Class: Direct-acting Skeletal Muscle Relaxants
VA Class: MS200
Chemical Name: 1-[[[5-(4-Nitrophenyl)-2-furanyl]methylene]amino]-2,4-imidazolidinedione sodium salt, hydrate (2:7)
Molecular Formula: C₁₄H₉N₄NaO₅•3½H₂O
CAS Number: 24868-20-0
Brands: Dantrium, Revonto, Ryanodex

Medically reviewed by Drugs.com. Last updated on Oct 5, 2020.

• Overview
• Side Effects
• Dosage
• Professional
• Interactions
• More

Introduction

Skeletal muscle relaxant.^{108 109 115 116 117 119}

Uses for Dantrolene

Spasticity

Used orally for management of spasticity resulting from upper motor neuron disorders (e.g., multiple sclerosis, cerebral palsy, spinal cord injury, stroke syndrome).^{109 a}

Evidence supporting use is limited and the drug is associated with many adverse effects, some of which may be severe (e.g., hepatotoxicity);^{123 124 125 126 127 128 130} however, subtle but meaningful improvement (e.g., decrease in severity of spasticity, ability to resume daily function) may occasionally occur in some patients.¹⁰⁹

Ineffective in the treatment of amyotrophic lateral sclerosis (ALS).^a

Not indicated for the treatment of muscle spasms resulting from rheumatic disorders or musculoskeletal trauma.^{109 a}

Malignant Hyperthermia Crisis

IV treatment of fulminant hypermetabolism of skeletal muscle that is characteristic of malignant hyperthermia crisis;^{108 115 116 117} should be used with and not as a substitute for supportive measures (e.g., oxygen, treatment of metabolic acidosis, cooling procedures).^{108 115 116 117}

Dantrolene sodium for injectable suspension (Ryanodex) is designated an orphan drug by FDA for this use.¹²²

Also has been used preoperatively to prevent or attenuate the development of malignant hyperthermia in susceptible individuals;^{108 109 115 116 117} however, prophylactic use no longer recommended because of adverse effects and questionable benefit.^{114 119}

Neuroleptic Malignant Syndrome†

Has been used for the treatment of neuroleptic malignant syndrome†; fatalities reported despite therapy with the drug.^{100 101 102 103 104 105 108 109 115 116}

Dantrolene Dosage and Administration

General

Spasticity

• Establish therapeutic goal before initiating therapy.¹⁰⁹ Use lowest possible effective dosage.¹⁰⁹ Discontinue drug if beneficial effects are not attained within 45 days.¹⁰⁹ (See Boxed Warning.)

• Subjective impressions of improvement may sometimes be confirmed by withdrawal of the drug for 2–4 days.¹⁰⁹

Malignant Hyperthermia Crisis

• Immediately discontinue all anesthetic agents or other potential triggering agents (e.g., succinylcholine) and institute IV dantrolene as soon as malignant hyperthermia crisis is recognized.^{108 115 116 117}

• Use in conjunction with supportive measures.^{108 115 116 117}

• When using injectable suspension formulation, administer a diuretic to prevent late kidney injury due to myoglobinuria; amount of mannitol contained in formulation is insufficient to maintain diuresis.^{113 117}

• When used preoperatively for prophylaxis, monitor for early clinical and metabolic signs of malignant hyperthermia; monitor vital signs (e.g., for possible respiratory depression).^{108 115 116}

Administration

Administer orally or by continuous IV infusion or rapid IV injection.^{108 109 115 116 117}

Oral Administration

Administer orally 1–4 times daily.¹⁰⁹

Extemporaneous Suspension

To prepare an oral suspension containing 25 mg of dantrolene sodium per 5 mL, empty five 100-mg capsules in a small amount of simple syrup NF, then add a solution containing 150 mg of citric acid in 10 mL of water followed by a sufficient volume of simple syrup NF to make 100 mL.¹¹⁸ Mix thoroughly before use.¹¹⁸ Other extemporaneously prepared suspensions of dantrolene also have been described.^{112 118}

IV Administration

For solution compatibility information, see Compatibility under Stability.

