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ALERT: U.S. Boxed Warning
The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling or www.fda.gov.
Pronunciation
(DAN troe leen)
Generic Available (U.S.)
Yes: Capsule
Index Terms
Brand Names: U.S.
Brand Names: Canada
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Treatment of spasticity associated with upper motor neuron disorders (eg, spinal cord injury, stroke, cerebral palsy, or multiple sclerosis); management of malignant hyperthermia; prevention of malignant hyperthermia in susceptible individuals (preoperative/postoperative administration)
Use: Unlabeled
Neuroleptic malignant syndrome (NMS)
Pregnancy Risk Factor
C
Pregnancy Considerations
Animal studies indicate an increased risk in fetal mortality. Dantrolene crosses the human placenta; cord blood concentrations are similar to those in the maternal plasma at term. There are no adequate and well-controlled studies in pregnant women.
Lactation
Enters breast milk/not recommended
Breast-Feeding Considerations
Low amounts of dantrolene are excreted into breast milk.
Contraindications
I.V.: There are no contraindications listed within the manufacturers labeling.
Oral: Active hepatic disease; should not be used when spasticity is used to maintain posture/balance during locomotion or to obtain/maintain increased function
Warnings/Precautions
Boxed warnings:
• Hepatotoxicity: See “Concerns related to adverse effects” below.
Concerns related to adverse effects:
• CNS effects: Lightheadedness and vertigo may occur; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving).
• Hepatotoxicity: [U.S. Boxed Warning]: Has potential for hepatotoxicity. Overt hepatitis has been most frequently observed between the third and twelfth month of therapy. Hepatic injury appears to be greater in females and in patients >35 years of age. Idiosyncratic and hypersensitivity reactions (sometimes fatal) of the liver have also occurred. Discontinue therapy if benefits not observed within 45 days when utilized for chronic spasticity.
• Photosensitivity: May cause photosensitivity; discontinue if skin erythema occurs. Use skin protection and avoid prolonged exposure to sunlight; do not use tanning equipment.
Disease-related concerns:
• Cardiovascular disease: Use oral therapy with caution in patients with severely impaired cardiac function due to myocardial disease.
• Hepatic disease: Use oral therapy with caution in patients with history of liver disease or dysfunction.
• Respiratory disease: Use oral therapy with caution in patients with impaired pulmonary function (particularly in obstructive pulmonary disease).
Concurrent drug therapy issues:
• Calcium channel blockers: Use of calcium channel blockers with I.V. dantrolene may increase risk for hyperkalemia and subsequent cardiac arrest. The combination of I.V. dantrolene and calcium channel blockers is not recommended.
Special populations:
• Pediatrics: Long-term use in patients <5 years of age has not been established.
Dosage form specific issues:
• Injection: Contains 3 g mannitol/vial; caution if additional mannitol required for prevention or treatment of renal complications; alkaline solution may cause tissue necrosis if extravasated.
Other warnings/precautions:
•Appropriate use: I.V. dantrolene is not the only therapeutic approach for management of malignant hyperthermia. Supportive measures, including discontinuing trigger agents (eg, anesthetic agents), administering oxygen, utilizing cooling methods, and monitoring blood gases, urinary output, urine color, and electrolytes, must also be utilized and individualized.
Adverse Reactions
Frequency not defined.
Cardiovascular: Blood pressure (altered), heart failure, tachycardia
Central nervous system: Chills, confusion, dizziness, drowsiness, fatigue, fever, headache, insomnia, lightheadedness, malaise, mental depression, nervousness, seizure, speech disturbance
Dermatologic: Eczematoid eruption, hair growth (abnormal), pruritus, rash, urticaria
Gastrointestinal: Abdominal cramps, anorexia, constipation, diarrhea, dysphagia, gastric irritation, gastrointestinal hemorrhage, nausea, taste change, vomiting
Genitourinary: Crystalluria, difficult erection, difficult urination, nocturia, polyuria, urinary frequency, urinary incontinence, urinary retention
Hematologic: Anemia (aplastic), leukopenia, thrombocytopenia
Hepatic: Hepatitis
Local: Injection site reaction (pain, erythema, swelling), thrombophlebitis, tissue necrosis
Neuromuscular & skeletal: Back pain, muscle weakness, myalgia
Ocular: Blurred vision, diplopia, tearing (excessive)
Renal: Hematuria
Respiratory: Feeling of suffocation, pleural effusion (associated with pericarditis), pulmonary edema, respiratory depression
Miscellaneous: Anaphylaxis, diaphoresis, lymphocytic lymphoma, sialorrhea
Metabolism/Transport Effects
Substrate of CYP3A4 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Drug Interactions
Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Risk C: Monitor therapy
CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Exceptions: Levocabastine (Nasal). Risk C: Monitor therapy
Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Risk X: Avoid combination
CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates. Risk D: Consider therapy modification
Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (e.g., opioids, barbiturates) with concomitant use. Risk D: Consider therapy modification
Herbs (CYP3A4 Inducers): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Ivacaftor: May increase the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce adult dose of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established. Risk D: Consider therapy modification
Selective Serotonin Reuptake Inhibitors: CNS Depressants may enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced. Risk C: Monitor therapy
Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Ethanol/Nutrition/Herb Interactions
Ethanol: May increase CNS depression; monitor for increased effects with coadministration. Caution patients about effects.
