Macimorelin

Co-administration of macimorelin with medicinal products with a potential to induce torsades de pointes (antipsychotic medicinal products e.g. chlorpromazine, haloperidol, antibiotics (e.g., moxifloxacin, erythromycin, clarithromycin), anti-arrhythmics Class Ia (e.g. quinidine), and Class III (e.g. amiodarone, procainamide, sotalol) or any other medicinal products that may induce torsades de pointes) should be avoided.

Administration of a CYP3A4 inducer (such as carbamazepine, dabrafenib, efavirenz, enzalutamide, eslicarbazepine, fosphenytoin, lumacaftor, modafinil, nevirapine, oxcarbazepine, phenobarbital, phenytoin, pioglitazone, pitolisant, primidone, rifabutin, rifampicin and St John’s wort (Hypericum perforatum)) may reduce the plasma macimorelin concentrations and may affect the diagnostic performance of the test and therefore should be avoided. A sufficient washout time of five elimination half-lives of the CYP3A4 inducer prior to administration of the test is recommended.

The safety and efficacy of macimorelin in patients with renal and/or hepatic impairment have not been established. No data are available. If macimorelin is administered to patients with renal and/or hepatic impairment, the potential for an increased macimorelin plasma concentration cannot be excluded. It is unknown whether this may affect QTc. Therefore, ECG controls may be indicated prior to the administration of macimorelin and 1 hour, 2 hours, 4 hours and 6 hours after administration of macimorelin. Based on current understanding, this potential is unlikely to decrease the specificity of the test.

Patients on replacement therapy with growth hormone (GH, somatotropin) or on medicinal products directly affecting the pituitary secretion of somatotropin (e.g. somatostatin analogues, clonidine, levopoda and dopamine agonists) should be advised to discontinue such treatment at least 1 month before receiving a test dose of macimorelin. Sufficient washout time (five elimination half-lives) of medicinal products prior to administration of macimorelin is recommended.

Exogenous GH or medicinal products directly affecting the pituitary gland could influence the somatotropic function of the pituitary gland and lead to unreliable GH stimulation results.

Concomitant use is to be avoided with:

• Medicinal products that directly affect the pituitary secretion of growth hormone (such as somatostatin, insulin, glucocorticoids, and cyclooxygenase inhibitors such as acetylsalicylic acid or indometacin).
• Medicinal products that may transiently elevate growth hormone concentrations (such as clonidine, levodopa, and insulin).
• Medicinal products that may blunt the growth hormone response to macimorelin (such as muscarinic antagonists: atropine, anti-thyroid medicinal products: propylthiouracil and growth hormone medicinal products).

Patients with a deficiency affecting hormones other than GH (e.g. adrenal, thyroidal and/or gonadal insufficiency, diabetes insipidus) should be adequately replaced with the other deficient hormones before any testing for a deficiency of GH stimulation is performed, to exclude a stimulation failure due to a secondary GH deficiency.

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.

Hypercortisolism has a significant impact on the hypothalamic-pituitary-adrenal axis. Therefore, the diagnostic performance of the test may by affected in patients with Cushing’s disease or on supra-physiologic glucocorticoid therapy (e.g. systemic administration of doses of hydrocortisone (or its equivalent) in excess of 15 mg/m²/day) and lead to false positive test results.

There are no data for the use of macimorelin in pregnant women. Studies in animals are insufficient with respect to reproductive toxicity. The potential risk for humans is unknown. Macimorelin is not recommended during pregnancy.

It is unknown whether macimorelin or its metabolites are excreted in human milk. A risk to the suckling child cannot be excluded. A decision must be made whether to discontinue breast-feeding or to abstain from macimorelin, taking into account the benefit of breast-feeding for the child and the benefit of the test for the woman.

Women of childbearing potential

Women of childbearing potential must use adequate contraceptive methods at the time when macimorelin will be administered.

Fertility

There are no data available on animal or human male and female fertility.

Macimorelin has minor influence on the ability to drive and use machines. Dizziness has been reported by some patients taking macimorelin. In case a patient should be reporting dizziness as side effect, the patient should be instructed to neither drive nor use machines.

Summary of the safety profile

The most common adverse reactions associated with macimorelin reported in Study 052 in 154 patients were dysgeusia (5%), headache fatigue, nausea (each 3%), dizziness (2%), as well as abdominal pain, diarrhoea, feeling hot, feeling cold, hunger, palpitations, sinus bradycardia, somnolence, thirst, tremor, and vertigo (each 1%). Overall, the adverse reactions reported were mostly of mild intensity and short duration without a specific treatment need.

Tabulated list of adverse reactions

Adverse reactions reported in Study 052 are listed below by MedDRA body system organ class and by frequency: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from available data).

Description of selected adverse reactions

Cardiac electrophysiology

During clinical development, two transient ECG abnormalities were observed in one test subject and reported as serious possibly adverse reactions. These ECG abnormalities consisted of T wave abnormalities and QT prolongation.

The effects of macimorelin on ECG parameters were investigated in a dedicated Thorough QT study of a supra-therapeutic dose of macimorelin (2 mg/kg) and in a single-ascending dose study, which included three dose levels of macimorelin (0.5 mg/kg, 1 mg/kg and 2 mg/kg). Macimorelin causes an increase of about 11 ms in the corrected QT (QTc) interval. The mechanism for the observed QTcF prolongation is unknown.