Dantrium Capsules (Dantrolene Sodium)

DANTRIUM® CAPSULES

Procter & Gamble Pharmaceuticals

Dantrolene Sodium

Skeletal Muscle Relaxant

Action And Clinical Pharmacology: Recordings of muscle tensions and electrical activity in both animal and man suggest that dantrolene has a direct inhibitory effect on the development of contractile tension. Spastic patients receiving dantrolene have shown a 40 to 70% reduction in the skeletal muscle tension induced by direct electrical stimulation of the motor nerve with no alteration of the EMG. This decrease in contractile tension can be attributed to an effect of dantrolene beyond the myoneural junction. Total paralysis does not occur since the dantrolene-induced change in the contractile state of skeletal muscle is limited in magnitude. The reduction in contractile activity accounts for the ability of dantrolene to diminish spasticity resulting from pathological states associated with a hyperative stretch reflex.

Dantrolene also produces CNS effects resulting in such manifestations as drowsiness, dizziness and generalized weakness.

Absorption of dantrolene is slow; dose-related blood levels are obtained which peak in 4 to 6 hours after a single oral dose. The peak pharmacologic effect generally occurs in 1 1/2 to 3 hours at concentrations of 50 to 75% of the peak plasma level. 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. Metabolism is rapid via hepatic microsomal enzymes. The major metabolites in humans are a 5-hydroxy analog and an acetamino analog. Urinary excretion of dantrolene and metabolites occurs in an initially rapid phase (t 1/2, 2.5 to 3 hours) followed by a slower phase over a 24 hour period. Dantrolene is also removed by biliary excretion.

Dantrolene causes marked, dose-dependent skeletal muscle relaxation in laboratory animals with a long duration of action. The pharmacologic profile of dantrolene in animals is unlike neuromuscular blocking agents in that total muscle paralysis and/or respiratory depression do not occur.

There is a wider margin between doses causing muscle relaxation and doses causing motor incoordination with dantrolene than with centrally acting muscle relaxants. Skeletal muscle relaxation is not associated with anesthetic or analgesic action. Impairment of cornea or pinna reflexes has not been observed in animals treated with dantrolene.

Various studies both in vivo and in vitro demonstrated the apparent selectivity of action of dantrolene for skeletal muscle. There were some non-specific depressant effects seen in several smooth muscle studies and insignificant effects in cardiac muscle in doses which cause skeletal muscle relaxation. Nerve transmission was not affected by dantrolene in severe animal studies.

It has been shown that dantrolene has no effect on the propagated action potential recorded on the muscle membrane, and the total membrane capacitance is not decreased by the drug, indicating that it does not disrupt the function of the transverse tubular system, and acts at a point beyond the electrically excitable surface membrane. Evidence obtained in vitro with muscle preparations exposed to caffeine, an agent known to cause muscle contractions by releasing internal Ca+stores in muscle, suggests that dantrolene acts on skeletal muscle by altering the Ca+release mechanisms. Such an action could explain the apparent specificity of dantrolene for skeletal muscle.

Animal studies have indicated that dantrolene is metabolized by hydrolysis, hydroxylation, nitro-reduction and acetylation of the resulting amine.

Four corresponding metabolites have been identified which probably do not contribute significantly to the activity of dantrolene. Maximal blood levels following oral administration are reached in approximately 1 hour. In dogs approximately 40% of an i.v. dose of dantrolene is excreted as the hydroxylated metabolite in bile whereas only 1% of the dose is excreted in this manner by the rat. High biliary concentrations of this metabolite have also been found in the Rhesus monkey. Total excretion of known metabolites in the urine is estimated at approximately 3% in the dog and approximately 10% in the rat.

Indications And Clinical Uses: To control the manifestations of chronic spasticity of skeletal muscle resulting from such conditions as spinal cord injury, cerebral palsy, multiple sclerosis, and stroke, whenever such spasticity results in a decrease in functional use of residual motor activity. Dantrolene is not indicated in the relief of skeletal muscle spasms due to rheumatic disorders.

Orally administered dantrolene is also indicated in the preoperative management of malignant hyperthermia-susceptible surgical patients, and for the post-crisis follow-up management of patients stabilized with the i.v. product (for information, consult the Dosage section of Dantrium Intravenous).

