GHRYVELIN 60 mg ORAL SUSPENSION GRANULES

2. What you need to know before you use GHRYVELIN

You must not receive GHRYVELIN

• if you are allergic to macimorelin or any of the other ingredients of this medicine (listed in section 6).

If you are not sure, talk to your doctor or nurse before receiving GHRYVELIN.

Warnings and precautions

To ensure that the test results are reliable, you must follow these rules:

• Fasting: you must not eat for at least 8 hours before the test and during the test.
• Physical exercise: avoid intense physical activities for 24 hours before the test.
• Drinking: you can drink up to 100 ml of still water in the hour before and in the hour after taking macimorelin.

Talk to your doctor or nurse if:

• you have recently received treatment with growth hormone (somatropin) or with medicines that affect the secretion of growth hormone by the pituitary gland. You will need to stop this treatment at least 1 month before the test.
• you have recently received treatment for Cushing's disease (a disorder that produces high levels of cortisol) or are receiving a high dose of hydrocortisone, as the test may produce false positive results.
• your body is deficient in other hormones, such as cortisol, thyroid hormones, or sex hormones, vasopressin (in case of diabetes insipidus), as they will need to be adequately replaced before analyzing the growth hormone deficiency.
• you have heart disease or have heart rhythm problems (such as congenital or acquired long QT syndrome or a history of torsades de pointes). GHRYVELIN may cause changes in the ECG (electrocardiogram), such as prolongation of the QT interval, which are associated with a higher risk of arrhythmias. If this happens, such changes will be limited and brief.

If any of the above situations apply to you or if you have any doubts, talk to your doctor or nurse before receiving this medicine.

GHRYVELIN is indicated as a diagnostic test in a single dose. There is no information available on the safety and effects of macimorelin during long-term use.

Possible need to repeat the test in early stages of the disease

If adult growth hormone deficiency has just started and is due to an injury in a part of the brain called the hypothalamus, the test result may be negative even if you actually have the disease. In this situation, it may be necessary to repeat the test.

Children and adolescents

GHRYVELIN must not be used in children and adolescents under 18 years of age, as the safety and efficacy in these groups have not yet been established.

Other medicines and GHRYVELIN

Tell your doctor if you are taking, have recently taken, or might take any other medicines.

Tell your doctor if you are taking medicines that may affect your heart rhythm, such as:

• medicines for treating psychosis (such as chlorpromazine or haloperidol)
• medicines for treating infections (antibiotics such as erythromycin, clarithromycin, or moxifloxacin)
• medicines for correcting heart rhythm (anti-arrhythmics such as amiodarone, procainamide, quinidine, or sotalol)
• any other medicine that may prolong the QT interval or induce torsades de pointes

Tell your doctor if you are taking medicines that may increase the breakdown of macimorelin, such as medicines for treating:

• seizures/epilepsy (carbamazepine, eslicarbazepine, fosphenytoin, oxcarbazepine, phenobarbital, phenytoin, primidone)
• sleep disorders (modafinil, pitolisant)
• mild or moderate episodes of depression (St. John's Wort [Hypericum perforatum])
• cystic fibrosis (lumacaftor)
• infections (antibiotics such as rifabutin or rifampicin)
• HIV infection (efavirenz, nevirapine)
• type 2 diabetes (pioglitazone)
• cancer (dabrafenib, enzalutamide)

Tell your doctor if you are taking medicines that may affect the accuracy of the diagnostic test. Avoid concomitant use of medicines:

• that may have a direct influence on the secretion of growth hormone by the pituitary gland, such as somatostatin, insulin, glucocorticoids, acetylsalicylic acid, or indomethacin
• that may increase growth hormone levels, such as clonidine, levodopa, or insulin
• that may reduce the growth hormone response to macimorelin, such as atropine, propylthiouracil, or growth hormone

Pregnancy and breastfeeding

If you are pregnant or breastfeeding, think you may be pregnant, or are planning to have a baby, ask your doctor or nurse for advice before taking this medicine.

GHRYVELIN is not recommended during pregnancy. If you are a woman of childbearing potential, you should use effective contraceptive methods to ensure you are not pregnant when you undergo the test. If you are breastfeeding or plan to breastfeed, it cannot be excluded that there is a risk to the baby. Ask your doctor if you should stop breastfeeding or avoid taking the macimorelin test.

Driving and using machines

GHRYVELIN may cause dizziness. If this happens, do not drive or use machines.

GHRYVELIN contains lactose

If your doctor has told you that you have an intolerance to some sugars, consult them before taking this medicine.

GHRYVELIN contains sodium

This medicine contains less than 1 mmol of sodium (23 mg) per sachet, which is essentially "sodium-free".

3. How to use GHRYVELIN

The preparation and use of GHRYVELIN must be supervised by a healthcare professional. At the end of this leaflet, instructions are provided on how to prepare the medicine for the test.

The description of this leaflet is for your information about the test procedure.

You must fast for at least 8 hours before receiving GHRYVELIN. You must not perform intense physical exercises for 24 hours before the test. You can drink up to 100 ml of still water 1 hour before and 1 hour after taking GHRYVELIN.

