Dantrolene

Description

DESCRIPTION Dantrolene Sodium for Injection, USP is a sterile, non-pyrogenic, lyophilized formulation. Dantrolene Sodium for Injection, USP is supplied in 100 mL vials containing 20 mg dantrolene sodium, 3,000 mg mannitol, and sufficient sodium hydroxide to yield a pH of approximately 9.5 when reconstituted with 60 mL sterile water for injection USP (without a bacteriostatic agent). Dantrolene sodium is classified as a direct-acting skeletal muscle relaxant. Chemically, dantrolene sodium is hydrated 1-[[[5-(4-nitrophenyl)-2­furanyl]methylene]amino]-2,4-imidazolidinedione sodium salt. The structural formula for the hydrated salt is: The hydrated salt contains approximately 15% water (3.5 moles) and has a molecular weight of 399. The anhydrous salt (dantrolene) has a molecular weight of 336. structure

What Is Dantrolene Used For?

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.

Dosage and Administration

DOSAGE AND ADMINISTRATION As soon as the malignant hyperthermia reaction is recognized, all anesthetic agents should be discontinued; the administration of 100% oxygen is recommended. Dantrolene Sodium for Injection should be administered by continuous rapid intravenous push beginning at a minimum dose of 1 mg/kg, and continuing until symptoms subside or the maximum cumulative dose of 10 mg/kg has been reached. If the physiologic and metabolic abnormalities reappear, the regimen may be repeated. It is important to note that administration of Dantrolene Sodium for Injection should be continuous until symptoms subside. The effective dose to reverse the crisis is directly dependent upon the individual's degree of susceptibility to malignant hyperthermia, the amount and time of exposure to the triggering agent, and the time elapsed between onset of the crisis and initiation of treatment. Pediatric Dose Experience to date indicates that the dose of Dantrolene Sodium for Injection for pediatric patients is the same as for adults. Preoperatively Dantrolene Sodium for Injection and/or Dantrolene Sodium 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. The recommended prophylactic dose of Dantrolene Sodium for Injection 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 Dantrolene Sodium for Injection 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 Dantrolene Capsules: Administer 4 to 8 mg/kg/day of oral Dantrolene Sodium 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 Dantrolene Sodium Capsules, USP. Post Crisis Follow-Up Dantrolene Sodium Capsules, 4 to 8 mg/kg/day, in four divided doses should be administered 1 to 3 days following a malignant hyperthermia crisis to prevent recurrence of the manifestations of malignant hyperthermia. Intravenous dantrolene sodium may be used postoperatively to prevent or attenuate the recurrence of signs of malignant hyperthermia when...

Side Effects (Adverse Reactions)

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 .

Drug Interactions

Drug Interactions Dantrolene sodium 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 dantrolene sodium 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.

Contraindications

CONTRAINDICATIONS None.

Pregnancy and Breastfeeding

Pregnancy Pregnancy Category C Dantrolene sodium 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. Dantrolene Sodium for Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

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.

Overdosage

OVERDOSAGE Because Dantrolene Sodium for Injection must be administered at a low concentration in a large volume of fluid, acute toxicity of dantrolene sodium could not be assessed in animals. In 14-day (subacute) studies, the intravenous formulation of dantrolene sodium was relatively non-toxic to rats at doses of 10 mg/kg/day and 20 mg/kg/day. While 10 mg/kg/day in dogs for 14 days evoked little toxicity, 20 mg/kg/day for 14 days caused hepatic changes of questionable biologic significance. 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 overdosage, general supportive measures should be employed. 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. The value of dialysis in dantrolene sodium overdose is not known.

How Supplied

HOW SUPPLIED Dantrolene Sodium for Injection, USP (NDC 0143-9297-01) is available in vials containing a sterile lyophilized mixture of 20 mg dantrolene sodium, 3,000 mg mannitol, and sufficient sodium hydroxide to yield a pH of approximately 9.5 when reconstituted with 60 mL sterile water for injection USP (without a bacteriostatic agent). Store reconstituted solution at 20° to 25°C (68º to 77°F) [See USP Controlled Room Temperature]. Protect from direct light. Store unreconstituted product at 20° to 25°C (68º to 77°F) [See USP Controlled Room Temperature]. Avoid prolonged exposure to light.