Clinical Uses: Dantrolene has been studied in the treatment of selected patients with moderate to severe skeletal muscle spasticity resulting from stroke, spinal cord injury, cerebral palsy, multiple sclerosis, and other neuropathies. It seems to act directly on the skeletal muscle and has been found useful whenever manifestations of spasticity such as increased muscular resistance to stretch, clonus and exaggerated reflex posturing interfere with therapeutic exercise programs, utilization of braces, transfer maneuvers, posture equilibrium, ambulation, and activities of daily living.

Marked reduction or even cessation of spontaneous involuntary movements was observed in many patients receiving dantrolene. The extent to which dantrolene may contribute toward improvement in spasticity and activities in daily living can be tested by withdrawing the drug for 2 to 4 days and observing whether an exacerbation of the patient’s condition occurs.

Contra-Indications: Skeletal muscle spasticity without suitable volitional activity (residual motor activity) may be of value in rehabilitation programs aimed toward sustaining upright posture and balance, and may assist a patient’s locomotor pattern. Relief of such spasticity would reduce rather than increase function. Therefore, in cases where spasticity is utilized to obtain or maintain increased function, dantrolene is contraindicated.

Dantrolene is contraindicated in patients with compromised pulmonary function, particularly those with obstructive pulmonary disease and active hepatic disease, such as hepatitis and cirrhosis.

Manufacturers’ Warnings In Clinical States: Dantrolene has a potential for hepatotoxicity, and should not be used in conditions other than those recommended. Risk of hepatic injury appears to be greater in female patients, in patients over 35 years of age, and in patients taking other medication(s). Dantrolene may exacerbate pre-existing liver dysfunction. Therefore, dantrolene should not be used without appropriate evaluation and monitoring of hepatic function before and throughout treatment, including frequent determinations of AST and ALT in blood serum. A trial administration of dantrolene is recommended and if after 45 days no observable benefit is evident, dantrolene should be discontinued. The lowest possible effective dose for the individual patient should be prescribed.

Fatal and nonfatal hepatitis have occurred at various dosage levels. The incidences reported in patients taking up to 400 mg/day are much lower than in those taking doses of 800 mg or more/day. Even sporadic short courses of the higher dosage levels markedly increased the risk of serious hepatic injury. Overt hepatitis has been observed most frequently after the second month of therapy. Liver dysfunction, as evidenced by elevated concentrations of liver enzymes in blood serum, has been observed in a number of patients receiving dantrolene for less than 60 days.

Toxicity studies in animals provided evidence of the low grade carcinogenic activity of dantrolene in the rat. In view of the animal findings, potential carcinogenicity in humans cannot be disregarded. Therefore, the potential benefits of the drug should be weighed against the possible risks of drug use for the individual patient. Consideration should be given as to whether the patient has responded to other medication and to the benefits of the trial administration of dantrolene as recommended above. In assessing risk acceptability, the age of the patient, the degree of disability and life expectancy should also be considered. The long-term safety of dantrolene has not yet been established.

Children: In view of the preceding warning, it is particularly important to assess risk acceptability before dantrolene is used in pediatric patients. Since there is insufficient experience with the use of dantrolene in young children (under 5 years of age), the drug is usually not recommended in this age group.

Pregnancy and Lactation: The safety of dantrolene in women who are or who may become pregnant has not been established; in such patients it should be given only when the potential benefits have been weighed against possible hazard to mother and child. Dantrolene should not be used in nursing mothers.

Precautions: Although subjective weakness attributable to dantrolene is usually transient, some patients feel excessively weak as long as therapy is continued. Such patients may not be able to manipulate rehabilitation devices such as wheel chairs, crutches, braces, walkers, or canes. Careful attention should be given to patients utilizing these devices. Dantrolene should be discontinued if the weakness persists and interferes with the use of a rehabilitation device.

Use with caution in patients with impaired pulmonary and myocardial function.

Occupational Hazards: Patients should be instructed not to drive a motor vehicle or participate in a hazardous occupation during the first week of therapy. Although the primary pharmacological effect of dantrolene is exerted directly on skeletal muscle, an apparent transient CNS effect also may exist. Therefore, caution should be exercised in the concomitant administration of tranquilizing agents.

Although photosensitization has not been a problem in clinical trials of dantrolene, it is possible that in some subjects the drug might evoke a phototoxic response.

The possibility of cross-sensitivity with compounds of related chemical structure exists; however, no such reactions were reported in extensive clinical trials.

In long-term therapy, perform periodic clinical and laboratory evaluation of organ systems, including hematopoietic, renal and hepatic studies.

