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Dantrolene Sodium

Pronunciation

Class: Direct-acting Skeletal Muscle Relaxants
VA Class: MS200
CAS Number: 24868-20-0
Brands: Dantrium

Warning(s)

  • Hepatic Effects of Oral Dantrolene
  • Risk of developing potentially fatal, hepatic injury (e.g., hepatitis); should not be used for unlabeled indications.109

  • Females, patients >35 years of age, and those receiving other drugs (especially estrogens) concomitantly are at greatest risk.109

  • Risk of symptomatic hepatitis (fatal and nonfatal) may be dose dependent; incidence much higher at dosages ≥800 mg daily than at dosages ≤400 mg daily.109 Even intermittent, short courses at higher dosages associated with increased risk.109 Use lowest possible effective dose.109

  • Overt hepatitis most frequently observed between 3rd and 12th month of therapy.109

  • Frequently monitor hepatic function.109 (See Hepatic Effects under Cautions.)

  • If benefits are not evident within 45 days, discontinue therapy.109

Introduction

Skeletal muscle relaxant.108 109

Uses for Dantrolene Sodium

Spasticity

Oral management of spasticity resulting from upper motor neuron disorders (e.g., multiple sclerosis, cerebral palsy, spinal cord injury, stroke syndrome).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

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Malignant Hyperthermia Crisis

IV treatment of fulminant hypermetabolism of skeletal muscle that is characteristic of malignant hyperthermia crisis;108 should be used with and not as a substitute for supportive measures.a

Preoperative and postoperative prevention or attenuation of malignant hyperthermia in susceptible individuals; used orally or IV (when oral therapy is not practical or feasible).108 109

Neuroleptic Malignant Syndrome

Has been used for the treatment of neuroleptic malignant syndrome; fatalities reported despite therapy with the drug.108 109

Dantrolene Sodium 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 and institute IV dantrolene as soon as malignant hyperthermia crisis is recognized.108

  • Monitor vital signs; employ the usual precautions associated with surgery in susceptible patients, since malignant hyperthermia may only be attenuated rather than prevented.108

Administration

Administer orally or by continuous IV infusion or rapid IV injection.108 109

Oral Administration

Administer orally 1–4 times daily.109

Extemporaneous Suspension

To prepare oral suspension containing 25 mg of dantrolene sodium per 5 mL, empty 5 100-mg capsules in 50 mL of Syrup NF, then add a solution containing 150 mg of citric acid in 10 mL of water followed by a sufficient volume of Syrup NF to make 100 mL.c Mix thoroughly before use.c

IV Administration

For solution compatibility information, see Compatibility under Stability.

For IV infusion, transfer reconstituted solution from the appropriate number of vials to plastic infusion bag.109 Do not use large glass containers; precipitate formation observed with some glass containers.108

Avoid extravasation (injection has high pH).108

Reconstitution

Add 60 mL of sterile water for injection (without bacteriostatic agent) to vial containing 20 mg of dantrolene sodium.108 Shake vial until solution is clear.108

Although reconstituted solutions are stable for 6 hours,108 infusions preferably should be prepared immediately before use.a

Rate of Administration

Preoperative prophylaxis: Infuse IV over approximately 1 hour beginning about 1.25 hours before anticipated anesthesia.108

Treatment of malignant hyperthermia syndrome: Rapid IV injection.108

Dosage

Available as dantrolene sodium; dosage expressed in terms of the salt.108 109

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 beginning about 1.25 hours before anticipated anesthesia; may give additional individualized doses intraoperatively, if necessary.108

Treatment
IV

Initially, 1 mg/kg or more by rapid IV injection.108 Repeat dose as necessary until physiologic and metabolic abnormalities subside or a maximum total dosage of 10 mg/kg is reached.108

Average total dosage: 2.5 mg/kg.a

Repeat regimen if physiologic and metabolic abnormalities reappear.108

Post-crisis Follow-up
Oral

4–8 mg/kg daily in 4 divided doses for up to 3 days after the crisis.109

IV

Initially, 1 mg/kg or more as clinically indicated.108 Individualize subsequent doses.108

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 beginning about 1.25 hours before anticipated anesthesia; may give additional individualized doses intraoperatively, if necessary.108

Treatment
IV

Initially, 1 mg/kg or more by rapid IV injection.108 Repeat dose as necessary until physiologic and metabolic abnormalities subside or a maximum total dosage of 10 mg/kg is reached.108

