INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION
DANTRIUM Capsules 25 mg
DANTRIUM Capsules 100 mg

SCHEDULING STATUS:
S4

PROPRIETARY NAME
(and dosage form):

DANTRIUM Capsules 25 mg
DANTRIUM Capsules 100 mg

COMPOSITION:
Each Dantrium Capsule contains either 25 mg or 100 mg dantrolene sodium.
Dantrolene sodium is 1-((5-(p-nitrophenyl) furfurylidene)amino) hydantoin sodium hydrate.

PHARMACOLOGICAL CLASSIFICATION:
A 17.1 Peripherally acting muscle relaxants.

PHARMACOLOGICAL ACTION:
In isolated nerve-muscle preparations, Dantrium has been shown to produce relaxation of the contractile state of the skeletal muscle by an effect beyond the myoneural junction and directly on the muscle itself. In these preparations, Dantrium uncouples the excitation and contraction of the skeletal muscle probably by interfering with the release of activator from the sarcoplasmic reticulum. This effect appears to be more pronounced in fast muscle fibers as compared to slow ones, but generally affects both.

A central nervous system effect occurs, with drowsiness, dizziness, and generalised weakness occasionally present. The extent of the involvement of the CNS centres in Dantrium-induced muscle relaxation is unknown.
The absorption of Dantrium after oral administration in humans is incomplete and slow but consistent and dose-related blood levels are obtained. The duration and intensity of skeletal muscle relaxation is related to the dosage and blood levels. The mean biologic half life of Dantrium in adults is 8,7 hours after a 100 mg dose.

Specific metabolic pathways in the degradation and elimination of Dantrium in human subjects have been established. Metabolic patterns are similar in adults and children.

In addition to the parent compound, dantrolene, which is found in measurable amounts in blood and urine, the major metabolites noted in body fluids are the 5-hydroxy analog and the acetamido analog. Since Dantrium is probably metabolized by hepatic microsomal enzymes, enhancement of its metabolism by other drugs is possible. However, neither phenobarbital nor diazepam appears to affect Dantrium metabolism.

INDICATIONS:
Dantrium is indicated in controlling the manifestations of clinical spasticity resulting from serious chronic disorders such as spinal cord injury, stroke, cerebral palsy, or multiple sclerosis. It is of particular benefit to the patient whose functional rehabilitation has been retarded by the sequelae of spasticity. Such patients must have presumably reversible spasticity where relief of spasticity will aid in restoring residual function. Dantrium is not indicated in the treatment of skeletal muscle spasm resulting from rheumatic disorders.
If improvement occurs, it will ordinarily occur within the dosage titration schedule (see Dosage and Directions for use), as manifested by a decrease in the severity of spasticity and the ability to resume a daily function not quite attainable without Dantrium.
A decision to continue the administration of Dantrium on a long term basis is justified if introduction of the drug into the patient’s regimen -

	produces a significant reduction in painful and/or disabling spasticity such as clonus, or
	permits a significant reduction in the intensity and/or degree of nursing care required, or
	rids the patient of an annoying manifestation of spasticity considered important by the patient himself.

In view of the potential for liver damage in long-term Dantrium use, therapy should be stopped if benefits are not evident within 45 days.

Occasionally, subtle but meaningful improvement in spasticity may occur with Dantrium therapy. In such instances, information regarding improvement should be solicited from the patient and those who are in constant daily contact and attendance with him. Brief withdrawal of Dantrium for a period of 2 to 4 days will frequently demonstrate exacerbation of the manifestation of spasticity and may serve to confirm a clinical impression.

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

Dantrium (dantrolene sodium) Capsules are indicated following a malignant hyperthermia crisis.

CONTRA-INDICATIONS:
Active hepatic disease, such as acute hepatitis and active cirrhosis, is a contra-indication for use of Dantrium.

Dantrium is contra-indicated where spasticity is utilized to sustain upright posture and balance in locomotion or whenever spasticity is utilized to obtain or maintain increased function.

WARNINGS :
It is important to recognise that liver disorders, fatal and non-fatal, may occur with Dantrium therapy.

Dantrium has a potential for hepatotoxicity and should not be used in conditions other than those recommended. Fatal hepatitis has been reported in approximately 0,1 to 0,2% of patients who have taken Dantrium for 60 days or longer. Some cases of hepatitis were considered to be definitely drug-related, whereas others may have been due to other causes. Symptomatic hepatitis has been observed in approximately 0,35 to 0,5% of patients who have taken Dantrium for 60 days or longer. Liver dysfunction as evidenced by blood chemical abnormalities alone, has been observed in approximately 0,7 to 1,0% of all patients exposed to Dantrium for varying periods of time. Risk of hepatic injury appears to be greater in females, and in patients over 35 years of age. No serious hepatic injury has yet been reported in patients receiving the drug for less than 60 days, although liver enzyme elevations have occurred.