Administer by rapid IV injection for acute treatment of malignant hyperthermia.^{108 115 116 117} May administer by IV infusion for prevention of malignant hyperthermia.^{108 115 116 117}

Commercially available as a lyophilized drug for injection (e.g., Dantrium, Revonto, or generic equivalents) or a lyophilized drug for injectable suspension (Ryanodex).^{108 115 116 117} Reconstitution procedures differ based on the preparation; consult manufacturer’s prescribing information for specific instructions.^{108 115 116 117}

Avoid extravasation (injection has high pH and can cause tissue necrosis).^{108 115 116 117}

Reconstitution and Administration

Dantrolene sodium for injection: Add 60 mL of sterile water for injection (without bacteriostatic agent) to vial containing 20 mg of the drug.^{108 115 116} Do not reconstitute with any other solution.^{108 115 116} Shake vial until solution is clear.^{108 115 116} Use reconstituted solution within 6 hours of reconstitution.^{108 115 116} For administration by IV infusion, transfer desired volume of reconstituted solution to an appropriate-size empty sterile IV plastic bag.^{108 115 116} Do not transfer to large glass containers because precipitate formation has been observed.^{108 115 116}

Dantrolene sodium for injectable suspension: Add 5 mL of sterile water for injection (without bacteriostatic agent) to vial containing 250 mg of the drug.¹¹⁷ Do not reconstitute with any other solution.¹¹⁷ Shake vial until an orange-colored uniform suspension is formed.¹¹⁷ Do not dilute or transfer reconstituted suspension to another container.¹¹⁷ Use reconstituted suspension within 6 hours after reconstitution.¹¹⁷ May administer reconstituted suspension into the IV catheter of a freely running IV infusion of 0.9% sodium chloride or 5% dextrose for injection, or into an indwelling catheter (after assuring its patency) without a freely running IV infusion.¹¹⁷ If an indwelling catheter is used, flush line to assure that there is no residual drug remaining in the catheter.¹¹⁷

Rate of Administration

Acute management of malignant hyperthermia crisis: Rapid IV injection.^{108 115 116 117}

Preoperative prophylaxis of malignant hyperthermia: Infuse IV over approximately 1 hour (for Dantrium, Revonto or generic equivalents) or over at least 1 minute (for Ryanodex).^{108 115 116 117}

Dosage

Available as dantrolene sodium; dosage expressed in terms of the salt.^{108 109 115 116 117}

Pediatric Patients

Spasticity

Oral

Children ≥5 years of age: 0.5 mg/kg once daily for 7 days, followed by 0.5 mg/kg 3 times daily for 7 days, then 1 mg/kg 3 times daily for 7 days, and then 2 mg/kg 3 times daily, if necessary.¹⁰⁹ Some patients may require doses 4 times daily.¹⁰⁹

If no additional benefit is observed at the next higher dosage, decrease dosage to the previous (lower) dosage.¹⁰⁹

Malignant Hyperthermia Crisis

Preoperative Prophylaxis

Oral

4–8 mg/kg daily in 3 or 4 divided doses for 1–2 days prior to surgery; give the last dose approximately 3–4 hours before surgery with small amount of water.¹⁰⁹

IV

2.5 mg/kg infused over approximately 1 hour (Dantrium, Revonto, or generic equivalents) or at least 1 minute (Ryanodex), beginning about 1.25 hours before anticipated anesthesia or surgery; may give additional individualized doses intraoperatively, if necessary.^{108 115 116 117}

Treatment

IV

Initially, 1 mg/kg or more by rapid IV injection.^{108 115 116 117} Administer continuous rapid IV injections as necessary until physiologic and metabolic abnormalities subside or a maximum total dosage of 10 mg/kg is reached.^{108 115 116 117}

Effective dosage will vary between patients based on their susceptibility to malignant hyperthermia, amount and time of exposure to the triggering agent, and rapidity of treatment.¹⁰⁸

Repeat regimen if physiologic and metabolic abnormalities reappear.^{108 115 116 117}

Post-crisis Follow-up

Oral

To prevent recurrence, 4–8 mg/kg daily in 4 divided doses for up to 3 days after the crisis.^{108 109 115 116}