Average total dosage: 2.5 mg/kg.a

Repeat regimen if physiologic and metabolic abnormalities reappear.108

Post-crisis Follow-up
Oral

4–8 mg/kg daily in 4 divided doses for up to 3 days after the crisis.109

IV

Initially, 1 mg/kg or more as clinically indicated.108 Individualize subsequent doses.108

Prescribing Limits

Pediatric Patients

Spasticity
Oral

Maximum 100 mg 4 times daily.109

Malignant Hyperthermia Crisis
Treatment
IV

Maximum 10 mg/kg.108

Adults

Spasticity
Oral

Maximum 100 mg 4 times daily.109

Malignant Hyperthermia Crisis
Treatment
IV

Maximum 10 mg/kg.108

Cautions for Dantrolene Sodium

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

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

Risks Associated with Long-term, Chronic Use

Long-term safety in humans yet to be established.109

Nephropathy, benign and malignant mammary and testicular tumors, hepatic lymphangiomas, and hepatic angiosarcomas reported following long-term use in animals; assess risk/benefits of chronic administration.109

Sensitivity Reactions

Photosensitivity

Possible photosensitivity reactions; limit exposure to sunlight.109

General Precautions

CNS Depression

Performance of activities requiring mental alertness may be impaired.108 109

Concurrent use of other CNS depressants may potentiate CNS depression.108 109 (See Specific Drugs under Interactions.)

Mannitol Content

If mannitol is used for the prevention or treatment of late renal complications of malignant hyperthermia, consider mannitol in the IV dantrolene formulation (3 g of mannitol per 20-mg vial) as part of the total amount administered.108

Concomitant Illnesses

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

Specific Populations

Pregnancy

Category C.108 109

Readily crosses the placenta.108 (See Distribution under Pharmacokinetics.)

Lactation

Distributed into milk;b use of oral dantrolene not recommended.109

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

Titrate dosage carefully.108

Hepatic Impairment

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

Common Adverse Effects

Muscle weakness, drowsiness, dizziness, lightheadedness, diarrhea, nausea, malaise, fatigue.a 109

Interactions for Dantrolene Sodium

Metabolized in the liver, but the precise enzymes responsible are unknown.108

Drugs Affecting Hepatic Microsomal Enzymes

Pharmacokinetic interaction with CYP enzyme inducers theoretically possible.108

Specific Drugs

Drug

Interaction

Comment

Calcium-channel blockers (e.g., verapamil)

Cardiovascular collapse reported rarely108

Concomitant use during malignant hyperthermia crisis not recommended108

Clofibrate

Decreased binding of dantrolene to plasma proteins108

CNS depressants

Possible additive CNS effects (e.g., dizziness)108 109

Use with caution108 109

Diazepam

Additive sedative effect; dantrolene metabolism and protein binding unaffacted108

Use with cautiona

Estrogens

Possible increased frequency of hepatotoxicity in women >35 years of age109

Potential for interaction not clearly established; use with caution109

Phenobarbital

Pharmacokinetic interaction unlikely; dantrolene metabolism unaffected108

Phenytoin

No change in binding of dantrolene to plasma proteins108

Tolbutamide

Increased binding of dantrolene to plasma proteins108

Vecuronium

Potentiation of vecuronium-induced neuromuscular blockade108

Warfarin

Decreased binding of dantrolene to plasma proteins108

Dantrolene Sodium Pharmacokinetics

Absorption

Bioavailability

Absorption following oral administration is incomplete and slow but consistent.109

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

Plasma Protein Binding

Substantially bound to plasma proteins (mostly albumin); binding is readily reversible.108

Elimination

Metabolism

Specific metabolic pathways not established.108 May undergo hydrolysis and subsequent oxidation forming nitrophenylfuroic acid.108

Elimination Route

Specific pathways not established.108

Half-life

Approximately 4–8 hours following IV administration.108

Approximately 9 hours following oral administration in adults.109

Stability

Storage

Oral

Capsules

<40°C.109

Parenteral

Powder for Injection

15–30°C.108 Avoid prolonged exposure to light.108

Store reconstituted solutions at 15–30°C for up to 6 hours.108 Protect from light.108

Compatibility

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

Parenteral

Solution Compatibility108

Incompatible

Dextrose 5% in water

Sodium chloride 0.9%

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

  • 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

  • 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 hepatoxicity with oral dantrolene.108 109

  • Risk of dizziness and muscle weakness; use caution when driving or operating machinery.108 109 Do not drive or operate machinery within 48 hours of receiving IV dantrolene.109

  • Risk of choking and difficulty swallowing; exercise caution during meals.108

  • 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

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, alcohol consumption, and any concomitant illnesses.108 109

  • Importance of informing patients of other important precautionary information.108 109 (See Cautions.)

