Ghryvelin (previously Macimorelin Aeterna Zentaris) · 4.4 Special warnings and precautions for use · 1

HOS-287235 · has-adverse-reaction-information · PDF-Seite 6

6 Summary of the safety profile The most common adverse reactions associated with GHRYVELIN reported in Study 052 (see section 5.1) 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). Not MedDRA organ class Common Uncommon known Dysgeusia (bitter/metallic taste) Somnolence Nervous system disorders Dizziness Tremor Headache Vertigo Ear and labyrinth disorders ECG QT Palpitations prolonged Cardiac disorders ECG T wave Sinus bradycardia abnormal Nausea Abdominal pain Gastrointestinal disorders Diarrhoea Feeling cold General disorders and administration Fatigue Hunger site conditions Feeling hot Thirst Description of selected adverse reactions Cardiac electrophysiology During clinical development,

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HOS-287231 · has-contraindication-information · PDF-Seite 3

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

HOS-287230 · has-indication-information · PDF-Seite 2

This medicinal product is for diagnostic use only. GHRYVELIN is indicated for the diagnosis of growth hormone deficiency (GHD) in adults (see section 5.1).

HOS-287233 · has-interaction-information · PDF-Seite 5

Macimorelin is metabolised mainly by CYP3A4 in vitro. Co-administration of a CYP3A4 inhibitor may increase the macimorelin plasma concentration, and this, in turn, could yield higher plasma GH levels. Based on current understanding, this is unlikely to decrease the specificity of the test. 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 (see section 4.2 and section 4.4). No drug-drug interaction studies have been performed in humans. 5 Medicinal products affecting growth hormone release The following medicinal products may impact the accuracy of the diagnostic test. Concomitant use is to be avoided with (see also section 4.2 and section 4.4): • 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). Growth hormone medicinal products should be discontinued at least 1 month before administering macimorelin. Sufficient washout time (five elimination half-lives) of medicinal products prior to administration of macimorelin is recommended. Medicinal products with a potential to induce torsades de pointes 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 produ

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HOS-287234 · has-pregnancy-information · PDF-Seite 6

Women of childbearing potential Women of childbearing potential must use adequate contraceptive methods at the time when macimorelin will be administered. Pregnancy There are no data for the use of macimorelin in pregnant women. Studies in animals are insufficient with respect to reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Macimorelin is not recommended during pregnancy. Breast-feeding 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. Fertility There are no data available on animal (see section 5.3) or human male and female fertility.

HOS-287232 · has-warning-information · PDF-Seite 3

3 Interpretation of macimorelin test results Clinical studies have established that a maximally stimulated serum GH level of less than 2.8 ng/mL (at the 45, 60 and 90 minutes timepoints) following macimorelin administration confirms a diagnosis of adult growth hormone deficiency. As with all GH stimulation tests, also the macimorelin test results should always be interpreted on basis of the outcome of all examinations within the diagnostic work-up for a patient. The safety and diagnostic performance of macimorelin have not been established for patients with body mass index (BMI) > 40 kg/m2. Macimorelin induced GH release was lower in patients with higher BMI. In patients with high BMI up to 40 kg/m2, diagnostic performance of MAC and of ITT were comparable. The cut-off point for macimorelin has not been established in the transition period from late puberty to full adult maturation. In patients between 18 and 25 years of age, the diagnostic performance of MAC and of ITT were comparable. QTc prolongation 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. Macimorelin causes an increase of about 11 ms in the corrected QT (QTc) interval by an unknown mechanism (see also section 5.1). 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 with medicinal products that are known to induce torsades de pointes should be avoided (see also section 4.5). Macimorelin should be used with caution in patients with proarrhythmic condition (e.g., history of myocardial infarction, heart failure or prolonged ECG QTc interval, as defined as QTc > 500 ms). For such patients, 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. In patients with known congenital or acquired long QT syndrome and in patients with a history of torsades de pointes, the use of macimorelin may only be considered in a cardiovascular clinical unit. Discontinuation of therapy with growth hormone (GH) or medicinal products directly affecting the pituitary secretion of somatotropin Patients on replacement therapy with growth hormone (GH, somatotropin) or on medicinal products directly affecting the pituitary se

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