Dantrium® (dantrolene sodium) capsules

Dantrium (dantrolene sodium) has a potential for hepatotoxicity, and should not be used in conditions other than those recommended. Symptomatic hepatitis (fatal and non-fatal) has been reported at various dose levels of the drug. The incidence reported in patients taking up to 400 mg/day is much lower than in those taking doses of 800 mg or more per day. Even sporadic short courses of these higher dose levels within a treatment regimen markedly increased the risk of serious hepatic injury. Liver dysfunction as evidenced by blood chemical abnormalities alone (liver enzyme elevations) has been observed in patients exposed to Dantrium for varying periods of time. Overt hepatitis has occurred at varying intervals after initiation of therapy, but has been most frequently observed between the third and twelfth month of therapy. The risk of hepatic injury appears to be greater in females, in patients over 35 years of age, and in patients taking other medication(s) in addition to Dantrium (dantrolene sodium). Dantrium should be used only in conjunction with appropriate monitoring of hepatic function including frequent determination of SGOT or SGPT. If no observable benefit is derived from the administration of Dantrium after a total of 45 days, therapy should be discontinued. The lowest possible effective dose for the individual patient should be prescribed.

The chemical formula of Dantrium (dantrolene sodium) is hydrated 1-[[[5-(4-nitrophenyl)-2-furanyl]methylene]amino]-2, 4-imidazolidinedione sodium salt. It is an orange powder, 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 (3-1/2 moles) and has a molecular weight of 399. The structural formula for the hydrated salt is:

Dantrium is supplied in capsules of 25 mg, 50 mg, and 100 mg.

In isolated nerve-muscle preparation, Dantrium has been shown to produce relaxation by affecting the contractile response of the skeletal muscle at a site beyond the myoneural junction, directly on the muscle itself. In skeletal muscle, Dantrium dissociates the excitation-contraction coupling, probably by interfering with the release of Ca⁺⁺ 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 generalized weakness occasionally present. Although Dantrium does not appear to directly affect the CNS, the extent of its indirect effect 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 pediatric patients. 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.

Clinical experience in the management of fulminant human malignant hyperthermia, as well as experiments conducted in malignant hyperthermia susceptible swine, have revealed that the administration of intravenous dantrolene, combined with indicated supportive measures, is effective in reversing the hypermetabolic process of malignant hyperthermia. Known differences between human and swine malignant hyperthermia are minor. The prophylactic administration of oral or intravenous dantrolene to malignant hyperthermia susceptible swine will attenuate or prevent the development of signs of malignant hyperthermia in a manner dependent upon the dosage of dantrolene administered and the intensity of the malignant hyperthermia triggering stimulus. Limited clinical experience with the administration of oral dantrolene to patients judged malignant hyperthermia susceptible, when combined with clinical experience in the use of intravenous dantrolene for the treatment of malignant hyperthermia and data derived from the above cited animal model experiments, suggests that oral dantrolene will also attenuate or prevent the development of signs of human malignant hyperthermia, provided that currently accepted practices in the management of such patients are adhered to (see INDICATIONS AND USAGE); intravenous dantrolene should also be available for use should the signs of malignant hyperthermia appear.

Active hepatic disease, such as hepatitis and cirrhosis, is a contraindication for use of Dantrium. Dantrium is contraindicated where spasticity is utilized to sustain upright posture and balance in locomotion or whenever spasticity is utilized to obtain or maintain increased function.

It is important to recognize that fatal and non-fatal liver disorders of an idiosyncratic or hypersensitivity type may occur with Dantrium 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.

Liver function studies (e.g., SGOT or SGPT) should be performed at appropriate intervals during Dantrium therapy. 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. 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 hospitalized 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, hepatocellular disease in these groups.

Dantrium should be used with 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. It should be used with caution in patients with a history of previous liver disease or dysfunction (see WARNINGS).

The most frequently occurring side effects of Dantrium have been drowsiness, dizziness, weakness, general malaise, fatigue, and diarrhea. These are generally transient, occurring early in treatment, and can often be obviated by beginning with a low dose and increasing dosage gradually until an optimal regimen is established. Diarrhea may be severe and may necessitate temporary withdrawal of Dantrium therapy. If diarrhea recurs upon readministration of Dantrium, therapy should probably be withdrawn permanently.

Other less frequent side effects, uled according to system, are:

Gastrointestinal: Constipation, rarely progressing to signs of intestinal obstruction, GI bleeding, anorexia, swallowing difficulty, gastric irritation, abdominal cramps, nausea and/or vomiting.

Hepatobiliary: Hepatitis (see WARNINGS).

Neurologic: Speech disturbance, seizure, headache, light-headedness, visual disturbance, diplopia, alteration of taste, insomnia, drooling.

Cardiovascular: Tachycardia, erratic blood pressure, phlebitis, heart failure.

Hematologic: Aplastic anemia, anemia, leukopenia, lymphocytic lymphoma, thrombocytopenia.

Psychiatric: Mental depression, mental confusion, increased nervousness.

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

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

Musculoskeletal: Myalgia, backache.

Respiratory: Feeling of suffocation, respiratory depression.

Special Senses: Excessive tearing.

Hypersensitivity: Pleural effusion with pericarditis, anaphylaxis.

Other: Chills and fever.

The published literature has included some reports of Dantrium use in patients with Neuroleptic Malignant Syndrome (NMS). Dantrium capsules are not indicated for the treatment of NMS and patients may expire despite treatment with Dantrium capsules.

Drug abuse and dependency potential has not been evaluated in human or animal studies.

Symptoms which may occur in case of overdose include, but are not limited to, muscular weakness and alterations in the state of consciousness (e.g. lethargy, coma), vomiting, diarrhea, and crystalluria. For acute overdose, 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 and its value in Dantrium overdose is not known.

Dantrium (dantrolene sodium) is available in:

25-mg opaque, orange and tan capsules:

NDC 0149-0030-05 bottle of 100
NDC 0149-0030-66 bottle of 500

50-mg opaque, orange and tan capsules:
NDC 0149-0031-05 bottle of 100

100-mg opaque, orange and tan capsules:
NDC 0149-0033-05 bottle of 100

Avoid excessive heat (over 104°F or 40°C).

Address medical inquiries to Procter & Gamble Pharmaceuticals, Medical Communications Department, PO Box 8006, Mason, Ohio 45040-8006.