IV

If oral therapy not practical or feasible, may administer IV starting with a dose of 1 mg/kg or more as clinically indicated based on individual requirements.^{108 115 116}

Adults

Spasticity

Oral

Initially, 25 mg once daily for 7 days, followed by 25 mg 3 times daily for 7 days, then 50 mg 3 times daily for 7 days, and then 100 mg 3 times daily, if necessary.¹⁰⁹ Some patients may require doses 4 times daily.¹⁰⁹

If no additional benefit is observed at the next higher dosage, decrease dosage to the previous (lower) dosage.¹⁰⁹

Malignant Hyperthermia Crisis

Preoperative Prophylaxis

Oral

4–8 mg/kg daily in 3 or 4 divided doses for 1–2 days prior to surgery; give the last dose approximately 3–4 hours before surgery with small amount of water.¹⁰⁹

IV

2.5 mg/kg infused over approximately 1 hour (Dantrium, Revonto, or generic equivalents) or over at least 1 minute (Ryanodex), beginning about 1.25 hours before anticipated anesthesia or surgery; may give additional individualized doses intraoperatively, if necessary.^{108 115 116 117}

Treatment

IV

Initially, 1 mg/kg or more by rapid IV injection.^{108 115 116 117} Administer continuous rapid IV injections as necessary until physiologic and metabolic abnormalities subside or a maximum total dosage of 10 mg/kg is reached.^{108 115 116 117}

Effective dosage will vary between patients based on their susceptibility to malignant hyperthermia, amount and time of exposure to the triggering agent, and rapidity of treatment.¹⁰⁸

Repeat regimen if physiologic and metabolic abnormalities reappear.^{108 115 116 117}

Post-crisis Follow-up

Oral

To prevent recurrence, 4–8 mg/kg daily in 4 divided doses for up to 3 days after the crisis.^{108 109 115 116}

IV

If oral therapy not practical or feasible, may administer IV starting with a dose of 1 mg/kg or more as clinically indicated based on individual requirements.^{108 115 116}

Prescribing Limits

Pediatric Patients

Spasticity

Oral

Maximum 100 mg 4 times daily.¹⁰⁹

Malignant Hyperthermia Crisis

Treatment

IV

Maximum total dose of 10 mg/kg.^{108 115 116 117}

Adults

Spasticity

Oral

Maximum 100 mg 4 times daily.¹⁰⁹

Malignant Hyperthermia Crisis

Treatment

IV

Maximum total dose of 10 mg/kg.^{108 115 116 117}

Cautions for Dantrolene

Contraindications

• Oral dantrolene contraindicated in patients with active hepatic disease (e.g., hepatitis, cirrhosis).¹⁰⁹

• Also contraindicated in patients who must utilize spasticity to maintain upright posture and balance in moving or to obtain or maintain increased body function.¹⁰⁹

• No contraindications to IV dantrolene for prophylaxis or management of malignant hyperthermia crisis.^{108 115 116 117}

Warnings/Precautions

Warnings

Hepatic Effects

Fatal and nonfatal hepatic disorders of idiosyncratic or hypersensitivity type possible with oral dantrolene.^{108 109} (See Boxed Warning.)

Obtain serum AST, ALT, alkaline phosphatase, and total bilirubin concentrations prior to and periodically during therapy or whenever symptoms of hepatitis occur.¹⁰⁹

If liver function test abnormalities occur alone, consider discontinuing therapy; continue or reinstitute the drug only if major benefits occurred during dantrolene therapy.¹⁰⁹

If symptoms of hepatitis are accompanied by liver function test abnormalities or jaundice, discontinue dantrolene.¹⁰⁹

Following discontinuance for clinical and/or laboratory evidence of hepatotoxicity, reinstitute dantrolene only in patients who clearly need the drug and only after symptoms and laboratory abnormalities of hepatotoxicity have resolved.¹⁰⁹ Hospitalize patient to reinitiate therapy with very small doses; gradually increase dosage with frequent monitoring of liver function; discontinue drug immediately if signs of liver abnormality recur.¹⁰⁹

