GHRYVELIN Granules for oral suspension Ref.[28093] Active ingredients: Macimorelin

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 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 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. 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 (see also section 4.2 and section 4.5).

Patients with a deficiency affecting hormones other than growth hormone (GH)

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.

Patients with Cushing’s disease or on supra-physiologic glucocorticoid therapy

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.

Potential for increased oral bioavailability and macimorelin plasma concentration with use of strong CYP3A4/P-gp-inhibitors

Drug-drug interaction studies with CYP3A4/P-gp-inhibitors have not been conducted. A potential for increased oral bioavailability and macimorelin plasma concentration with use of strong CYP3A4/P-gp-inhibitors cannot be excluded. It is unknown whether such potential interactions may also affect QTc (see above). Based on current understanding, this potential is unlikely to decrease the specificity of the test.

Potential for false positive test results with use of strong CYP3A4 inducers

Concomitant use of strong CYP3A4 inducers with GHRYVELIN can decrease macimorelin plasma levels significantly and thereby lead to a false positive result (see also section 4.5). Strong CYP3A4 inducers should be discontinued and a washout time of five elimination half-lives should be considered prior to test administration.

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.

Information about lactose and sodium

This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should take this medicinal product only if the expected benefit of the test clearly outweighs the potential risk associated with an intake of maximum 1,691.8 mg lactose per sachet. This medicinal product contains less than 1 mmol sodium (23 mg) per sachet that is to say essentially ‘sodium-free’.

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.

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 products that may induce torsades de pointes) should be avoided (see section 4.4).

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.

GHRYVELIN 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 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).

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 (see also section 4.4).

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 (see section 5.1). 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.

Not applicable.