Preparations

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

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

Dantrolene Sodium

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules

25 mg*

Dantrium

Procter & Gamble

Dantrolene Sodium Capsules

Amide, Global

50 mg*

Dantrium

Procter & Gamble

Dantrolene Sodium Capsules

Amide, Global

100 mg*

Dantrium

Procter & Gamble

Dantrolene Sodium Capsules

Amide, Global

Parenteral

For injection

20 mg

Dantrium Intravenous (with mannitol 3 g)

Procter & Gamble

Revonto Intravenous (with mannitol 3 g)

US WorldMeds

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Dantrium 100MG Capsules (JHP PHARMACEUTICALS): 45/$99.99 or 135/$291.99

Dantrium 25MG Capsules (JHP PHARMACEUTICALS): 45/$58.98 or 135/$164.96

Dantrium 50MG Capsules (JHP PHARMACEUTICALS): 45/$81.99 or 135/$234.97

Dantrolene Sodium 100MG Capsules (GLOBAL PHARMACEUTICAL CORP): 45/$76.99 or 135/$219.97

Dantrolene Sodium 25MG Capsules (GLOBAL PHARMACEUTICAL CORP): 30/$34.99 or 90/$81.97

Dantrolene Sodium 50MG Capsules (GLOBAL PHARMACEUTICAL CORP): 45/$63.99 or 135/$175.97

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions October 9, 2012. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

Only references cited for selected revisions after 1984 are available electronically.

100. Coons DJ, Hillman FJ, Marshall RW. Treatment of neuroleptic malignant syndrome with dantrolene sodium: a case report. Am J Psychiatry. 1982; 139:944-5. [IDIS 154797] [PubMed 6124135]

101. Goekoop JG, Carbaat PAT. Treatment of neuroleptic malignant syndrome with dantrolene. Lancet. 1982; 2:49-50.

102. May DC, Morris SW, Stewart RM et al. Neuroleptic malignant syndrome: response to dantrolene sodium. Ann Intern Med. 1983; 98:183-4. [IDIS 164929] [PubMed 6824251]

103. Daoudal P, Delacour JL. Treatment of neuroleptic malignant syndrome with dantrolene. Lancet. 1982; 2:217. [PubMed 6123917]

104. Granato JE, Stern BJ, Ringel A et al. Neuroleptic malignant syndrome: successful treatment with dantrolene and bromocriptine. Ann Neurol. 1983; 14:89-90. [IDIS 173103] [PubMed 6614876]

105. Goulon M, de Rohan-Chabot P, Elkharrat D et al. Beneficial effects of dantrolene in the treatment of neuroleptic malignant syndrome: a report of the two cases. Neurology. 1983; 33:516-8. [IDIS 169146] [PubMed 6682201]

106. Rappaport PL. Extemporaneous dosage preparations for pediatrics. Can J Hosp Pharm. 1983; 36:66-70,74. [PubMed 10262678]

107. Kaplan RF, Feinglass NG, Webster W et al. Phenelzine overdose treated with dantrolene sodium. JAMA. 1986; 255:642-4. [IDIS 210184] [PubMed 3944965]

108. Procter & Gamble Pharmaceuticals. Dantrium IV (dantrolene sodium) for injection prescribing information. Cincinnati, OH; 2001 May.

109. Procter & Gamble Pharmaceuticals. Dantrium (dantrolene sodium) capsules prescribing information. Cincinnati, OH; 1997 Feb.

110. Rubin AS, Zablocki AD. Hyperkalemia, verapamil, and dantrolene. Anesthesiology. 1987; 66:246-9. [IDIS 227329] [PubMed 3813090]

111. Dantrolene (Dantrium) interactions: verapamil (e.g., Calan). In: Hansten PD, Horn JR. Hansten and Horn’s drug interactions, analysis and managements. St. Louis, MO. Facts and Comparisons; 2002:450a.

a. AHFS drug information 2003. McEvoy GK, ed. Dantrolene. Bethesda, MD: American Society of Health-System Pharmacists; 2003:1321-5.

b. Briggs GG, Freeman RK, Yaffe SJ. Drugs in Pregnancy and lactation. 6th ed. Baltimore, MD: Williams & Wilkins; 2002:364-6.

c. Nahata MC, Hipple TF. Pediatric drug formulations. 4th ed. Cincinnati, Ohio: Harvey Whitney Books Company; 2000: 35.

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