Revonto 0.333 MG/ML Injectable Solution
WARNINGS
The use of Revonto 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 i.v. 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 i.v. dantrolene.
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.
OVERDOSAGE
Because Revonto 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.
DESCRIPTION
Revonto is a sterile, non-pyrogenic, lyophilized formulation of dantrolene sodium for injection. Revonto is supplied in 65 mL vials containing 20 mg dantrolene sodium, 3000 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)-2-furanyl] 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. Chemical Structure
HOW SUPPLIED
Revonto (NDC 27505-003-68) is available in vials containing a sterile lyophilized mixture of 20 mg dantrolene sodium, 3000 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 unreconstituted product at 20-25° C (68-77° F) [see USP Controlled Room Temperature] and avoid prolonged exposure to light.
GERIATRIC USE
Geriatric Use Clinical studies of Revonto 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.
INDICATIONS AND USAGE
Revonto (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. Revonto 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). Revonto 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.
PREGNANCY
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. Revonto® (dantrolene sodium for injection) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
NUSRING MOTHERS
Nursing Mothers Dantrolene has been detected in human milk at low concentrations (less than 2 micrograms per milliliter) 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.
INFORMATION FOR PATIENTS
Information for Patients Based upon data in human volunteers, perioperatively, it is appropriate to tell patients who receive Revonto 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 dantrolene sodium capsules: 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 dantrolene sodium 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 dantrolene sodium. Dantrolene sodium 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 dantrolene sodium therapy.
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. Revonto 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 Revonto 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 Revonto for pediatric patients is the same as for adults. Preoperatively Revonto 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. Revonto The recommended prophylactic dose of Revonto is 2.5 mg/kg, starting approximately 1.25 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 Revonto 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 CLINCAL PHARMACOLOGY, WARNINGS, and PRECAUTIONS). Additional doses must be individualized. Oral Administration of Dantrolene Sodium 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. Post Crisis Follow-Up Dantrolene sodium 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 dantrolene sodium may be used postoperatively to prevent or attenuate the recurrence of signs of malignant hyperthermia when oral dantrolene sodium administration is not practical. The i.v. dose of dantrolene sodium in the postoperative period must be individualized, starting with 1 mg/kg or more as the clinical situation dictates.