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DANTRIUM Vials 20 mg

SCHEDULING STATUS:
S4

PROPRIETARY NAME
(and dosage form):

DANTRIUM Vials 20 mg

COMPOSITION:
Each 70 mL vial contains 20 mg dantrolene sodium, 3000 mg mannitol, and sufficient sodium hydroxide to yield a pH of approximately 9,5 when reconstituted with 60 mL sterile water.
Chemically, the drug is hydrated 1-[[[5-(4-nitro-phenyl)-2-furanyl)methylene)amino)-2,4-imidazolidinedione sodium salt.
The hydrated salt contains approximately 15% water (3½ moles) and has a molecular weight of 399. The anhydrous salt (dantrolene) has a molecular weight of 336.

PHARMACOLOGICAL CLASSITICATION:
A.17. 1 Peripherally acting muscle relaxants

PHARMACOLOGICAL ACTION:
Clinical Pharmacology:
Dantrolene sodium is a muscle relaxant acting specifically on skeletal muscle. It does not affect neuromuscular transmission nor does it have measurable effects on the electrically excitable surface membrane. Studies show that in the presence of dantrolene sodium, the responses of the muscle to caffeine are decreased or delayed.
In isolated muscle preparations, dantrolene sodium uncouples the excitation and contraction of skeletal musclep probably by interfering with the release of calcium from the sarcoplasmic reticulum. In the anaesthetic-induced malignant hyperthermia syndrome, evidence points to an intrinsic abnormality of muscle tissue. In affected humans and swine, it has been postulated that “triggering agents” induce a sudden rise in myoplasmic calcium either by preventing the sarcoplasmic reticulum from accumulating calcium adequately, or by accelerating its release.
This rise in myoplasmic calcium activates acute catabolic processes common to the malignant hyperthermia crisis.
Dantrolene sodium may prevent the increase in myoplasmic calcium and the acute catabolism within the muscle cell by interfering with the release of calcium from the sarcoplasmic reticulum to the myoplasm Thus the physiologic, metabolic and biochemical changes associated with the crisis may be reversed or attenuated.
Specific metabolic pathways in the degradation and elimination of dantrolene sodium in humans have been established. Dantrolene is found in measurable amounts in blood and urine. In addition, its major metabolites in body fluids are the 5-hydroxy analogue and the acetamido analogue. -Another metabolite with an unknown structure appears related to acetylamino-dantrolene. Dantrolene sodium may also undergo hydrolysis and subsequent oxidation forming nitrophenylfuroic acid.
Since dantrolene sodium is metabolized by the liver, enhancement of its metabolism by other drugs is possible. However, neither phenobarbital nor diazepam appears to affect dantrolene sodium metabolism.
The mean biologic half-life of dantrolene sodium after intravenous administration is about 5 hours. Based on assays of whole blood and plasma slightly greater amounts of dantrolene are associated with red blood cells than with the plasma fraction of blood. Significant amounts of dantrolene are bound to plasma proteins, mostly albumin, and this binding is readily reversible. Binding to plasma protein is not significantly altered by diazepam diphenylhydantoin, or phenylbutazone. Binding to plasma proteins is reduced by warfarin and clofibrate and increased by tolbutamide.
In animals, dantrolene sodium given intravenously has no appreciable effect on the cardiovascular system or on respiratory function. A transient inconsistent effect on smooth muscle has been observed at high doses.

INDICATIONS:
Dantrium intravenous injection is indicated for treatment of malignant hyperthermia. It should be administered by intravenous injection as soon as the malignant hyperthermia reaction is recognised (i.e. tachycardia, tachypnoea, central venous desaturation, central venous hypercarbia, metabolic acidosis, fever skeletal muscle rigidity or cyanosis and mottling of the skin). At the same time it is important to recognise that appropriate supportive measures be instituted for treatment of the physiologic and metabolic abnormalities.

CONTRA-INDICATIONS:
No known contra-indications.

