INDICATIONS AND USAGE Dantrolene Sodium for Injection is indicated, along with appropriate supportive measures, for the management of the fulminant hypermetabolism of skeletal muscle characteristic of malignant hyperthermia crises in patients of all ages.

Dantrolene Sodium for Injection should be administered by continuous rapid intravenous push as soon as the malignant hyperthermia reaction is recognized (i.e., tachycardia, tachypnea, central venous desaturation, hypercarbia, metabolic acidosis, skeletal muscle rigidity, increased utilization of anesthesia circuit carbon dioxide absorber, cyanosis and mottling of the skin, and, in many cases, fever).

Dantrolene Sodium for Injection is also indicated preoperatively, and sometimes postoperatively, to prevent or attenuate the development of clinical and laboratory signs of malignant hyperthermia in individuals judged to be malignant hyperthermia susceptible.

WARNINGS The use of Dantrolene Sodium for Injection 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 dantrolene sodium related skeletal muscle weakness, including possible respiratory depression, cannot be predicted, patients who receive intravenous dantrolene sodium preoperatively should have vital signs monitored.

If patients judged malignant hyperthermia susceptible are administered intravenous or oral dantrolene sodium 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 intravenous dantrolene.

ADVERSE REACTIONS There have been occasional reports of death following malignant hyperthermia crisis even when treated with intravenous dantrolene; incidence figures are not available (the pre-dantrolene mortality of malignant hyperthermia crisis was approximately 50%).

Most of these deaths can be accounted for by late recognition, delayed treatment, inadequate dosage, lack of supportive therapy, intercurrent disease and/or the development of delayed complications such as renal failure or disseminated intravascular coagulopathy.

In some cases there are insufficient data to completely rule out therapeutic failure of dantrolene.

There are reports of fatality in malignant hyperthermia crisis, despite initial satisfactory response to intravenous dantrolene, which involve patients who could not be weaned from dantrolene after initial treatment.

The administration of intravenous Dantrolene Sodium for Injection to human volunteers is associated with loss of grip strength and weakness in the legs, as well as drowsiness and 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 intravenous dantrolene possibly contributed.

There have been reported cases of hepatotoxicity following the use of intravenous dantrolene products.

Elevated liver enzymes have occurred hours to days following use of intravenous dantrolene, though many of these cases were observed in patients with comorbidities (e.g., critical illness).

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 intravenous dantrolene sodium.

There has been one case of anaphylaxis.

Injection site reactions (pain, erythema, swelling), commonly due to extravasation, have been reported.

The following events have been reported in patients receiving oral dantrolene: aplastic anemia, leukopenia, lymphocytic lymphoma, and heart failure.

(See package insert for dantrolene sodium capsules for a complete listing of adverse reactions.) The published literature has included some reports of dantrolene sodium use in patients with Neuroleptic Malignant Syndrome (NMS).

Dantrolene Sodium for Injection is not indicated for the treatment of NMS and patients may expire despite treatment with Dantrolene Sodium for Injection.

For medical advice about adverse reactions contact your medical professional.

To report SUSPECTED ADVERSE REACTIONS, contact Hikma Pharmaceuticals USA Inc.

at 1-877-845-0689 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .