Dantrium IV 20 mg – Summary of Product Characteristics (SmPC) for healthcare professionals

1 NAME OF THE MEDICINAL PRODUCT

Dantrium^® IV 20mg

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial contains 20mg dantrolene sodium.

For the full list of excipients, see 6.1.

3 PHARMACEUTICAL FORM

Powder for solution for injection.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

In combination with adequate support measures, Dantrium IV is indicated in adults and children in the treatment of malignant hyperthermia.

4.2 Posology and method of administration

Posology

Dantrium IV should be administered by rapid intravenous injection at least 2.5mg/kg body weight (8-10 vials in adults). As long as the main clinical symptoms of tachycardia, hypoventilation, sustained hyperacidity (pH and pCO2 monitoring required) and hyperthermia persist, bolus injection should be repeated. In most cases, a total dose of 10mg/kg body weight per 24hr is sufficient. This dose (10mg/kg) may need to be exceeded in individual cases. Safe uses up to 40mg/kg have been described. Based on this experience, higher dosages can be administered in isolated cases if required.

Paediatric population

No dosage adjustment required.

Method of administration

For intravenous administration.

The reconstituted solution should be filtered using the single use filter provided.

For instructions on reconstitution and filtration of the medicinal product before administration, see section 6.6.

4.3 Contraindications

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

4.4 Special warnings and precautions for use

The use of Dantrium IV in the management of malignant hyperthermic crisis is not a substitute for other supportive measures.

These must be individually continued in their various forms. Dantrium IV may only be infused intravenously. Due to the high pH value of the solution (pH 9.5), extravascular injection/infusion must be avoided as it can lead to tissue necrosis. Due to the risk of vascular occlusion, intraarterial injections must be avoided. Spill of the solution on skin should be avoided. If solution gets on the skin, it must be removed with sufficient water.

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.

Each vial of Dantrium IV contains 3g mannitol (for adjustment of isotonic solutions). This amount should be considered if mannitol is used to prevent and treat renal complications related to malignant hyperthermia.

Caution should be exercised if hyperkalaemia symptoms occur (muscular paralysis, ECG 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 trials as a result of dantrolene.

Liver damage may occur during dantrolene therapy. This is dependent on the dosage and duration of therapy and may run a lethal course.

This medicine contains less than 1mmol sodium (23mg) per vial that is to say essentially “sodium free”.

4.5 Interaction with other medicinal products and other forms of interaction

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. It is recommended that Dantrium IV and calcium channel blockers should not be used at the same time.

Concomitant administration of Dantrium IV with non-depolarising muscle relaxants such as vecuronium can enhance their effect.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no or limited data from the use of dantrolene in pregnant women. Animal studies are insufficient with respect to reproductive toxicity (see section 5.3). 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

No information is available on the use of dantrolene sodium 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 Dantrium IV. Based on the 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.

4.7 Effects on ability to drive and use machines

Dantrium IV has major influence on the ability to drive and use machinery, as it can lead to weakness, dizziness and light-headedness. This applies particularly in combination with alcohol or other medicines that depress the central nervous system.

4.8 Undesirable effects

Tabulated list of adverse reactions

Adverse Drug Reactions related to dantrolene sodium 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 (≥ 1/1000 to < 1/100)

Rare (≥ 1/10000 to < 1/1000)

Very rare (<1/10000)

Not known: frequency could not be estimated due to the present data

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.

4.9 Overdose

None stated.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Muscle relaxants, directly acting agents, ATC code: M03CA01

Dantrolene decouples nerve impulse and contraction in skeletal muscle probably by interfering with calcium release from the sarcoplasmic reticulum. Its action is specific and has no influence on neuromuscular transmission or any measurable effect on the excitable surface membrane.

In anaesthetic-induced malignant hyperthermia, signs indicate a genetic-related anomaly of the muscle cell. It is assumed that the triggering agents cause a sudden rise in myoplasmic calcium, by increasing its release and preventing storage in the sarcoplasmic reticulum. The resulting increase in myoplasmic calcium leads to hypermetabolism, which is the cause of hyperthermia, metabolic acidosis and other symptoms of malignant hyperthermia.

Dantrolene can prevent acute catabolism within the muscle cell by inhibiting the release of calcium from the sarcoplasmic reticulum within the myoplasm. Thus, the physiologic, metabolic and biochemical changes associated with the crisis can be reversed or attenuated. However, dantrolene therapy can only work when calcium has not yet entirely been emptied from the sarcoplasmic reticulum, i.e. dantrolene should be used as early as possible, provided that muscle perfusion is still adequately assured.

