The most frequently occurring side effects include drowsiness, dizziness, weakness, general malaise, fatigue, and diarrhea.[3][4]
It is marketed by Par Pharmaceuticals LLC as Dantrium (in North America) and by Norgine BV as Dantrium, Dantamacrin, or Dantrolen (in Europe). A hospital is recommended to keep a minimum stock of 36 dantrolene vials totaling 720 mg, sufficient for a 70-kg person.[10]
patients in whom spasticity is utilized to maintain upright posture and balance
patients with a hypersensitivity to dantrolene
There are no contraindications for intravenous dantrolene used for prophylaxis or management of
malignant hyperthermia.[12]
Pregnancy and breastfeeding
If needed in pregnancy, adequate human studies are lacking, therefore the drug should be given in pregnant women only if clearly indicated. It may cause hypotonia in the newborn if given closely before delivery.[9]
Interactions
Dantrolene may interact with the following drugs:[13]
Calcium channel blockers of the
diltiazem/
verapamil type: Intravenous treatment with dantrolene and concomitant calcium channel blocker treatment may lead to severe cardiovascular collapse,
abnormal heart rhythms, myocardial depressions, and high blood potassium.
Chemically it is a
hydantoin derivative, but does not exhibit antiepileptic activity like other hydantoin derivates such as
phenytoin.[9]
The poor water
solubility of dantrolene leads to certain difficulties in its use.[9][14] A more water-soluble
analog of dantrolene,
azumolene, is under development for similar indications.[14] Azumolene has a
bromine residue instead of the
nitro group found in dantrolene, and is 30 times more water-soluble.[9]
Dantrolene was first described in the scientific literature in 1967, as one of several
hydantoin derivatives proposed as a new class of muscle relaxant.[15] Dantrolene underwent extensive further development, and its action on
skeletal muscle was described in detail in 1973.[16]
Dantrolene was widely used in the management of
spasticity[17] before its efficacy in treating malignant hyperthermia was discovered by South African anesthesiologist Gaisford Harrison and reported in a landmark 1975 article published in the British Journal of Anaesthesia.[18] Harrison experimentally induced malignant hyperthermia with
halothane anesthesia in genetically susceptible
pigs, and obtained an 87.5% survival rate, where seven of his eight experiments survived after
intravenous administration of dantrolene. The efficacy of dantrolene in humans was later confirmed in a large, multicenter study published in 1982,[19] and confirmed epidemiologically in 1993.[20] Before dantrolene, the only available treatment for malignant hyperthermia was
procaine, which was associated with a 60% mortality rate in animal models.[18]
Society and culture
Legal status
In March 2024, the
Committee for Medicinal Products for Human Use (CHMP) of the
European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Agilus, intended for the treatment of malignant hyperthermia in combination with adequate support measures.[21] The applicant for this medicinal product is Norgine B.V.[21] In the formulation of Agilus, the mannitol and sodium hydroxide have been replaced with hydroxypropyl-beta-cyclodextrin (HP-β-CD) and Macrogol 3350 to shorten the preparation time and improve the ease of use.[21] It was designated an orphan drug.[21][22]
^Zucchi R, Ronca-Testoni S (March 1997). "The sarcoplasmic reticulum Ca2+ channel/ryanodine receptor: modulation by endogenous effectors, drugs and disease states". Pharmacological Reviews. 49 (1): 1–51.
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^Kumar S, Barker K, Seger D (2002). "Dinitrophenol-Induced Hyperthermia Resolving With Dantrolene Administration. Abstracts of the North American Congress of Clinical Toxicology". Clin Toxicol. 40 (5): 599–673.
doi:
10.1081/clt-120016859.
S2CID218865517.
^Barker K, Seger D, Kumar S (2006). "Comment on "Pediatric fatality following ingestion of Dinitrophenol: postmortem identification of a 'dietary supplement'"". Clinical Toxicology. 44 (3): 351.
doi:
10.1080/15563650600584709.
PMID16749560.
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^
abSnyder HR, Davis CS, Bickerton RK, Halliday RP (September 1967). "1-[(5-arylfurfurylidene)amino]hydantoins. A new class of muscle relaxants". Journal of Medicinal Chemistry. 10 (5): 807–810.
doi:
10.1021/jm00317a011.
PMID6048486.
^Ellis KO, Castellion AW, Honkomp LJ, Wessels FL, Carpenter JE, Halliday RP (June 1973). "Dantrolene, a direct acting skeletal muscle relaxant". Journal of Pharmaceutical Sciences. 62 (6): 948–951.
doi:
10.1002/jps.2600620619.
PMID4712630.
^Pinder RM, Brogden RN, Speight TM, Avery GS (January 1977). "Dantrolene sodium: a review of its pharmacological properties and therapeutic efficacy in spasticity". Drugs. 13 (1): 3–23.
doi:
10.2165/00003495-197713010-00002.
PMID318989.
S2CID7936488.
^
abcd"Agilus EPAR". European Medicines Agency. 21 March 2024. Retrieved 23 March 2024. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.