Ghryvelin (Previously Macimorelin Aeterna Zentaris)

The use of GHRYVELIN must be supervised by a physician or healthcare professional experienced in diagnosing growth hormone deficiency. Posology The dose is calculated based on the patient´s body weight. The recommended single dose of the reconstituted suspension is 500 micrograms macimorelin per kg body weight.

The growth hormone release is to be evaluated with three blood samples collected at 45, 60 and 90 minutes after the administration of the medicinal product. g. somatostatin analogues, clonidine, levopoda and dopamine agonists) should be advised to discontinue such treatment at least 1 month before receiving macimorelin.

5). 2). 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.

4). Based on current understanding, this potential is unlikely to decrease the specificity of the test. Elderly Growth hormone secretion normally decreases with age. The efficacy of macimorelin in patients aged over 65 years has not been established.

In patients with age up to 60 years, diagnostic performance of MAC and ITT were comparable. In the age group 60 years up to 65 years, the limited data available do not indicate the need for a separate cut-off point. 2). No data are available.

Method of administration Oral use. GHRYVELIN granules are to be reconstituted with water and must be used within 30 minutes after preparation. Reconstituted suspension should be administered orally to patients fasting for at least 8 hours and who did not have strenuous physical exercises 24 hours before the test, since both could affect growth hormone levels.

The number of test sachets needed is based on body weight. One sachet will be required for a patient ≤ 120 kg, two sachets will be required if the patient weighs more than 120 kg. The entire contents of one sachet is dissolved in 120 mL, and two sachets are dissolved in 240 mL, as applicable.

5 mg/kg equals the patient's body weight in kg. For example, a 70 kg patient will require 70 mL of the macimorelin suspension. Assessment of fasted condition and lack of prior strenuous physical exercise Before using GHRYVELIN it is important to ensure that the patient is in fasting condition for at least 8 hours and did not have strenuous physical exercises 24 hours before the test, since both could affect GH levels.

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).

MedDRA organ class Common Uncommon Not known Nervous system disorders Dysgeusia (bitter/metallic taste) Somnolence Dizziness Tremor Headache Ear and labyrinth disorders Vertigo Cardiac disorders Palpitations ECG QT prolonged Sinus bradycardia ECG T wave abnormal Gastrointestinal disorders Nausea Abdominal pain Diarrhoea General disorders and administration site conditions Fatigue Feeling hot Feeling cold Hunger Thirst 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.

4). 5 mg/kg, 1 mg/kg and 2 mg/kg). 1). The mechanism for the observed QTcF prolongation is unknown. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important.

It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 8

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.

1). QT prolongation can lead to development of torsade de pointes-type ventricular tachycardia with the risk increasing as the degree of prolongation increases. 5). , 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.

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. 5). 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.

1.