Agilus

HOS-288930 · has-adverse-reaction-information · PDF-Seite 5

Agilus is a skeletal muscle relaxant. The most commonly reported adverse event of intravenous dantrolene administration, skeletal muscle weakness, is related to this mode of action. The adverse reactions observed are linked to dantrolene and its formulations for acute, intravenous use and for chronic, oral use. Some of the adverse reactions listed may also be observed as a result of the underlying malignant hyperthermia crisis. Adverse reactions are presented below according to system organ class and frequency. Frequencies are defined according to: 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: frequency could not be estimated from the available data. Table 2: List of adverse drug reactions System Organ Class Frequency Adverse Drug Reactions Immune system disorders Not known Hypersensitivity, Anaphylactic reaction Metabolism and nutrition Not known Hyperkalaemia disordersa Nervous system disorders Not known Dizziness, Somnolence, Seizure, Dysarthria, Headache Eye disorders Not known Visual impairment Cardiac disordersa Not known Cardiac failure, Bradycardia, Tachycardia Vascular disorders Not known Thrombophlebitis Respiratory, thoracic and Not known Respiratory failure, Respiratory depression mediastinal disorders Gastrointestinal disorders Not known Abdominal pain, Nausea, Vomiting, Gastrointestinal haemorrhage, Diarrhoea, Dysphagia Hepatobiliary disorders Not known Jaundiceb, Hepatitisb, Hepatic function abnormal, Hepatic failure including fatal outcomeb, Idiosyncratic or hypersensitive liver diseases Skin and subcutaneous tissue Not known Urticaria, Erythema, Hyperhidrosis disorders 5  Musculoskeletal and Not known Muscle weakness, Muscle fatigue connective tissue disorders Renal and urinary disordersa Not known Crystalluria Reproductive system and Not known Uterine hypotonus breast disorders General disorders and Not known Fatigue, Administra

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HOS-288926 · has-contraindication-information · PDF-Seite 3

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

HOS-288925 · has-indication-information · PDF-Seite 2

In combination with adequate support measures, Agilus is indicated for the treatment of malignant hyperthermia in adults and children of all ages.

HOS-288928 · has-interaction-information · PDF-Seite 4

Isolated case reports and animal studies indicate an interaction between dantrolene and calcium channel blockers, such as verapamil and diltiazem, in the form of heart failure. Concomitant use of Agilus and calcium channel blockers is not recommended (see section 4.4). Concomitant administration of Agilus with non-depolarising muscle relaxants, such as vecuronium, can enhance their effect.

HOS-288929 · has-pregnancy-information · PDF-Seite 4

Pregnancy There are no or limited data for the use of dantrolene in pregnant women. Animal studies are insufficient with respect to reproductive toxicity (see section 5.3). Postpartum uterine atony has been reported after intravenous dantrolene therapy. The risk of floppy child syndrome in neonates has also been described when intravenous dantrolene was administered to the mother during caesarean section. Dantrolene crosses the placenta and should only be used during pregnancy when the potential benefit outweighs the possible risk to mother and child. 4 Breast-feeding No information is available on the use of dantrolene during breastfeeding. According to its safety profile, a risk to a breastfed infant cannot be excluded as dantrolene is excreted in breastmilk. Therefore, breastfeeding should be discontinued during administration of Agilus. Based on elimination half-life of dantrolene, breastfeeding can be restarted 60 hours after the last dose. Fertility Data on the effects of dantrolene on fertility in humans are not available. In animal studies, no adverse effects on fertility were observed (see section 5.3).

HOS-288927 · has-warning-information · PDF-Seite 3

The use of Agilus in the management of malignant hyperthermic crisis is not a substitute for other supportive measures. These must be individually continued in their various forms. Caution should be exercised if hyperkalaemia symptoms occur (muscular paralysis, electrocardiogram changes, bradycardic arrhythmias) or in cases of pre-existing hyperkalaemia (renal insufficiency, digitalis intoxication etc.), as an increase in serum potassium has been demonstrated in animal studies as a result of the co-administration of dantrolene with verapamil. Concomitant use of Agilus and calcium channel blockers is not recommended (see section 4.5). 3 Agilus is only for intravenous use. Due to the high pH value of the solution (pH 9.5), extravascular injection must be avoided as it can lead to tissue necrosis. Due to the risk of vascular occlusion, intraarterial injections must be avoided. Spill of solution on skin should be avoided. If solution gets on the skin, it must be removed with sufficient water (see section 6.6). Liver damage may occur during dantrolene therapy. This has been observed during longer term, oral administration and may run a lethal course. Excipients Hydroxypropylbetadex Agilus contains 3530 mg hydroxypropylbetadex (a cyclodextrin) in each vial, which is equivalent to 156.2 mg/mL in the reconstituted solution. Hydroxypropylbetadex increases solubility of dantrolene and thereby reduces preparation time and fluid volume. Hydroxypropylbetadex has been associated with ototoxicity in animal studies (see section 5.3); and cases of hearing impairment have been observed in studies in other clinical settings. Cases of hearing impairment have been observed at hydroxypropylbetadex exposure levels comparable to the higher range of recommended Agilus doses. In most cases the hearing impairment has been transient and of slight to mild severity. For patients requiring high Agilus doses (above 10 mg/kg) the diagnosis should be re-evaluated (see section 4.2). The potential risk for hearing impairment may be of particular concern in patients with increased risk for hearing loss, e.g. recurring/chronic ear infections. Exposure to hydroxypropylbetadex from Agilus is expected to be higher in patients with renal impairment. The potential risks associated with hydroxypropylbetadex may be higher in these patients. Sodium This medicinal product contains 6.9 mg sodium per vial, equivalent to 0.345% of

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