Adverse Reactions: Side effects most frequently reported were drowsiness, weakness, dizziness, malaise, fatigue and diarrhea. Less commonly reported effects are listed by systems: Cardiovascular: tachycardia, erratic blood pressure, phlebitis.

Gastrointestinal: constipation, anorexia, gastric irritation and bleeding, abdominal cramps, swallowing difficulty, nausea with or without vomiting and liver failure.

CNS: speech and visual disturbances, seizure, headache, lightheadedness, taste alterations, mental depression, confusion, nervousness, diplopia, insomnia.

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

Musculoskeletal: myalgia, backache.

Integumentary: acne like rash, pruritus, urticaria, eczematoid eruption, abnormal hair growth, sweating.

Hypersensitivity: pleural effusion with pericarditis.

Other: chills, fever, excessive tearing, feeling of suffocation.

Alterations of liver function studies attributable to dantrolene have been observed. It is therefore advisable to perform liver function tests before and during therapy (see Warnings).

Side effects listed as most frequently occurring were generally transient and may be avoided with initial low doses and a gradual increase to optimal doses. Diarrhea may be of sufficient severity to warrant temporary or possibly permanent withdrawal of medication.

Symptoms And Treatment Of Overdose: Symptoms: A single case has been reported of a patient with an 18 year history of multiple sclerosis who consumed 1 600 mg of Dantrium per day for 13 days (a total of 20 800 mg). Other than feeling slightly weaker and “rubbery”, the patient appeared to suffer no clinical manifestations of overdosage. Liver function values were transiently elevated although the patient did not become jaundiced.

Treatment: For acute overdosage employ general supportive measures along with immediate gastric lavage. I.V. fluids should be administered in fairly large quantities to avert the possibility of crystalluria. An adequate airway should be maintained and artificial resuscitation equipment made available. ECG monitoring should be instituted, and the patient carefully observed. No experience has been reported with dialysis, hence its value in dantrolene overdosage is not known.

Dosage And Administration: Prior to the administration of dantrolene, 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 dantrolene. Refer to Indications, Clinical Uses for description of possible areas of response.

It is important to establish a therapeutic goal (regain and maintain a specific function such as therapeutic, exercise program, utilization of braces, transfer maneuvers, etc.) before beginning dantrolene 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 during long-term use, therapy with dantrolene should be discontinued if benefits are not evident within 45 days (see Warnings).

Adults: Begin therapy with 25 mg once daily; increase to 25 mg 2, 3 or 4 times daily and then, by increments of 25 mg, to 100 mg 2, 3 or 4 times daily, if necessary. As most patients will respond to a dose of 400 mg/day or less, rarely should doses higher than 400 mg/day be used. Each dosage level should be maintained for 4 to 7 days, depending on the patient’s tolerance, and should be increased only if the therapeutic goal has not been attained.

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 0.5 mg/kg of body weight twice daily; this is increased to 0.5 mg/kg 3 or 4 times daily and then, by increments of 0.5 mg/kg up to as high as 3.0 mg/kg 2, 3 or 4 times daily if necessary. Doses higher than 100 mg 4 times daily should not be used in children.

Availability And Storage: 25 mg: Each opaque orange and brown capsule, coded with 1 black bar and DANTRIUM 25 mg 0149 0030, contains: dantrolene sodium 25 mg. Nonmedicinal ingredients: edible black ink, gelatin, lactose, magnesium stearate, starch, talc, titanium dioxide, carnauba wax, iron oxide red, FD&C Yellow #6, iron oxide yellow, and may contain one or more of the following: FD&C Blue #2, D&C Red #33. Bisulfite-, gluten-, paraben- and tartrazine-free. Bottles of 100 and 500.

100 mg: Each opaque orange and brown capsule, coded with 3 black bars and DANTRIUM 100 mg 0149 0033, contains: dantrolene sodium 100 mg. Nonmedicinal ingredients: edible black ink, gelatin, lactose, magnesium stearate, starch, talc, titanium dioxide, carnauba wax, iron oxide red, FD&C Yellow #6, iron oxide yellow, and may contain one or more of the following: FD&C Blue #2, D&C Red #33. Bisulfite-, gluten-, paraben- and tartrazine-free. Bottles of 100.

Store below 40°C.

DANTRIUM® CAPSULES Procter & Gamble Pharmaceuticals Dantrolene Sodium Skeletal Muscle Relaxant

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Multiple Sclerosis

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