5.2 Pharmacokinetic properties

Distribution

Dantrolene is reversibly bound to plasma albumin; as an in vitro binding constant, a value of 4.3x104M -1 was established. For the transplacental passage of dantrolene, a factor of 0.4 was found.

Metabolism

Metabolism in the liver takes place through microsomal enzymes both via 5-hydroxylation at the hydantoin ring and via reduction of the nitro group to amine with subsequent acetylation. 5-hydroxydantrolene has similar activity to that of the parent substance, while the aceamino dantrolene does not have any muscle relaxant effect.

Elimination

Excretion is mainly renal and biliary, whereby renal excretion takes place, even in long-term use, at a ration of 79% 5-hydroxydantrolene, 17% acetylamino-dantrolene and 1 to 4% unchanged dantrolene. Renal clearance (5-OH-dantrolene) is 1.8 to 7.8L/h.

Following intravenous administration, the average elimination half-life of dantrolene is variable, generally it is between 4 and 8 hours, in a malignant hyperthermia patient it is 12 hours. Pharmacokinetic studies in children have shown an average elimination half-life of approximately 7.4 to 12.6 hours.

5.3 Preclinical safety data

Acute toxicity

Non clinical data for intravenous administration are not available. Following intraperitoneal administration, the LD50 is around 800 mg/kg body weight in rats (human equivalent dose 129 mg/kg) and following oral administration the LD50 is around 3 g/kg in newborn rats (human equivalent dose 484 mg/kg). No LD50 values could be determined following oral administration to adult animals, due to a lack of mortality.

With subacute intravenous administration of dantrolene at doses of up to 20 mg/kg/day, the sole observations were reduced body weight gain in rats (human equivalent dose 3.2 mg/kg) and hepatic changes in dogs (human equivalent dose 11.1 mg/kg).

Chronic toxicity

In chronic toxicity studies, rats, dogs and monkeys oral administration of >30 mg/kg/day (human equivalent dose 4.8 mg/kg, 16.2 mg/kg and 9.6 mg/kg, respectively) for 12 months led to a reduction of growth or body weight gain. Hepatotoxic effects and possibly renal obstruction were observed, which were reversible.

Mutagenicity

Dantrolene yielded positive results in the Ames S. typhyimurium test both in the present and absence of a liver activating system.

Carcinogenicity

Dietary doses of dantrolene sodium in rats at doses of up to 60 mg/kg/day (human equivalent dose 9.6 mg/kg) for to 18 months resulted in increases in benign hepatic lymphatic neoplasms, increased hepatic lymphangiomas and hepatic angiosarcomas, and in females only, an increase in mammary tumours. The relevance of these data for clinical use of dantrolene is not known.

Reproductive toxicity

In male and female adult rats dantrolene up to an oral dose of 45 mg/bodyweight/day (human equivalent dose 7.3 mg/kg/day) did not have any adverse effects on fertility or general reproductive capability Administration of dantrolene to pregnant rabbits (45 mg/kg/day; human equivalent dose 14.5 mg/kg/day) led to increased formation of unilateral or bilateral supernumerary ribs in the pups.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Mannitol

Sodium hydroxide

6.2 Incompatibilities

Dantrium IV should not be mixed with other intravenous infusions.

6.3 Shelf life

Three years. The reconstituted solution should be used within six hours.

6.4 Special precautions for storage

Unopened product: Do not store above 25ºC.

Reconstituted solution: store between 15 and 25ºC. Do not refrigerate or freeze. Protect from direct light.

6.5 Nature and contents of container

Type I glass vial with bromobutyl rubber stopper and an aluminum cap with a polypropylene flip-off disk. Each vial is provided with a single-use filtration device. Supplied in packs of 12 or 36 vials.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

Reconstitution

Each vial of Dantrium IV should be reconstituted by adding 60ml of water for injection Ph.Eur, and shaken until the powder is dissolved.

Filter the reconstituted product with the single-use filtration device provided when drawing up the solution into the syringe. The reconstituted solution must be used within 6 hours but filtered immediately before use. Remove the filtration device from the syringe prior to attachment to an intravenous cannula or giving set.

Discard the filtration device and product vial in an approved sharps collector. Use a new filtration device with every vial of Dantrium IV. Administer Dantrium IV immediately upon filtration.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Only use the filtration device provided.

7. MARKETING AUTHORISATION HOLDER

Norgine Pharmaceuticals Limited

ARC Uxbridge, Building 01,

Sanderson Road,

Uxbridge,

UB8 1DH, UK

8 MARKETING AUTHORISATION NUMBER(S)

PL 20011/0034

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

14/02/1980

10 DATE OF REVISION OF THE TEXT

14/04/2025