Subclinical or overt hepatitis accompanied by abnormalities in liver function test (SGOT, SGPT) has occurred in varying times after initiation of Dantrium therapy. Jaundice, with or without fever may occur, with onset usually between the third and twelfth months of therapy. At the start of Dantrium therapy, it is desirable to do liver function studies (SGOT, SGPT, alkaline phosphatase, total bilirubin) for a baseline or to establish whether there is pre-existing liver disease. If baseline liver abnormalities exist and are confirmed, there is a clear possibility that the potential for Dantrium hepatotoxicity could be enhanced, although such a possibility has not yet been established.

Regular liver function studies (e.g. SGOT, SGPT) should be performed on patients taking Dantrium. If such studies reveal abnormal values, therapy should generally be discontinued. Only where benefits of the drug have been of major importance to the patient, should reinitiation or continuation of therapy be considered. Some patients have revealed a return to normal laboratory values in the face of continued therapy while others have not.

If symptoms compatible with hepatitis, accompanied by abnormalities in liver function tests or jaundice appear, Dantrium should be discontinued. If caused by Dantrium and detected early, the abnormalities in liver function characteristically have reverted to normal when the drug was discontinued.

Decrease of hypertonicity may cause instability in certain patients who have become accustomed to their spastic musculature.

Dantrium therapy has been reinstituted in a few patients who have developed clinical and/or laboratory evidence of hepatocellular injury. If such reinstitution of therapy is done, it should be attempted only in patients who clearly need Dantrium and only after previous symptoms and laboratory abnormalities have cleared. The patient should be hospitalised and the drug should be restarted in very small and gradually increasing doses. Laboratory monitoring should be frequent and the drug should be withdrawn immediately if there is any indication of recurrent liver involvement. Some patients have reacted with unmistakable signs of liver abnormality upon administration of a challenge dose, while others have not.

Dantrium should be used with particular caution in females and in patients over 35 years of age in view of apparent greater likelihood of drug-induced, potentially fatal, hapatocallular disease in these groups.

Long-term safety and efficacy of Dantrium in humans have not been established. Chronic studies in rats, dogs and monkeys at dosages greater than 30 mg/kg/day showed growth or weight depression and signs of hepatopathy and possible occlusion nephropathy all of which were reversible upon cessation of treatment. Sprague-Dawley female rats fed dantrolene sodium for 18 months at dosage levels of 15, 30 and 60 mg/kg/day showed an increased incidence of benign and malignant mammary tumours compared with concurrent controls, and at the highest dosage, on increase in the incidence of hepatic lymphangiomas and hepatic angiosarcomas. These effects were not seen in 2½ year studies in rats of the Fischer 344 strain or in 2 year studies in mice of the HaM/ICR strain. Carcinogenicity in humans cannot be fully excluded, so that this possible risk of chronic administration must be weighed against the benefits of the drug (i.e. after a brief trial) for the individual patient.

USAGE IN PREGNANCY:
The safety of Dantrium in women who are or who may become pregnant has not been established; hence it should be given only when the potential benefits have been weighed against possible hazard to mother and child. Dantrium should not be used in nursing mothers.

USAGE IN CHILDREN:
The safety of Dantrium in children under the age of 5 years has not been established. Because of the possibility that adverse effects of the drug could become apparent only after many years, a benefit-risk consideration of the long-term use of Dantrium is particularly important in paediatric patients.

DRUG INTERACTIONS
While a definite drug interaction with oestrogen therapy has not yet been established, caution should be observed if the two drugs are to be given concomitantly. Hepatotoxicity has occurred more often in women over 35 years of age receiving concomitant oestrogen therapy.

DOSAGE AND DIRECTIONS FOR USE:
Prior to the administration of Dantrium, consideration should be given to the potential response to treatment. A decrease in spasticity sufficient to allow a daily function not otherwise attainable should be the therapeutic goal of treatment with Dantrium. Refer to ‘Indications’ section for description of response.

It is important to establish goal (regain and maintain a specific function such as therapeutic exercise program, utilization of braces, transfer manoeuvres, etc.) before beginning Dantrium therapy. Dosage should be increased until the maximum performance compatible with the dysfunction due to underlying disease is achieved. No further increase in dosage is then indicated.

