DANTRIUM IV 20 MG - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

DANTRIUM IV

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

For the treatment of malignant hyperthermia.

4.2 Posology and method of administration

Posology

As soon as the malignant hyperthermia syndrome is recognised all anaesthetic agents should be discontinued. An initial Dantrium IV dose of 1mg/kg should be given rapidly into the vein. If the physiological and metabolic abnormalities persist or reappear, this dose may be repeated up to a cumulative dose of 10mg/kg. Clinical experience to date has shown that the average dose of Dantrium IV required to reverse the manifestations of malignant hyperthermia has been 2.5mg/kg. If a relapse or recurrence occurs, Dantrium IV should be readministered at the last effective dose.

Method of administration

Dantrium 20 mg powder for solution is for intravenous use only.

After reconstitution, the solution must be filtered with the filtration device provided when drawing up the solution into the syringe (see section 4.4).. Remove the single-use filtration device from the syringe prior to attachment to an intravenous cannula or giving set.

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

4.3 Contraindications

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

4.4 Special warnings and precautions for use

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

4.5 Interaction with other medicinal products and other forms of interaction

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.

4.6 Fertility, pregnancy and lactation

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

4.7 Effects on ability to drive and use machines

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.

4.8 Undesirable effects

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.

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

Mechanism of action

The receptor molecule for dantrolene has not been identified.

Radiolabelled dantrolene sodium binds to specific components of the striated muscle cell, namely the t-tubules and the sarcoplasmic reticulum, however, the kinetics of binding vary between these two organelles. The binding of ryanodine is thought to compete with the binding of calcium in these organelles; further evidence for the specificity of binding is that dantrolene inhibits the binding of ryanodine to heavy sarcoplasmic reticulum vesicles from rabbit skeletal muscle. Under some conditions, dantrolene will lower intra-sarcoplasmic calcium concentrations in the resting state. This may be more important in diseased muscle (e.g. In malignant hyperthermia in humans and swine stress syndrome) than in muscle with normal function.

Dantrolene does not bind to the same sites as calcium channel blocking drugs such as nitrendipine or calmodulin. There is no electrophysio­logical evidence that dantrolene interferes with the influx of calcium from outside the cell. This may be one reason why paralysis by dantrolene has never been reported in animals or man; the muscle cell has alternative sources of calcium which are not influenced by dantrolene.

Pharmacodynamic effects

Whatever the molecular mechanism, the cardinal property of dantrolene sodium is that it lowers intracellular calcium concentration in skeletal muscle. Calcium concentrations may be lower in both the quiescent state, and as a result of a reduction in the release of calcium, from the sarcoplasmic reticulum in response to a standard stimulus. This effect has been observed in striated muscle fibres from several species, and is not seen in the myocardium. Fast fibres may be more sensitive than slow fibres to the action of dantrolene sodium.

Clinical efficacy and safety

Diverse other properties of dantrolene sodium have been observed in vitro, and in animal studies. Dantrolene sodium may inhibit the release of calcium from the smooth endoplasmic reticulum of smooth muscle, but the significance of this observation is questionable; for example, dantrolene sodium has no effect on isolated human urinary bladder smooth muscle.

Calcium dependent, pre-synaptic neurotransmitter release may also be inhibited by dantrolene sodium. Again, the clinical significance of this has not been demonstrated.

Studies on Isolated, Functional Muscle

Elevation of intracellular, free calcium ion concentration is an obligatory step in excitation-contraction coupling of skeletal muscle. Dantrolene sodium, therefore, acts as a muscle relaxant by a peripheral mechanism, which is quite different, and easily distinguishable from neuromuscular junction blocking drugs. In contrast with compounds that relax the skeletal muscle by acting principally on the central nervous system, dantrolene sodium acts directly on skeletal muscle cells. In rabbit atria, dantrolene sodium has no effect alone, but it may antagonise inotropic agents which act by increasing intramyocardial cell calcium e.g. anthopleurin-a.

5.2 Pharmacokinetic properties

Distribution

Dantrolene sodium is a highly lipophobic drug. In addition, it lacks hydrophilicity. Dantrolene sodium binds to human serum albumin (HSA) with a molar ratio of 0.95 to 1.68 in-vitro. The association constant in-vitro is 2.3 to 5.4 × 10 (-5) per mol. In- vitro dantrolene sodium can be displaced from HSA by warfarin, clofibrate and tolbutamide but these interactions have not been confirmed in humans (Re. Manufacturer's da­tabase). Single intravenous dose studies suggest that the primary volume of distribution is about 15 litres.

Metabolism and Elimination

The biological half-life in plasma in most human subjects is between 5 and 9 hours, although half-lives as long as 12.1 ±1.9 hours have been reported after a single intravenous dose. Inactivation is by hepatic metabolism in the first instance. There are two alternative pathways. Most of the drug is hydroxylated to 5-hydroxydantrolene.

The minor pathway involves nitro-reduction to amino-dantrolene, which is then acetylated (compound F-490). The 5-hydroxy metabolite is a muscle relaxant with nearly the same potency as the parent molecule, and may have a longer half-life than the parent compound. Compound F-490 is much less potent and is probably inactive at the concentrations achieved in clinical samples. Metabolites are subsequently excreted in the urine in the ratio of 79 5 hydroxy-dantrolene: 17 compound F-490: 4 unaltered dantrolene (salt or free acid). The proportion of drug excreted in the faeces depends upon dose size.

5.3 Preclinical safety data

Carcinogenicity

Whilst there is no clinical evidence of carcinogenicity in humans, this possibility cannot be absolutely excluded.

Dantrolene sodium has shown some evidence of tumourgenicity at high dose levels in Sprague-Dawley female rats, but these effects have not been seen in other studies in Fisher 344 rats or HaM/ICR mice.

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 25°C.

Reconstituted solution: store between 15 and 25°C. 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 Intravenous 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

Norgine House

Widewater Place

Moorhall Road

Harefield

Uxbridge

UB9 6NS

UK

8 MARKETING AUTHORISATION NUMBER(S)

PL 20011/0034

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THEAUTHORISATION

14/02/1980