Label: information for the user

Agilus 120 mg powder for injectable solution

dantrolene sodium hemihydrate

Read the entire label carefully, as it contains important information for you.

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

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

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

This medication is used for the treatment of malignant hyperthermia in adults and children of all ages, in combination with other supportive measures. Malignant hyperthermia is a potentially life-threatening condition that requires urgent attention in which the skeletal muscles of the body are overstimulated and cannot relax. This can cause a very rapid increase in body temperature and/or an accumulation of waste products in the body (metabolic acidosis), which can prevent vital organs from functioning properly.

You should not be given Agilus

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

Warnings and precautions

You may have been given this medication before reading this leaflet.

Consult your doctor or nurse if:

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

Long-term oral use of dantrolene sodium has been associated with liver damage in patients. Inform your doctor if you think you have symptoms of liver damage (e.g., if your skin and eyes appear yellowish or if you have abdominal pain and swelling).

Other medications and Agilus

Inform your doctor if you are taking, have recently taken, or may need to take any other medication.

The following medications may affect the mechanism of action of Agilus, or Agilus may affect their mechanism of action:

• blood pressure medications and angina medications 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 potentiate the muscle-relaxing effect of Agilus if given at the same time.

Pregnancy and breastfeeding

If you are pregnant or breastfeeding, or think you may be pregnant, inform your doctor or nurse as soon as possible before receiving this medication.

Pregnancy

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

Breastfeeding

You should not breastfeed while receiving Agilus or for 60 hours after the last dose. Inform your doctor if you are breastfeeding.

Driving and operating machinery

After receiving Agilus, it is possible that the muscles of your hands and legs may weaken and you may feel dizziness or disorientation. These effects may last up to 48 hours after receiving Agilus. Do not drive or operate machinery during this time.

Agilus contains cyclodextrin and sodium

This medication contains 3530 mg of hydroxypropyl beta-cyclodextrin (a cyclodextrin) in each vial, which is equivalent to 156.2 mg/ml in the reconstituted solution.

Inform 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 who received hydroxypropyl beta-cyclodextrin to treat other diseases at higher doses than those recommended for Agilus. This hearing loss is usually mild and of short duration. For patients who need high doses of Agilus (above 10 mg/kg), the treatment will need to be reevaluated due to this risk.

The possible risk associated with hydroxypropyl beta-cyclodextrin may increase if the kidneys do not function correctly.

This medication contains 6.9 mg of sodium (the main component of table salt) in each vial.

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

This injection will be administered intravenously by a healthcare professional. The dose of Agilus administered will depend on your body weight. The dose will be repeated every 10 minutes until symptoms improve. If symptoms do not improve after receiving the medication, the doctor may re-examine your diagnosis and consider other treatments. If you experience a relapse, your healthcare professional will administer Agilus again.

If You Receive More Agilus Than You Should

If you have received more Agilus than you should have, adverse effects may occur. You may experience intense muscle weakness, which could affect breathing. Your doctor will closely monitor you.

If you have any other questions about the use of this medication, ask your doctor or nurse.

Like all medicines, this medicine may cause side effects, although not everyone will experience them. With the active ingredient Agilus, the following side effects have been observed:

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

Severe side effects: your doctor will stop administering Agilus immediately

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

Other side effects

With the active ingredient Agilus, the following side effects have been observed:

• Allergic reactions (hypersensitivity)

• High levels of potassium in the blood (hyperkalemia), which may cause fatigue, muscle weakness, feeling unwell, and changes in heart rhythm
• Dizziness, drowsiness, seizures, difficulty speaking (dysarthria), headache
• Visual disturbances
• Heart failure, slow heart rate (bradycardia), rapid heartbeats (tachycardia)
• Phlebitis, a blood clot and obstruction in a vein
• Difficulty breathing (respiratory insufficiency), slow and shallow breathing (respiratory depression)
• Abdominal pain, nausea, vomiting, gastrointestinal and intestinal bleeding with symptoms of blood in the stool or vomit (gastrointestinal hemorrhage), diarrhea, difficulty swallowing (dysphagia)
• Yellowing of the eyes and skin (jaundice)*, hepatitis*, potentially fatal liver insufficiency*, changes in liver function tests, liver disease due to an unknown cause or allergic reaction
• Hives, redness of the skin (erythema), excessive sweating (hyperhidrosis)
• Muscle weakness, tired muscles
• Crystals in the urine (crystalluria)
• Weak uterine contractions during childbirth (uterine hypotonia)
• Feeling tired (fatigue), general weakness (asthenia), reactions at the injection site

*These side effects were observed in situations where dantrolene treatment was administered orally for an extended period.

Reporting side effects

If you experience any type of side effect, consult your doctor or nurse, even if it is a possible side effect that does not appear in this leaflet. You can also report them directly through thenational notification system included in theAppendix V. By reporting side effects, you can contribute to providing more information about the safety of this medicine.

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

This medication will be stored in the hospital and these instructions are intended exclusively for healthcare personnel.

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

Reconstituted solution: Use within 24 hours. The reconstituted solution must be protected from light. Do not store at a temperature above 25 °C and do not refrigerate.

Do not use this medication after the expiration date appearing on the label and on the outer box of the vials after “EXP”. The expiration date is the last day of the month indicated.

For single use only. Dispose of any remaining reconstituted solution.

Agilus Composition

The active principle is dantrolene sodium hemihydrate.

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

The other components are hydroxypropyl beta-cyclodextrin (a cyclodextrin) and macrogol (E1521). See section 2, "Agilus contains cyclodextrin and sodium."

Product Appearance and Packaging Contents

Glass vials with rubber stoppers and seals containing 120 mg of yellow-orange powder for injectable solution.

Box of 6 or 10 vials.

Only some package sizes may be marketed.

Marketing Authorization Holder and Responsible Manufacturer

Norgine B.V.

Antonio Vivaldistraat 150

1083 HP Amsterdam

Netherlands

Last Review Date of this Leaflet

Other Information Sources

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

This leaflet is available in all languages of the European Union/European Economic Area on the European Medicines Agency website.

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This information is intended solely for healthcare professionals:

Dosage and Administration

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

Dosage

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

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

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

Table 1: Dosage Examples

a The total volume of a reconstituted vial is 22.6 ml.

b For all body weights, the initial dose and any repeated dose should not exceed 300 mg, equivalent to 2.5 vials.

Recurrence Treatment (Recurrence)

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

Pediatric Population

No dose adjustment is necessary.

Administration

Intravenous.

Special Precautions for Storage, Preparation, and Handling

Preparation

Each vial must be reconstituted by adding 20 ml of injectable water and agitating for approximately 1 minute, before inspecting for the presence of particles. It may be necessary to agitate further. The reconstituted solution should be yellow-orange in color and particle-free.

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

Chemical and physical stability has been demonstrated in use for 24 hours at 25°C. From a microbiological standpoint, unless the opening/reconstitution method eliminates the risk of microbial contamination, the reconstituted product should be used immediately. If not used immediately, the storage conditions and shelf life during use 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 should be protected from light. Do not store at temperatures above 25°C and do not refrigerate.

Handling

In the absence of compatibility studies, this medication should not be mixed with others.

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

It should be avoided to spill the solution on the skin. If the solution comes into contact with the skin, it should be washed off with plenty of water.

This medication is for single use only, and any residual reconstituted solution should be discarded.

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