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.

dults. preoperatively dantrium intravenous and/or dantrium capsules may be administered preoperatively to patients judged malignant hyperthermia susceptible as part of the overall patient management to prevent or attenuate the development of clinical and laboratory signs of malignant hyperthermia. dantrium intravenous the recommended prophylactic dose of dantrium intravenous is 2.5 mg/kg, starting approximately 1-1/4 hours before anticipated anesthesia and infused over approximately 1 hour. this dose should prevent or attenuate the development of clinical and laboratory signs of malignant hyperthermia provided that the usual precautions, such as avoidance of established malignant hyperthermia triggering agents, are followed. additional dantrium intravenous may be indicated during anesthesia and surgery because of the appearance of early clinical and/or blood gas signs of malignant hyperthermia or because of prolonged surgery (see also clinical pharmacology , warnings , and precautions ). additional doses must be individualized. oral administration of dantrium capsules administer 4 to 8 mg/kg/day of oral dantrium in three or four divided doses for 1 or 2 days prior to surgery, with the last dose being given with a minimum of water approximately 3 to 4 hours before scheduled surgery. adjustment can usually be made within the recommended dosage range to avoid incapacitation (weakness, drowsiness, etc.) or excessive gastrointestinal irritation (nausea and/or vomiting). see also the package insert for dantrium capsules . post crisis follow-up dantrium capsules , 4 to 8 mg/kg/day, in four divided doses should be administered for 1 to 3 days following a malignant hyperthermia crisis to prevent recurrence of the manifestations of malignant hyperthermia. intravenous dantrium may be used postoperatively to prevent or attenuate the recurrence of signs of malignant hyperthermia when oral dantrium administration is not practical. the i.v. dose of dantrium in the postoperative period must be individualized, starting with 1 mg/kg or more as the clinical situation dictates. preparation each vial of dantrium intravenous should be reconstituted by adding 60 ml of sterile water for injection usp (without a bacteriostatic agent), and the vial shaken until the solution is clear. 5% dextrose injection usp, 0.9% sodium chloride injection usp, and other acidic solutions are not compatible with dantrium intravenous and should not be used. the contents of the vial must be protected from direct light and used within 6 hours after reconstitution. store reconstituted solutions between 15° to 30°c (59° to 86°f). reconstituted dantrium intravenous should not be transferred to large glass bottles for prophylactic infusion due to precipitate formation observed with the use of some glass bottles as reservoirs. for prophylactic infusion, the required number of individual vials of dantrium intravenous should be reconstituted as outlined above. the contents of individual vials are then transferred to a larger volume sterile intravenous plastic bag. stability data on file at par pharmaceutical indicate commercially available sterile plastic bags are acceptable drug delivery devices. however, it is recommended that the prepared infusion be inspected carefully for cloudiness and/or precipitation prior to dispensing and administration. such solutions should not be used. while stable for 6 hours, it is recommended that the infusion be prepared immediately prior to the anticipated dosage administration time. parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.

d dizziness. the following adverse reactions are in approximate order of severity: there are rare reports of pulmonary edema developing during the treatment of malignant hyperthermia crisis in which the diluent volume and mannitol needed to deliver i.v. dantrolene possibly contributed. there have been reports of thrombophlebitis following administration of intravenous dantrolene; actual incidence figures are not available. tissue necrosis secondary to extravasation has been reported. there have been rare reports of urticaria and erythema possibly associated with the administration of i.v. dantrium . there has been one case of anaphylaxis. injection site reactions (pain, erythema, swelling), commonly due to extravasation, have been reported. none of the serious reactions occasionally reported with long-term oral dantrium use, such as hepatitis, seizures, and pleural effusion with pericarditis, have been reasonably associated with short-term dantrium intravenous therapy. the following events have been reported in patients receiving oral dantrolene: aplastic anemia, leukopenia, lymphocytic lymphoma, and heart failure. (see package insert for dantrium (dantrolene sodium) capsules for a complete listing of adverse reactions.) the published literature has included some reports of dantrium use in patients with neuroleptic malignant syndrome (nms). dantrium intravenous is not indicated for the treatment of nms and patients may expire despite treatment with dantrium intravenous . for medical advice about adverse reactions contact your medical professional. to report suspected adverse reactions, contact par pharmaceutical, inc. at 1-800-828-9393 or fda at 1-800-fda-1088 or www.fda.gov/medwatch.

levated myoplasmic calcium. this elevated myoplasmic calcium activates acute cellular catabolic processes that cascade to the malignant hyperthermia crisis. it is hypothesized that addition of dantrium to the "triggered" malignant hyperthermic muscle cell reestablishes a normal level of ionized calcium in the myoplasm. inhibition of calcium release from the sarcoplasmic reticulum by dantrium reestablishes the myoplasmic calcium equilibrium, increasing the percentage of bound calcium. in this way, physiologic, metabolic, and biochemical changes associated with the malignant hyperthermia crisis may be reversed or attenuated. experimental results in malignant hyperthermia susceptible swine show that prophylactic administration of intravenous or oral dantrolene prevents or attenuates the development of vital sign and blood gas changes characteristic of malignant hyperthermia in a dose related manner. the efficacy of intravenous dantrolene in the treatment of human and porcine malignant hyperthermia crisis, when considered along with prophylactic experiments in malignant hyperthermia susceptible swine, lends support to prophylactic use of oral or intravenous dantrolene in malignant hyperthermia susceptible humans. when prophylactic intravenous dantrolene is administered as directed, whole blood concentrations remain at a near steady state level for 3 or more hours after the infusion is completed. clinical experience has shown that early vital sign and/or blood gas changes characteristic of malignant hyperthermia may appear during or after anesthesia and surgery despite the prophylactic use of dantrolene and adherence to currently accepted patient management practices. these signs are compatible with attenuated malignant hyperthermia and respond to the administration of additional i.v. dantrolene (see dosage and administration ). the administration of the recommended prophylactic dose of intravenous dantrolene to healthy volunteers was not associated with clinically significant cardiorespiratory changes. specific metabolic pathways for the degradation and elimination of dantrium in humans have been established. dantrolene is found in measurable amounts in blood and urine. its major metabolites in body fluids are 5-hydroxy dantrolene and an acetylamino metabolite of dantrolene. another metabolite with an unknown structure appears related to the latter. dantrium may also undergo hydrolysis and subsequent oxidation forming nitrophenylfuroic acid. the mean biologic half-life of dantrium after intravenous administration is variable, between 4 to 8 hours under most experimental conditions. 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. cardiopulmonary depression has not been observed in malignant hyperthermia susceptible swine following the administration of up to 7.5 mg/kg i.v. dantrolene. this is twice the amount needed to maximally diminish twitch response to single supramaximal peripheral nerve stimulation (95% inhibition). a transient, inconsistent, depressant effect on gastrointestinal smooth muscles has been observed at high doses.

o 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/m 2 basis) showed no adverse effects on fertility or general reproductive performance.