Sensitivity Reactions

Photosensitivity

Possible photosensitivity reactions; limit exposure to sunlight.¹⁰⁹

Other Warnings/Precautions

Supportive Therapy

In the treatment of malignant hyperthermia, must use in conjunction with supportive measures (e.g., oxygen, treatment of metabolic acidosis, cooling procedures) and discontinue all suspect triggering agents (e.g., inhaled anesthetics, succinylcholine); monitor urinary output and serum electrolytes.^{108 115 116 117} Use of IV dantrolene is not a substitute for these supportive measures.^{108 115 116}

Musculoskeletal Effects

Skeletal muscle weakness (e.g., loss of grip strength, leg weakness) may occur with IV dantrolene.^{108 117} Patients should not be permitted to ambulate without assistance until normal strength and balance return.¹¹⁷

Dysphagia reported; monitor patients for difficulty swallowing and choking.^{108 117}

Administration Precautions

Injection site reactions (pain, erythema, swelling), commonly due to extravasation, reported with IV dantrolene therapy.^{108 115 116 117} IV formulations have high pH; care must be taken to prevent extravasation.^{108 115 116 117}

Mannitol Content

If mannitol is used for prevention or treatment of late renal complications of malignant hyperthermia, consider the amount of mannitol in the IV dantrolene formulation (e.g., 3 g of mannitol per 20-mg vial of Dantrium, Revonto, or generic equivalents; 125 mg of mannitol per 250-mg vial of Ryanodex) as part of the total amount administered.^{108 115 116 117} (See General under Dosage and Administration.)

Concomitant Conditions

Use with caution in patients with severe cardiac impairment secondary to myocardial disease or with impaired pulmonary function (particularly obstructive pulmonary disease).¹⁰⁹

CNS Effects

Drowsiness and dizziness may occur, and may persist for up to 48 hours.^{108 115 116 117} Performance of activities requiring mental alertness may be impaired.¹⁰⁹ (See Advice to Patients.)

Concurrent use of other CNS depressants may cause additive CNS effects.^{109 117} (See Specific Drugs under Interactions.)

Respiratory Effects

Respiratory effects including respiratory depression, a feeling of suffocation, dyspnea, respiratory muscle weakness, and decreased inspiratory capacity reported.^{109 117} Use with caution in patients with impaired pulmonary function.¹⁰⁹ Monitor patients for adequate ventilation and vital signs.^{108 117}

Rarely, pulmonary edema has developed during treatment of malignant hyperthermia crisis in which the diluent volume and amount of mannitol associated with IV dantrolene may have contributed.^{108 115 116}

Specific Populations

Pregnancy

Category C.^{108 109 115 116 117}

No adequate and well-controlled studies in pregnant women.^{108 109 115 116 117} Embryocidal effects and decreased pup survival observed in animal studies.^{108 115 116 117}

Readily crosses the placenta.^{108 109 115 116 117} (See Distribution under Pharmacokinetics.)

Lactation

Distributed into milk;^{108 115 116 117} discontinue nursing or the drug.^{108 115 116 117}

Pediatric Use

Long-term safety of oral dantrolene not established in children <5 years of age.¹⁰⁹

Weigh possible risks against potential benefits before initiating long-term oral therapy; adverse effects may become evident only after many years.¹⁰⁹

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.^{108 109 115 116 117}

Spontaneous reports suggest that geriatric patients receiving oral dantrolene may have a higher risk of hepatic events with fatal outcomes; however, majority of these reports were complicated by confounding factors (e.g., comorbid illnesses, concomitant use of hepatotoxic drugs).¹⁰⁹

Titrate dosage carefully.^{108 109 115 116 117}

Hepatic Impairment

Use with caution in patients with a history of hepatic impairment.¹⁰⁹

Common Adverse Effects

Oral or IV: Muscle weakness,^{108 109 115 116 117} drowsiness,^{108 109 115 116 117} dizziness,^{108 109 115 116 117} lightheadedness,^{108 115 116} diarrhea,¹⁰⁹ nausea,^{109 117} malaise,¹⁰⁹ fatigue.¹⁰⁹

