Limitations of Use

The safety and diagnostic performance of MACRILEN have not been established for subjects with a body mass index (BMI) > 40 kg/m2.

2.1 Recommended Dose

The recommended dose is a single oral dose of 0.5 mg/kg of macimorelin. The dose is administered as a reconstituted solution [see Dosage and Administration (2.3)] in patients fasted for at least 8 hours.

2.2 Important Recommendations Before MACRILEN Use

•

Discontinue strong CYP3A4 inducers prior to MACRILEN use [see Warning and Precautions (5.2) and Drug Interactions (7.2)].

•

Discontinue growth hormone (GH) therapy at least one week before administering MACRILEN [see Drug Interactions (7.3)].

•

Avoid the use of MACRILEN with drugs known to affect pituitary GH secretion [see Drug Interactions (7.3)].

•

For patients with deficiencies in sex hormones, thyroid hormone and/or glucocorticoid, adequately replace each of the missing hormones before administering MACRILEN.

•

Ensure that the patient has fasted for at least 8 hours before MACRILEN use.

2.3 Directions for Preparation and Administration

Prepare and administer by a healthcare professional exactly as follows.

Prepare the MACRILEN solution:

a.

Weigh the patient in kilograms (i.e., kg).

b.

Determine the number of MACRILEN pouches needed to prepare the dose:

i. For a patient weighing up to 120 kg, use 1 pouch.

ii. For a patient weighing more than 120 kg, use 2 pouches.

c.

Use a glass or transparent plastic container with graduation in milliliters (i.e., mL) to dissolve the entire contents of the pouch(es) in the appropriate volume of water.

i. For 1 pouch dissolve in 120 mL of water (corresponds to 60 mg/120 mL).

ii. For 2 pouches dissolve in 240 mL of water (corresponds to 120 mg/240 mL).

d.

Stir the MACRILEN solution gently for about 2 to 3 minutes (a small amount of un-dissolved particles will remain). The solution will have a final concentration of 0.5 mg/mL.

e.

Use the MACRILEN solution within 30 minutes after preparation.

f.

Discard any unused MACRILEN solution.

Determine the volume of MACRILEN solution needed for the test:

g.

Determine the recommended dose to be administered by multiplying the patient weight in kilogram by 0.5 mg/kg.

For example, a 70 kg patient will need a 35 mg dose.

h.

Determine the volume of prepared MACRILEN solution to be administered by dividing the recommended dose by 0.5 mg/mL.

For example, a patient requiring a dose of 35 mg will need 70 mL of reconstituted MACRILEN solution.

i.

Use a syringe (without a needle) with graduations in mL to measure the exact volume of MACRILEN solution to be administered and transfer the required volume of MACRILEN solution into a drinking glass.

Administer the MACRILEN solution and perform the test:

j.

Have the patient being tested drink the entire volume of MACRILEN solution in the drinking glass (i.e., the dose) within 30 seconds.

k.

Observe the patient being tested per routine for the duration of the test.

l.

Draw venous blood samples for GH determination at 30 minutes, 45 minutes, 60 minutes and 90 minutes after administration of MACRILEN.

m.

Prepare serum samples and send to a laboratory for growth hormone determinations.

n.

o.

p.

q.

r.

s.

t.

u.

v.

2.4 Interpretation of MACRILEN Test Results

Clinical studies have established that a maximally stimulated serum GH level of less than 2.8 ng/mL (i.e., at the 30, 45, 60 and 90 minute timepoints) following MACRILEN administration confirms the presence of adult growth hormone deficiency.

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.

6.1 Clinical Studies Experience

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/m2 (range: 16 – 40 kg/m2). 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.

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

8.2 Lactation

8.4 Pediatric Use

The safety and efficacy of MACRILEN in pediatric patients have not been established.

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.

12.1 Mechanism of Action

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

12.2 Pharmacodynamics

12.3 Pharmacokinetics

The mean plasma macimorelin concentrations are similar between patients with AGHD and healthy subjects for 1.5 hours following administration of a single oral dose of 0.5 mg macimorelin/kg body weight.

Absorption

The maximum plasma macimorelin concentrations (Cmax) were observed between 0.5 hour and 1.5 hours following oral administration of 0.5 mg macimorelin/kg body weight to patients with AGHD under fasting for at least 8 hours. A liquid meal decreased the macimorelin Cmax and AUC by 55% and 49%, respectively.

Elimination

An in vitro human liver microsomes study showed that CYP3A4 is the major enzyme to metabolize macimorelin.

Macimorelin was eliminated with a mean terminal half-life (T1/2) of 4.1 hours following administration of a single oral dose of 0.5 mg macimorelin/kg body weight in healthy subjects.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Results

One hundred and fifty-seven subjects underwent at least one of the two tests in this study, 59% were male, 41% female, and 86% of white origin. The median age was 41 years (range: 18 – 66 years) and body mass index 27.5 kg/m2 (range: 16 – 40 kg/m2). The study relied on a cross-over design and each participant was to undergo the two diagnostic tests and serve as his or her own control. Data on both tests were available for 140 subjects; 38 (27%) in Group A, 37 (26%) in Group B, 40 (29%) in Group C, and 25 (18%) in Group D. One out of 154 MACRILEN tests (0.6%) performed failed due to a technical error and 27 out of 157 ITTs (17.2%) performed failed because induction of severe hypoglycemia (i.e., the stimulus) could not be achieved.

Two-by-two tables presenting the pre-specified primary analysis results for the ITT and MACRILEN test are shown below for all subjects (Groups A, B, C, and D combined) and for each group separately (see Table 3). The estimates for negative and positive agreement between MACRILEN and the ITT in the overall study population were 94% and 74% with lower 95% confidence interval bounds 85% and 63%, respectively. Negative and positive agreement between MACRILEN and the ITT in subjects with intermediate or low risk (Groups B and C) were 93% and 61% with lower 95% confidence interval bounds 80% and 43%, respectively. These results are based on peak GH values (maximum GH concentrations across all measurement timepoints).

Repeatability was tested in a subset of 34 subjects who underwent two MACRILEN tests. Agreement between the result of the first test and the second test was observed in 31 cases (91.2%).