DOSAGE AND DIRECTIONS FOR USE:
As soon as the malignant hyperthermia reaction is recognised, all anaesthetic agents should be discontinued. An initial Dantrium intravenous dose of 1 mg/kg should be given rapidly. If the physiologic and metabolic abnormalities persist or reappear, this dose may be repeated up to a cumulative dose of 10 mg/kg. Based on clinical experience to date reversal of the manifestations of malignant hyperthermia may be achieved with an average cumulative dose of 2,5 mg/kg of Dantrium. However, it is recommended that 36 vials (720 mg) are available which would provide a dosage of 10 mg/kg body mass for patients with body mass up to 70 kg

Each vial of Dantrium should be reconstituted by adding 60 mL of sterile Water for Injections B.P. and the vial shaken until the solution is clear. The contents of the vial must be protected from direct light and used within 6 hours after reconstitution, because being a hydantoin, dantrolene sodium may form hydrate in aqueous solution which has lesser solubility than the dantrolene salt and may occasionally precipitate. This has never been found before 6 hours. Protect the reconstituted solutions from temperatures above 30°C (86°F) and below 15°C (59°F).

Children's Dose:
Experience to date indicates that the dose for children is the same as for adults.

Preoperatively:
Dantrium (dantrolene sodium) capsules are indicated preoperatively as possible protection against the development of a malignant hyperthermia crisis in individuals thought to be susceptible.

Oral Administration of Dantrium Capsules:
Administer 4 to 8 mg/kg/day of oral dantrolene in 3 or 4 divided doses for one or two days prior to surgery, with the last dose being given approximately 3 to 4 hours before scheduled surgery, with a minimum of water.
This dosage usually will be associated with skeletal muscle weakness and sedation (sleepiness or drowsiness); adjustment can usually be made within the recommended dosage range to avoid incapacitation or excessive gastro-intestinal irritation (including nausea and/or vomiting). See also the package insert for oral dantrolene sodium (Dantrium capsules).

Post Crises follow-up:
Dantrium (dantrolene sodium) capsules should also be administered following a malignant hyperthermia crisis in doses of 4 to 8 mg per day in four divided doses, for a one to three day period to prevent recurrence of the manifestations of malignant hyperthermia.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS:
The serious reactions reported with chronic oral Dantrium use have been hepatitis, seizures, and pleural effusion with pericarditis. Hypersensitivity with attendant skin reactions has been infrequently noted. None of the reactions reported in patients taking oral Dantrium have been reported in patients treated with short-term Dantrium intravenous therapy for malignant hyperthermia.

Precautions:

(a)	Because of the high pH of the intravenous formulation of Dantrium, care must be taken to prevent extravasation of the intravenous solution into the surrounding tissues.
(b)	Pregnancy: The safety of Dantrium intravenous in women who are or who may become pregnant has not been established; it should be given only when the potential benefits have been weighed against the possible risk to mother and child.
(c)	Drug interactions: 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. It is recommended that the combination of intravenous dantrolene sodium and calcium channel blockers, such as verapamil, not be used during reversal of a malignant hyperthermia crisis until the relevance of these findings to humans is established.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT:
No overdosage has to date occurred.

IDENTIFICATION:
Dantrium injection is a sterile lyophilized formulation of dantrolene sodium, and in this form provides a preparation for intravenous use.

PRESENTATION:
Dantrium in injection is available in vials containing a sterile lyophilised mixture of 20 mg dantrolene sodium, 3000 mg mannitol, and sufficient sodium hydroxide to yield a pH of approximately 9,5 when reconstituted with 60 mL sterile water.

STORAGE INSTRUCTIONS:
Store the unopened vials in a cool, dark place. The contents of the vial must be protected from direct light and used within 6 hours after reconstitution, because being a hydantoin, dantrolene sodium may form hydrate in aqueous solution, which has lesser solubility than the dantrolene salt and may occasionally precipitate. This has never been found before 6 hours. Protect the reconstituted solutions from temperatures above 30°C (86° F) and below l5° C (59°F).
KEEP OUT OF REACH OF CHILDREN.

REGISTRATION NUMBER:
M/17.1/253

NAME AND BUSINESS ADDRESS OF APPLICANT:
SmithKline Beecham Pharmaceutical (Pty) Ltd.
6 Carey Street
Wynberg Ext. 6
Johannesburg 2090.

DATE OF PUBLICATION OF THIS PACKAGE INSERT:
20.08.1986.

P0181
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