AGILUS 120 mg POWDER FOR INJECTABLE SOLUTION

Introduction

Package Leaflet: Information for the User

Agilus 120 mg powder for solution for injection

dantrolene sodium hemiheptahydrate

Read all of this leaflet carefully, because it contains important information for you.

This medicine is used in emergency situations and your doctor will have decided that you need it.

• Keep this leaflet, you may need to read it again.
• If you have any further questions, ask your doctor.
• If you experience side effects, consult your doctor, even if they are not listed in this leaflet. See section 4.

Contents of the pack

1. What is Agilus and what is it used for
2. What you need to know before Agilus is administered
3. How Agilus is administered
4. Possible side effects
5. Storage of Agilus
6. Contents of the pack and further information

1. What is Agilus and what is it used for

Agilus contains dantrolene sodium. It is a type of medicine called a direct-acting muscle relaxant. It binds to a target inside muscle cells and helps the body's muscles to relax when they are over-stimulated.

This medicine is used to treat malignant hyperthermia in adults and children of all ages, in combination with other supportive measures. Malignant hyperthermia is a life-threatening condition that requires urgent attention, in which the body's skeletal muscles are over-stimulated and cannot relax. This can cause a very rapid increase in body temperature and/or a build-up of waste products in the body (metabolic acidosis), which can prevent vital organs from working properly.

2. What you need to know before Agilus is administered

Agilus must not be administered

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

Warnings and precautions

It is likely that you will have been given this medicine before you read this leaflet.

Tell your doctor or nurse if:

• you are currently taking medicines for high blood pressure or angina called “calcium antagonists”. Taking these medicines at the same time as Agilus may increase the amount of potassium in the blood, which could cause an irregular heartbeat or inability to move some of the muscles.
• if you think any medicine has spilled onto your skin, you should wash it off with water.

Liver damage has been observed in patients exposed to prolonged oral use of dantrolene sodium. Tell your doctor if you think you have symptoms of liver damage (e.g. if your skin and eyes look yellow or if you have abdominal pain and swelling).

Other medicines and Agilus

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

The following medicines may affect the way Agilus works, or Agilus may affect the way they work:

• medicines for high blood pressure and angina called “calcium antagonists”, such as verapamil or diltiazem, may cause heart failure if given at the same time as Agilus (see warnings and precautions).
• muscle relaxants, such as vecuronium, may enhance the muscle relaxant effect of Agilus if given at the same time.

Pregnancy and breast-feeding

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, tell your doctor or nurse before you are given this medicine.

Pregnancy

Agilus will not be used if you are pregnant, unless it is considered necessary. After administration of Agilus, the muscles of the uterus (womb) may be weakened. If you are given Agilus during a caesarean section, your newborn baby may experience muscle weakness.

Breast-feeding

You must not breast-feed while you are being given Agilus and for 60 hours after the last dose. Tell your doctor if you are breast-feeding.

Driving and using machines

After administration of Agilus, it is possible that the muscles in your hands and legs may be weakened and you may feel dizzy or lightheaded. These effects may last for up to 48 hours after administration of Agilus. Do not drive or operate machinery during this time.

Agilus contains cyclodextrin and sodium

This medicine contains 3,530 mg of hydroxypropyl betadex (a cyclodextrin) in each vial, which is equivalent to 156.2 mg/ml in the reconstituted solution.

Tell your doctor if you have experienced hearing problems in the past, for example if you are prone to ear infections. Cases of hearing loss have been observed in patients given hydroxypropyl betadex to treat other conditions at higher doses than those recommended for Agilus. This hearing loss is usually mild and short-lived. For patients who need high doses of Agilus (above 10 mg/kg), treatment will need to be re-evaluated due to this risk.

The potential risk associated with hydroxypropyl betadex may be increased if the kidneys are not working properly.

This medicine contains 6.9 mg of sodium (a major component of table salt) in each vial.

This represents less than 0.5% of the maximum recommended daily intake of sodium for an adult.

3. How Agilus is administered

This injection will be given to you in a vein by a healthcare professional. The dose of Agilus that you are given will depend on your body weight. The dose will be repeated every 10 minutes until your symptoms improve. If your symptoms do not improve after you have been given the medicine, your doctor may re-examine your diagnosis and consider other treatments. If you have a relapse, your healthcare professional will give you Agilus again.

If you are given more Agilus than you should

If you have been given more Agilus than you should, side effects may occur. Severe muscle weakness may occur, which could affect your breathing. Your doctor will monitor you closely.

If you have any other questions about 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. The following side effects have been observed with the active ingredient of Agilus:

The frequency of the following side effects is not known(it cannot be estimated from the available data)

Serious side effects: your doctor will stop giving you Agilus immediately

• sudden and severe allergic reaction with difficulty breathing, swelling, dizziness, fast heartbeat, sweating and loss of consciousness (anaphylactic reaction)

Other side effects

The following side effects have been observed with the active ingredient of Agilus:

• allergic reactions (hypersensitivity)

