DANTRIUM Powder for solution for injection Ref.[8168] Active ingredients: Dantrolene

In some subjects as much as 10mg/kg of Dantrium IV has been needed to reverse the crisis. In a 70kg man this dose would require approximately 36 vials. Such a volume has been administered in approximately one and a half hours.

When mannitol is used for prevention or treatment of renal complication of malignant hyperthermia, the 3 grams of mannitol present as an excipient in each 20mg vial of intravenous dantrolene sodium should be taken into consideration when calculating total mannitol dose to be administered.

Because of the high pH of the intravenous formulation of Dantrium and potential for tissue necrosis, care must be taken to prevent extravasation of the intravenous solution into the surrounding tissues. In addition, due to the potential for undissolved crystals/particles to appear in the re-constituted product and the subsequent potential risk of exacerbation of injection site reactions/tissue necrosis from crystals within affected vials, use of the filtration device when drawing up the solution is required at all times.

The use of Dantrium IV in the management of malignant hyperthermia is not a substitute for other supportive measures. It will be necessary to discontinue the suspect triggering agents, attend to increased oxygen requirements and manage the metabolic acidosis. When necessary institute cooling, attend to urinary output and monitor for electrolyte imbalance.

Hepatic dysfunction, including hepatitis and fatal hepatic failure, has been reported with dantrolene sodium therapy. Whilst the licensed indications of intravenous dantrolene do not generally necessitate prolonged therapy, the risk of hepatic dysfunction may increase with dose and duration of treatment, based on experience with oral therapy. However in some patients it is of an idiosyncratic or hypersensitivity type, and could occur after a single dose.

The combination of therapeutic doses of intravenous dantrolene sodium and verapamil in halothane/alpha-chloralose anaesthetised swine has resulted in ventricular fibrillation and cardiovascular collapse in association with marked hyperkalaemia. Hyperkalaemia and myocardial depression have also been reported rarely in malignant hyperthermia-susceptible patients receiving intravenous dantrolene and concomitant calcium channel blockers.

It is recommended that the combination of intravenous dantrolene sodium and calcium channel blockers, such as verapamil, is not used during the reversal of a malignant hyperthermia crisis until the relevance of these findings to humans is established.

Administration of dantrolene may potentiate vecuronium-induced neuromuscular block.

Pregnancy

The safety of Dantrium IV in pregnant women has not been established. Dantrolene crosses the placenta, and should be given only when the potential benefits have been weighed against the possible risk to mother and child.

Breast-feeding

Dantrolene has been detected in human milk at low concentrations (less than 2 micrograms per millilitre) during repeat intravenous administration over 3 days. Dantrium IV should be used by nursing mothers only if the potential benefit justifies the potential risk to the infant.

Fertility

There are no data on the effects of Dantrium IV on fertility in humans.

A decrease in grip strength and weakness of leg muscles, especially walking down stairs, can be expected post-operatively. In addition, symptoms such as “lightheadedness” may be noted. Since some of these symptoms may persist for up to 48 hours, patients must not operate an automobile or engage in other hazardous activity during this time.

Summary of the safety profile

There have been occasional reports of death following malignant hyperthermia crisis even when treated with intravenous dantrolene sodium; incidence figures are not available (the pre-dantrolene sodium mortality of malignant hyperthermia crisis was approximately 50%). Most of these deaths can be accounted for by late recognition, delayed treatment, inadequate dosage, lack of supportive therapy, intercurrent disease and/or the development of delayed complications such as renal failure or disseminated intravascular coagulopathy. In some cases there are insufficient data to completely rule out therapeutic failure of dantrolene sodium.

The administration of intravenous dantrolene sodium to human volunteers is associated with loss of grip strength and weakness in the legs, as well as subjective central nervous system complaints.

There are rare reports of pulmonary oedema developing during the treatment of malignant hyperthermia crisis in which the diluent volume and mannitol needed to deliver i.v. dantrolene sodium possibly contributed. Extravasation may lead to tissue necrosis (see section 4.4).

Tabulated list of adverse reactions

Frequency cannot be estimated from available data.

Nervous system disorders

Unknown: Dizziness, somnolence, convulsion speech disorder

Cardiac disorders

Unknown: Cardiac failure, bradycardia, tachycardia

Respiratory, thoracic and mediastinal disorders

Unknown: Pulmonary oedema (dilutent volume and mannitol needed to deliver dantrolene IV may contribute to the event), Pleural effusion, respiratory failure, respiratory depression

Gastrointestinal disorders

Unknown: Abdominal pain, nausea, vomiting, gastrointestinal bleeding

Hepatobiliary disorders

Unknown: Hepatic dysfunction including fatal hepatic failure (see section 4.4), jaundice, hepatitis

Skin and subcutaneous disorders

Unknown: Hyperhidrosis

Renal and urinary disorders

Unknown: Crystalluria

General disorders and administration site conditions

Unknown: Rash, erythema, localised pain and thrombophlebitis

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 Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Dantrium IV should not be mixed with other intravenous infusions.