label Study Number of Subjects (n = 154) Proportion of Subjects (%) Dysgeusia 7

4.5 Dizziness 6

3.9 Headache 6

3.9 Fatigue 6

3.9 Nausea 5

3.2 Hunger 5

3.2 Diarrhea 3

1.9 Upper respiratory tract infection 3

1.9 Feeling hot 2

1.3 Hyperhidrosis 2

1.3 Nasopharyngitis 2

1.3 Sinus bradycardia 2

1.3 The safety of Macrilen was evaluated in 126 pediatric patients. The overall safety profile in the pediatric population was consistent with that observed in adults.

7.1 Drugs that Prolong QT Interval Co-administration of MACRILEN with drugs that prolong the QT interval (such as antipsychotic medications (e.g., chlorpromazine, haloperidol, thioridazine, ziprasidone), antibiotics (e.g., moxifloxacin), Class 1A (e.g., quinidine, procainamide) and Class III (e.g., amiodarone, sotalol) antiarrhythmic medications or any other medications known to prolong the QT interval) may lead to development of torsade de pointes-type ventricular tachycardia. Avoid concomitant use of MACRILEN with drugs that prolong the QT interval. Sufficient washout time of drugs that are known to prolong the QT interval prior to administration of MACRILEN is recommended [see Dosage and Administration ( 2.2 ) and Warnings and Precautions ( 5.1 )] .

7.2 Cytochrome P450 (CYP) 3A4 Inducers Co-administration of a strong CYP3A4 inducer with MACRILEN (e.g., carbamazepine, enzalutamide, mitotane, phenytoin, rifampin, St. John's wort, bosentan, efavirenz, etravirine, modafinil, armodafinil, rufinamide) may reduce the plasma macimorelin concentrations and may lead to false positive test results. Discontinue strong CYP3A4 inducers prior to MACRILEN use. Sufficient washout time of strong CYP3A4 inducers prior to administration of MACRILEN is recommended [see Dosage and Administration ( 2.2 ) and Warnings and Precautions ( 5.2 )] .

7.3 Drugs Affecting Growth Hormone Release The following drugs may impact the accuracy of the MACRILEN diagnostic test. Avoid concomitant use of MACRILEN with the following [see Dosage and Administration ( 2.2 )] : Drugs that directly affect the pituitary secretion of growth hormone (such as somatostatin, insulin, glucocorticoids, and cyclooxygenase inhibitors such as aspirin or indomethacin). Drugs that may transiently elevate growth hormone concentrations (such as clonidine, levodopa, and insulin). Drugs that may blunt the growth hormone response to MACRILEN (such as muscarinic antagonists: atropine, anti-thyroid medication: propylthiouracil, and growth hormone products). Discontinue growth hormone products at least one week before administering the MACRILEN diagnostic test. Sufficient washout time of drugs affecting growth hormone release prior to administration of MACRILEN is recommended.

8.1 Pregnancy Risk summary There are no available data with MACRILEN use in pregnant women to inform a drug associated risk for adverse developmental outcomes. Animal reproduction studies have not been conducted with MACRILEN. MACRILEN is indicated as a single dose which limits the risk of adverse developmental outcomes from exposure to MACRILEN. The estimated background risk of major birth defects and miscarriage for the indicated populations 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 – 4% and 15 – 20%, respectively.

8.2 Lactation Risk Summary There are no data on the presence of macimorelin in human or animal milk, the effects on the breastfed infant or the effects on milk production. The lack of clinical data during lactation precludes a clear determination of the risk of MACRILEN to an infant during lactation; therefore, the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for MACRILEN and any potential adverse effects on the breastfed infant from MACRILEN or the underlying maternal condition.

8.4 Pediatric Use The safety and efficacy of MACRILEN in pediatric patients have not been established. The use of MACRILEN for the diagnosis of Growth Hormone Deficiency (GHD) was evaluated in two open-label studies in pediatric patients aged 3 to 17 years of age. Study 1 (Phase 2) was an open-label, group comparison, dose-escalation single dose escalation study in 24 pediatric patients with suspected GHD. No serious adverse events (SAEs) and no adverse events (AEs) were associated with the macimorelin growth hormone stimulation test (GHST). The study demonstrated a dose-dependent increase in macimorelin exposure and growth hormone (GH) stimulation. Study 2 (Phase 3) was a multicenter, open-label, randomized, crossover study in 102 pediatric patients with suspected GHD. Patients received a single oral dose of MACRILEN on two different occasions, compared to two standard growth hormone stimulation tests (arginine and clonidine). The primary efficacy endpoint was the area under the receiver operating characteristic (ROC) curve (AUC) assessing the diagnostic accuracy of MACRILEN compared to the adjudicated GHD status. The study failed to meet its primary endpoint; the lower bound of the 97.5% confidence interval for the ROC AUC was 0.66, which did not meet the pre-specified threshold of >0.70. Diagnostic performance (sensitivity and specificity) was evaluated against a cut-off point of 25.59 ng/mL, which was derived from the study data. Using this cut-off, sensitivity was 78.6% (95% CI: 63.2, 89.7) and specificity was 67.9% (95% CI: 53.7, 80.1). These results did not meet the pre-specified success criteria. An appropriate diagnostic cut-off point could not be established to consistently distinguish between GHD and non-GHD patients in the pediatric population.

8.5 Geriatric Use Growth hormone secretion normally decreases with age. Therefore, elderly subjects might require a lower cut-off point for diagnosis of adult growth hormone deficiency. Clinical studies of MACRILEN did not include a sufficient number of subjects aged 65 and over to determine whether elderly patients respond differently from younger subjects.

Macimorelin stimulates GH release by activating growth hormone secretagogue receptors present in the pituitary and hypothalamus.