IV: thrombophlebitis,^{108 115 116 117} tissue necrosis secondary to extravasation,^{108 115 116 117} urticaria,^{108 115 116 117} erythema,^{108 115 116 117} injection site reactions (pain, erythema, swelling).^{108 115 116 117}

Interactions for Dantrolene

Metabolized in the liver.^{108 109 115 116 117}

Drugs Affecting Hepatic Microsomal Enzymes

Pharmacokinetic interaction with CYP enzyme inducers theoretically possible.^{108 109 115 116 117}

Specific Drugs

Dantrolene Pharmacokinetics

Absorption

Bioavailability

Absorption following oral administration is incomplete and slow but consistent.¹⁰⁹ Oral bioavailability is 70%.^{119 120}

Distribution

Extent

Readily crosses the placenta, with maternal and fetal whole blood concentrations approximately equal at delivery; neonatal concentrations then fall approximately 50% per day for 2 days before declining sharply.^{108 109 115 116 117}

Plasma Protein Binding

Substantially bound to plasma proteins (mostly albumin); binding is readily reversible.^{108 115 116 117}

Elimination

Metabolism

Major metabolites are 5-hydroxydantrolene and an acetylamino metabolite.^{108 115 116 117} May undergo hydrolysis and subsequent oxidation forming nitrophenylfuroic acid.^{108 115 116 117}

Elimination Route

Mainly excreted in urine and bile.¹¹⁹

Half-life

Approximately 4–11.4 hours following IV administration.^{108 115 116 117}

Approximately 9 hours (depending on preparation) following oral administration in adults.¹⁰⁹

Stability

Storage

Oral

Capsules

20–25°C.¹⁰⁹

Parenteral

Powder for Injection

Dantrium: 20–25°C.¹⁰⁸ Avoid prolonged exposure to light.¹⁰⁸ Store reconstituted solutions at 15–30°C for ≤6 hours; protect from light.¹⁰⁸

Revonto or generic dantrolene sodium for injection: 20–25°C. ^{115 116} Avoid prolonged exposure to light.^{115 116} Store reconstituted solutions at 20–25°C for ≤6 hours; protect from direct light.^{115 116}

Powder for Injectable Suspension

Ryanodex: 20–25°C (may be exposed to 15–30°C).¹¹⁷ Avoid prolonged exposure to light.¹¹⁷ Store reconstituted suspension at 20–25°C for ≤6 hours.¹¹⁷

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution Compatibility

Dantrolene sodium for injection (Dantrium, Revonto, or generic equivalents) is incompatible with sodium chloride 0.9% and dextrose 5% injection.^{108 115 116}

Reconstituted dantrolene sodium suspension (Ryanodex) is compatible with small amounts of sodium chloride 0.9% or dextrose 5% injection when administered into the IV catheter of a freely running IV infusion of these solutions.^{113 117}

Actions

• Causes skeletal muscle relaxation through a direct effect on skeletal muscle, probably by interfering with release of calcium from the sarcoplasmic reticulum.^{108 109 115 116 117 119}

• Interference with calcium release from the sarcoplasmic reticulum may prevent the increase in myoplasmic calcium that activates acute catabolism of skeletal muscle cells in patients with anesthesia-induced malignant hyperthermia.^{108 115 116 117}

• Has little or no effect on the contraction of cardiac or intestinal smooth muscle, except possibly at concentrations higher than those required for effects on skeletal muscle contraction.^a

Advice to Patients

• Risk of hepatotoxicity with oral dantrolene.^{108 109}

• Risk of dizziness, somnolence, and muscle weakness; do not ambulate without assistance until strength and balance have returned to normal.^{108 109 115 116 117} Do not drive or operate machinery within 48 hours of receiving IV dantrolene.^{108 115 116 117}

• Risk of choking and difficulty swallowing; exercise caution during meals.^{108 115 116 117}

• Risk of photosensitivity reactions; limit exposure to sunlight.¹⁰⁹

• Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.^{108 109 115 116 117}

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, alcohol consumption, and any concomitant illnesses.^{108 109 115 116 117}

• Importance of informing patients of other important precautionary information.^{108 109 115 116 117} (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

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