Dose

The recommended dose is 0.5 mg of GHRYVELIN per kilogram of body weight.

This corresponds to a volume of 1 ml of the prepared suspension per kilogram of body weight.

You must drink the entire dose for the test within 30 seconds.

Three blood samples will be taken to determine growth hormone levels at 45, 60, and 90 minutes after taking the test dose.

If you receive more GHRYVELIN than you should

If you receive more GHRYVELIN than you should, talk to your doctor or nurse. Possible side effects in case of overdose may include headache, nausea, vomiting, and diarrhea. If you experience changes in heart rhythm, an ECG will be performed.

If you have any further questions on the use of this medicine, ask your doctor or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Common side effects(may affect up to 1 in 10 people):

• bitter or metallic taste (dysgeusia)
• fatigue
• headache
• nausea
• dizziness
• diarrhea
• feeling of heat

These side effects are mostly mild, do not last long, and usually disappear quickly without treatment.

Uncommon side effects(may affect up to 1 in 100 people):

• abdominal pain
• feeling of cold
• hunger
• palpitations
• slower than normal heart rate (sinus bradycardia)
• sleepiness
• thirst
• tremor
• vertigo

Frequency not known(cannot be estimated from the available data):

• changes in the electrocardiogram (ECG)

Reporting of side effects

If you experience any side effects, talk to your doctor or nurse, even if they are not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects, you can help provide more information on the safety of this medicine.

5. Storage of GHRYVELIN

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the carton and on the sachet after EXP. The expiry date is the last day of the month shown.

Store in the original package to protect from light and moisture.

Store in a refrigerator (between 2°C and 8°C).

Unopened sachet

The shelf life of a sachet is 4 years.

Reconstituted suspension

The suspension must be taken within 30 minutes of preparation.

The doctor or nurse will discard the leftover suspension according to local regulations.

Medicines should not be disposed of via wastewater or household waste. This will help protect the environment.

6. Contents of the pack and other information

Composition of GHRYVELIN

• The active substance is macimorelin. Each sachet contains 60 mg of macimorelin (as acetate). 1 ml of the reconstituted suspension contains 500 micrograms of macimorelin.
• The other ingredients are: lactose monohydrate (see "GHRYVELIN contains lactose" in section 2), colloidal anhydrous silica, crospovidone type A, sodium saccharin dihydrate, and sodium stearyl fumarate (see "GHRYVELIN contains sodium" in section 2).

Appearance and pack contents

GHRYVELIN is presented as a white or off-white granule for oral suspension. Each sachet contains 1.817 mg of granule. Each carton contains 1 sachet.

Marketing authorisation holder

Atnahs Pharma Netherlands B.V.

Copenhagen Towers

Ørestads Boulevard 108, 5.tv

DK-2300 København S

Denmark

Manufacturer

Aeterna Zentaris GmbH

Weismüllerstrasse 50

D-60314 Frankfurt am Main

Germany

Date of last revision of this leaflet

Other sources of information

Detailed information on this medicine is available on the European Medicines Agency website: http://www.ema.europa.eu

The following information is intended for healthcare professionals only:

INSTRUCTIONS FOR PREPARATION AND USE

The suspension must be prepared and administered by a healthcare professional.

Required items: GHRYVELIN sachet, tap water in a measuring cup, graduated glass or transparent plastic container, stirrer, 50 ml graduated syringe without needle, drinking glass

Step 1

Weigh the patient.

Step 2

Determine the number of GHRYVELIN sachets needed based on body weight: one sachet is needed if the patient weighs up to 120 kg or two sachets if the patient weighs more than 120 kg.

Step 3

Add the required volume of water to a graduated glass or transparent plastic container. Dissolve the entire contents of the sachet in water: one sachet in 120 ml or two sachets in 240 ml, as applicable.

Gently stir the suspension for 2 minutes (a small amount of particles will remain undissolved, resulting in a slightly turbid suspension). The suspension must be stirred until it is slightly turbid and no particles are visible at the bottom of the container. The suspension must be stirred again if some particles settle at the bottom of the container, such as after leaving the suspension upright for a period of time.

Step 4

Determine the volume of suspension needed to administer the recommended dose of macimorelin of 0.5 mg/kg. The volume of the suspension in milliliters is equal to the patient's body weight in kilograms. For example, a patient weighing 70 kg will need 70 ml of the macimorelin suspension.

Measure the required volume with a 50 ml graduated syringe without needle.

Transfer the measured amount to a drinking glass.

Step 5

Instruct the patient to drink the entire contents of the glass within 30 seconds.

The suspension must be used within 30 minutes of preparation. The leftover suspension must not be stored and must be discarded.

Disposal of unused medicine and all materials that have come into contact with it will be carried out in accordance with local regulations.

Step 6

Take blood samples to determine growth hormone levels at 45, 60, and 90 minutes after administration.

Step 7

Prepare the plasma or serum samples and send them to a laboratory for growth hormone determination.