WARNINGS
The use of Dantrium Intravenous
in the management of malignant hyperthermia crisis is not a substitute for previously known supportive measures. These measures must be individualized, but it will usually be necessary to discontinue the suspect triggering agents, attend to increased oxygen requirements, manage the metabolic acidosis, institute cooling when necessary, monitor urinary output, and monitor for electrolyte imbalance.
Since the effect of disease state and other drugs on Dantrium related skeletal muscle weakness, including possible respiratory depression, cannot be predicted, patients who receive i.v. Dantrium preoperatively should have vital signs monitored.
If patients judged malignant hyperthermia susceptible are administered intravenous or oral Dantrium preoperatively, anesthetic preparation must still follow a standard malignant hyperthermia susceptible regimen, including the avoidance of known triggering agents. Monitoring for early clinical and metabolic signs of malignant hyperthermia is indicated because attenuation of malignant hyperthermia, rather than prevention, is possible. These signs usually call for the administration of additional i.v. dantrolene.
PRECAUTIONS
General
Care must be taken to prevent extravasation of Dantrium solution into the surrounding tissues due to the high pH of the intravenous formulation and potential for tissue necrosis.
When mannitol is used for prevention or treatment of late renal complications of malignant hyperthermia, the 3 g of mannitol needed to dissolve each 20 mg vial of i.v. Dantrium should be taken into consideration.
Information for Patients
Based upon data in human volunteers, perioperatively, it is appropriate to tell patients who receive Dantrium Intravenous that symptoms of muscle weakness should be expected postoperatively (i.e. decrease in grip strength and weakness of leg muscles, especially walking down stairs). 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. Caution is also indicated at meals on the day of administration because difficulty swallowing and choking has been reported. Caution should be exercised in the concomitant administration of tranquilizing agents.
Hepatotoxicity seen with Dantrium 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.
Fatal and non-fatal liver disorders of an idiosyncratic or hypersensitivity type may occur with Dantrium therapy.
Drug Interactions
Dantrium is metabolized by the liver, and it is theoretically possible that its metabolism may be enhanced by drugs known to induce hepatic microsomal enzymes. However, neither phenobarbital nor diazepam appears to affect Dantrium metabolism. 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.
Cardiovascular collapse in association with marked hyperkalemia has been reported in patients receiving dantrolene in combination with calcium channel blockers. It is recommended that the combination of intravenous dantrolene sodium and calcium channel blockers, such as verapamil, not be used together during the management of malignant hyperthermia crisis.
Administration of dantrolene may potentiate vecuronium-induced neuromuscular block.
Carcinogenesis, Mutagenesis, and Impairment of Fertility
Sprague-Dawley female rats fed Dantrium for 18 months at dosage levels of 15, 30, and 60 mg/kg/day showed an increased incidence of benign and malignant mammary tumors compared with concurrent controls. At the highest dose level (approximately the same as the maximum recommended daily dose on a mg/m2 basis), there was an increase in the incidence of benign hepatic lymphatic neoplasms. In a 30-month study in Sprague-Dawley rats fed dantrolene sodium, the highest dose level (approximately the same as the maximum recommended daily dose on a mg/m2 basis) produced a decrease in the time of onset of mammary neoplasms. Female rats at the highest dose level showed an increased incidence of hepatic lymphangiomas and hepatic angiosarcomas.
The only drug-related effect seen in a 30-month study in Fischer-344 rats was a dose-related reduction in the time of onset of mammary and testicular tumors. A 24-month study in HaM/ICR mice revealed no evidence of carcinogenic activity.
The significance of carcinogenicity data relative to use of Dantrium in humans is unknown.
Dantrolene sodium has produced positive results in the Ames S. Typhimurium bacterial mutagenesis assay in the presence and absence of a liver activating system.
Dantrolene sodium administered to male and female rats at dose levels up to 45 mg/kg/day (approximately 1.4 times the maximum recommended daily dose on a mg/m2 basis) showed no adverse effects on fertility or general reproductive performance.
Pregnancy
Pregnancy Category C
Dantrium has been shown to be embryocidal in the rabbit and has been shown to decrease pup survival in the rat when given at doses seven times the human oral dose. There are no adequate and well-controlled studies in pregnant women. Dantrium Intravenous should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Labor and Delivery
In one uncontrolled study, 100 mg per day of prophylactic oral Dantrium was administered to term pregnant patients awaiting labor and delivery. Dantrolene readily crossed the placenta, with maternal and fetal whole blood levels approximately equal at delivery; neonatal levels then fell approximately 50% per day for 2 days before declining sharply. No neonatal respiratory and neuromuscular side effects were detected at low dose. More data, at higher doses, are needed before more definitive conclusions can be made.
Nursing Mothers
Dantrolene has been detected in human milk at low concentrations (less than 2 micrograms per mL) during repeat intravenous administration over 3 days. Because of the potential for serious adverse reactions in nursing infants from dantrolene, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Geriatric Use
Clinical studies of Dantrium Intravenous did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
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