USUAL DOSAGE:
It is important that the dosage be titrated and individualized for maximum effect. The lowest dose compatible with optimal response is recommended.

In view of the potential for liver damage in long-term Dantrium use, therapy should be stopped if benefits are not evident within 45 days.

ADULTS:
Begin therapy with 25 mg once daily; increase to 25 mg two, three or four times daily and then by increments of 25 mg up to as high as 100 mg two, three or four times daily if necessary. An occasional patient will require up to 200 mg four times daily.
Each dosage level should be maintained for four to seven days to determine the patient’s response. The dose should not be increased beyond, and may even have to be reduced to the amount at which the patient received maximal benefit without adverse effects.

CHILDREN:
A similar approach should be utilized starting with 1,0 mg/kg of body weight once daily; this is increased to 1,0 mg/kg two, three or four times daily and then by increments of 0,5 mg/kg up to as high as 3,0 mg/kg two, three or four times daily if necessary. Doses higher than 100 mg four times daily should not be used in children.

PROTECTION AGAINST THE DEVELOPMENT OF A MALIGNANT HYPERTHERMIA CRISIS:
PREOPERATIVELY:
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 dosage 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).

POST CRISIS FOLLOW-UP:
Doses of 4 to 8 mg/kg 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 most frequent occurring side-effects of Dantrium have been drowsiness, dizziness, weakness, general malaise, fatigue, and diarrhoea. Other side-effects, listed according to system are:

Gastrointestinal:
Constipation, G.I. bleeding, anorexia, swallowing difficulty, gastric irritation, abdominal cramps.

Hepatobiliary:
Hepatitis (See ‘Warnings’).

Neurologic:
Speech disturbance, seizure, headache, lightheadedness, visual disturbance, diplopia, alteration of taste, insomnia.

Cardiovascular:
Tachycardia, erratic blood pressure, phlebitis.

Psychiatric:
Mental depression, mental confusion, increased nervousness.

Urogenital:
Increased urinary frequency, crystalluria, difficult erection, urinary incontinence and/or nocturia, difficult urination and/or urinary retention.

PRECAUTIONS:
It should be used with extreme caution in patients with impaired pulmonary function, particularly those with obstructive pulmonary disease, and in patients with severely impaired cardiac-function due to myocardial disease. If should be used with caution in patients with a history of previous liver disease or dysfunctionion (see ‘Warnings’).

Patients should be cautioned against driving a motor vehicle or participating in hazardous occupations while taking Dantrium. Caution should be exercised in the concomitant administration of tranquillizing agents.

Dantrium might possibly evoke a photosensitivity reaction; patients should be cautioned about exposure to sunlight while taking it.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT:
For acute overdosage, general supportive measures should be employed along with immediate gastric lavage.

Intravenous fluids should be administered in fairly large quantities to avert the possibility of crystalluria. An adequate airway should be maintained and artificial resuscitation equipment should be at hand. Electrocardiographic monitoring should be instituted, and the patient carefully observed. To date, no experience has been reported with dialysis; its value in Dantrium overdosage is not known.

IDENTIFICATION:
Dantrium capsules 25 mg: Opaque orange and brown capsules with “Dantrium 25 mg”in black on the orange part and the code ‘0149 0030’ with a single coding bar in black on the brown part of the capsules.

Dantrium capsules 100 mg: Opaque orange and brown capsules with “Dantrium 100 mg”in black on the orange part and the code ‘0149 0033’with triple coding bars in black on the brown part of the capsules.

The powder is slightly soluble in water, but due to its slightly acidic nature, the solubility increases somewhat in alkaline solution. The anhydrous salt has a molecular weight of 336. The hydrated salt contains approximately 15% water (3½ moles), and has a molecular weight of 399.

PRESENTATION:
Dantrium is available in opaque orange and brown capsules of 25 mg and 100 mg supplied in bottles containing 50 capsules.

STORAGE INSTRUCTIONS:
Store in a cool, dry place.

KEEP OUT OF REACH OF CHILDREN.

REGISTRATION NUMBERS:

Dantrium capsules 25 mg:	H/17.1/64
Dantrium capsules 100 mg:	H/17.1/65

NAME AND BUSINESS ADDRESS OF THE APPLICANT:
Smith Kline Beecham Pharmaceuticals (Pty) Limited
6 Carey Street Wynberg Ext. 6
Johannesburg, 2090

DATE OF PUBLICATION OF THIS PACKAGE INSERT:
20-08-1986

P0179
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