DANTROLENE- dantrolene sodium injection, powder, for solution
Hikma Pharmaceuticals USA Inc.
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.
In isolated nerve-muscle preparation, dantrolene sodium has been shown to produce relaxation by affecting the contractile response of the muscle at a site beyond the myoneural junction. In skeletal muscle, dantrolene sodium dissociates the excitation-contraction coupling, probably by interfering with the release of Ca++ from the sarcoplasmic reticulum. The administration of intravenous dantrolene sodium to human volunteers is associated with loss of grip strength and weakness in the legs, as well as subjective CNS complaints (see also PRECAUTIONS , Information for Patients). Information concerning the passage of dantrolene sodium across the blood-brain barrier is not available.
In the anesthetic-induced malignant hyperthermia syndrome, evidence points to an intrinsic abnormality of skeletal muscle tissue. In affected humans, it has been postulated that “triggering agents” (e.g., general anesthetics and depolarizing neuromuscular blocking agents) produce a change within the cell which results in an elevated myoplasmic calcium. This elevated myoplasmic calcium activates acute cellular catabolic processes that cascade to the malignant hyperthermia crisis.
It is hypothesized that addition of dantrolene sodium 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 dantrolene sodium 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 intravenous 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 dantrolene sodium 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. Dantrolene sodium may also undergo hydrolysis and subsequent oxidation forming nitrophenylfuroic acid.
The mean biologic half-life of dantrolene sodium 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 intravenous 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.
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.
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.
Care must be taken to prevent extravasation of dantrolene sodium 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 intravenous dantrolene sodium should be taken into consideration.
Based upon data in human volunteers, perioperatively, it is appropriate to tell patients who receive Dantrolene Sodium for Injection 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.
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