New malignant hyperthermia antidote: Convenience worth the cost?

April 10, 2015

A new dantrolene sodium suspension with improved properties offers an advantage over the older formulations- and a much higher price tag.

Malignant hyperthermia (MH) is a rare but potentially fatal myopathy-triggered reaction to inhaled halogenated volatile anesthetics such as halothane, or to depolarizing neuromuscular blocking agents such as succinylcholine. Because susceptibility to MH is inherited as an autosomal dominant trait, MH clusters appear in family groups.

“For this reason, the incidence of MH varies geographically, depending on the concentration of MH families in a given area,” said Gary Stewart, MD, MBA, Queen City Anesthesiologists, Inc., Cincinnati, Ohio. High incidence areas in the United States include Wisconsin, Nebraska, West Virginia, and Michigan. Stewart believes that the key to optimal MH treatment is early recognition and diagnosis.

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Old and new formulations

The Malignant Hyperthermia Association of the United States (MHAUS) has issued guidelines on MH that stress the importance of preparedness, awareness, and immediate response to symptoms. Initial treatment of MH crisis involves discontinuation of the triggering agent and administration of dantrolene sodium, a hydantoin derivative that was first developed as a muscle relaxant.

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Although dantrolene has been used successfully for years in the treatment of MH, the older formulations (Dantrium; Par Pharmaceutical, and Revonto; US WorldMeds) have several disadvantages, including cumbersome preparation and administration procedures, and excess fluid load.

A major factor that delays prompt administration of older dantrolene formulations is the significant time required to reconstitute numerous vials and to deliver the total dose. Each dantrolene vial has to be dissolved in 60 mL of sterile water for injection and administered through a large vein to prevent tissue necrosis in the event of accidental extravascular injection.

In light of these limitations, Ryanodex (Eagle Pharmaceuticals), the new dantrolene sodium suspension with improved properties, offers an advantage over the older formulations. Ryanodex can be prepared and administered in a more expedient manner, potentially reducing MH-related complications.

Per package insert, for the treatment of MH, Ryanodex can be administered via IV push at a minimum of 1 mg/kg, up to a maximum cumulative dose of 10 mg/kg. For prevention of MH, a dose of 2.5 mg/kg IV over at least one minute, starting about 75 minutes prior to surgery, is recommended. Because of its greater solubility in water, a 250-mg vial of Ryanodex lyophilized powder can be reconstituted and administered in only 5 mL of sterile water for injection - substantially reducing the fluid load compared to what was required for older formulations.

 

Preparedness

MHAUS recommends that an MH cart containing dantrolene be stocked in all facilities, including ambulatory surgery centers and offices, where MH-triggering anesthetics and depolarizing muscle relaxants are administered. MHAUS suggests stocking a minimum of 36 20-mg vials of Dantrium or Revonto, or three vials of Ryanodex.

“The reduced number of vials and steps required for reconstitution with Ryanodex may potentially translate to decreased medication errors,” said John B. Hertig, PharmD, MS, CPPS, associate director, Center for Medication Safety Advancement, Purdue University College of Pharmacy in Indiana.

However, both Hertig and Stewart pointed out that the potential clinical benefits associated with more prompt dose delivery require further validation. While Ryanodex provides more convenience, it costs more than twice as much - about $7,000 for three vials - and has a shorter half-life (two years) than do Dantrium and Revonto, which have a three-year shelf life. Stewart believes that in comparison to older dantrolene formulations, Ryanodex may be a more attractive option for facilities located in areas with a high MH incidence; however, they will have to weigh the increased cost against convenience.

Cost

The cost of stocking dantrolene has been a concern for most institutions. According to a study published in Anesthesiology in 2014, stocking dantrolene for the treatment of MH in ambulatory surgery centers as recommended by MHAUS was found to be cost-effective when compared with the estimated values of statistical life used by U.S. regulatory agencies.

The incremental effectiveness of dantrolene compared with supportive care was 33 more lives saved per year, and the incremental cost-effectiveness ratio was $196,320 (in 2010 dollars) per life saved compared with a supportive care strategy.

Hertig recommends that pharmacists should collaborate with their institutions’ key stakeholders to develop an MH treatment algorithm and provide education about dantrolene, including recommended dose, administration, and potential adverse events.

“A team approach will help facilitate optimal patient care in this emergency situation,” said Hertig. Other strategies to help reinforce preparedness for an MH crisis include conducting practice drills and assigning specific responsibilities to anesthesia providers and perioperative staff.

Monica Shah, PharmD, is a writer and hospital pharmacist in New Jersey.