• high levels of potassium in the blood (hyperkalemia), which can cause tiredness, muscle weakness, feeling unwell and changes in heart rhythm
• dizziness, drowsiness, seizures, difficulty speaking (dysarthria), headache
• vision changes
• heart failure, slow heart rate (bradycardia), fast heart rate (tachycardia)
• inflammation in a vein that causes a blood clot and blockage (thrombophlebitis)
• difficulty breathing (respiratory failure), breathing that is too slow and shallow (respiratory depression)
• stomach pain (abdominal pain), feeling sick (nausea), vomiting, intestinal and stomach bleeding with symptoms of blood in the stool or vomit (gastrointestinal bleeding), diarrhea, difficulty swallowing (dysphagia)
• yellowing of the eyes and skin (jaundice)*, inflammation of the liver (hepatitis)*, potentially life-threatening liver failure*, changes in liver function tests, liver disease due to an unknown cause or allergic reaction
• itching (urticaria), redness of the skin (erythema), excessive sweating (hyperhidrosis)
• muscle weakness, tired muscles
• crystals in the urine (crystalluria)
• weak contractions during childbirth (uterine hypotonia)
• feeling tired (fatigue), general weakness (asthenia), reactions at the injection site

*These side effects were observed in situations where treatment with dantrolene was given orally for a long time.

Reporting of side effects

If you experience any side effects, tell 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 Agilus

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

This medicine will be stored in the hospital and these instructions are intended solely for healthcare professionals.

Unopened vial: no special storage temperature is required. Store the vial in the original packaging to protect it from light.

Reconstituted solution: use before 24 hours. The reconstituted solution must be protected from light. Do not store above 25°C and do not refrigerate.

Do not use this medicine after the expiry date which is stated on the label and on the outer carton of the vials after “EXP”. The expiry date is the last day of the month stated.

For single use only. Discard any remaining reconstituted solution.

6. Contents of the pack and further information

Composition of Agilus

The active substance is dantrolene sodium hemiheptahydrate.

Each vial contains 120 mg of dantrolene sodium hemiheptahydrate. After reconstitution with 20 ml of water for solution for injection, each milliliter of solution contains 5.3 mg of dantrolene sodium hemiheptahydrate.

The other ingredients are hydroxypropyl betadex (a cyclodextrin) and macrogol (E1521). See section 2, “Agilus contains cyclodextrin and sodium”.

Appearance and pack size

Orange-yellow powder in glass vials with a rubber stopper and seal, containing 120 mg of powder for solution for injection.

Box of 6 or 10 vials.

Not all pack sizes may be marketed.

Marketing authorisation holder and manufacturer

Norgine B.V.

Antonio Vivaldistraat 150

1083 HP Amsterdam

Netherlands

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 leaflet for this medicine is available in all EU/EEA languages on the European Medicines Agency website.

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This information is intended only for healthcare professionals:

Dosage and administration

Treatment with Agilus should be started as soon as malignant hyperthermia is suspected, i.e. characteristic presentation of muscle rigidity, metabolic acidosis and/or rapid increase in body temperature.

Dosage

Agilus should be administered rapidly by intravenous injection with an initial dose of 2.5 mg/kg body weight in adult and pediatric patients.

While the main clinical symptoms of tachycardia, hypoventilation, sustained hyperacidity [pH and carbon dioxide partial pressure (pCO2) monitoring is required] and hyperthermia persist, an intravenous bolus injection of 2.5 mg/kg should be repeated every 10 minutes until physiological and metabolic abnormalities improve. If a cumulative dose of 10 mg/kg or more is being considered, the diagnosis of malignant hyperthermia should be re-examined.

The following table shows how to dose according to the vials needed for the rapid injection of the initial dose of 2.5 mg/kg:

Table 1: Dosing examples

aThe total volume of a reconstituted vial is 22.6 ml.

bFor all body weights, the initial dose and any repeat dose should not exceed 300 mg, equivalent to 2.5 vials.

Treatment of recurrence (relapse)

Note that the hypermetabolic response associated with malignant hyperthermia may recur within the first 24 hours. If a recurrence occurs, a dose of Agilus of 2.5 mg/kg should be administered again every 10 minutes until the signs of malignant hyperthermia have resolved again. The considerations that apply to monitoring metabolic abnormalities and adjusting doses in an initial episode also apply to the treatment of recurrence.

Pediatric population

No dose adjustment is necessary.

Method of administration

Intravenous route.

Special precautions for storage, preparation and handling

Preparation

Each vial should be reconstituted by adding 20 ml of water for solution for injection and shaking for approximately 1 minute, before inspecting for particles. Further shaking may be necessary. The reconstituted solution should be orange-yellow in color and free of particles.

The volume of the solution in a reconstituted vial is 22.6 ml.

Chemical and physical stability after reconstitution has been demonstrated for 24 hours at 25°C. From a microbiological point of view, unless the opening/reconstitution method precludes the risk of microbial contamination, the reconstituted product should be used immediately. If not used immediately, the in-use storage times and conditions are the responsibility of the user and should not exceed 24 hours at 25°C.

Storage

The unopened vial does not require any special storage temperature. Store the vial in the outer packaging to protect it from light.

The reconstituted solution must be protected from light. Do not store above 25°C and do not refrigerate.

Handling

In the absence of compatibility studies, this medicine should not be mixed with other medicines.

The reconstituted solution of Agilus should not be mixed with other solutions or administered through the same intravenous access.

Spilling the solution onto the skin should be avoided. If the solution comes into contact with the skin, it should be washed off with plenty of water.

This medicine is for single use only and any remaining reconstituted solution should be discarded.

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