Herb/Nutraceutical: Avoid valerian, St John's wort, kava kava, gotu kola (may increase CNS depression).
Storage
Protect from light. Use reconstituted solution within 6 hours; avoid glass bottles for I.V. infusion due to potential for precipitate formation.
Dantrium®: Store unreconstituted vials and reconstituted solutions at controlled room temperature of 15°C to 30°C (59°F to 86°F).
Revonto™: Store unreconstituted vials and reconstituted solutions at controlled room temperature of 20°C to 25°C (68°F to 77°F).
Reconstitution
Reconstitute vial by adding 60 mL of sterile water for injection USP (not bacteriostatic water for injection); incompatible with D5W, NS, and other acidic solutions; avoid glass bottles for I.V. infusion due to potential for precipitate formation.
Revonto™: Dissolution time reduced; shake vial for ~20 seconds or until solution is clear.
Compatibility
Incompatible with D5W, NS, and other acidic solutions
Mechanism of Action
Acts directly on skeletal muscle by interfering with release of calcium ion from the sarcoplasmic reticulum; prevents or reduces the increase in myoplasmic calcium ion concentration that activates the acute catabolic processes associated with malignant hyperthermia
Pharmacodynamics/Kinetics
Absorption: Oral: Slow and incomplete
Metabolism: Hepatic
Half-life elimination: 4-8 hours
Excretion: Feces (45% to 50%); urine (25% as unchanged drug and metabolites)
Dosage
Spasticity: Oral:
Children: Children: Initial: 0.5 mg/kg/dose once daily for 7 days; increase to 0.5 mg/kg/dose 3 times/day for 7 days, increase to 1 mg/kg/dose 3 times/day for 7 days, and then increase to 2 mg/kg/dose 3 times/day; not to exceed 400 mg/day
Adults: Initial: 25 mg once daily for 7 days; increase to 25 mg 3 times/day for 7 days, increase to 50 mg 3 times/day for 7 days, and then increase to 100 mg 3 times/day; not to exceed 400 mg/day
Malignant hyperthermia: Children and Adults:
Preoperative prophylaxis:
Oral: 4-8 mg/kg/day in 4 divided doses, begin 1-2 days prior to surgery with last dose 3-4 hours prior to surgery
I.V.: 2.5 mg/kg ~11/4 hours prior to anesthesia and infused over 1 hour with additional doses as needed and individualized
Crisis: I.V.: 2.5 mg/kg; continuously repeat dose until symptoms subside or a cumulative dose of 10 mg/kg is reached; if physiologic and metabolic abnormalities reappear, repeat regimen (Note: Manufacturer's labeling suggests an initial dose of 1 mg/kg; however, guidelines recommend 2.5 mg/kg initially [www.mhaus.org]).
Postcrisis follow-up: Oral: 4-8 mg/kg/day in 4 divided doses for 1-3 days; I.V. dantrolene may be used when oral therapy is not practical; individualize dosage beginning with 1 mg/kg or more as the clinical situation dictates
Neuroleptic malignant syndrome (unlabeled use): I.V.: 1-2.5 mg/kg, may repeat dose up to maximum cumulative dose of 10 mg/kg/day, then switch to oral dosage (Strawn, 2007; Susman, 2001)
Administration: I.V.
Therapeutic or emergency dose can be administered with rapid continuous I.V. push. Follow-up doses should be administered over 2-3 minutes.
Administration: I.V. Detail
pH ~9.5 (after reconstitution)
Monitoring Parameters
Motor performance should be monitored for therapeutic outcomes; nausea, vomiting, and liver function tests should be monitored for potential hepatotoxicity; intravenous administration requires cardiac monitor and blood pressure monitor
Patient Education
Do not use alcohol. You may experience drowsiness, dizziness, lightheadedness, nausea, vomiting, or diarrhea.
Geriatric Considerations
There is little experience with this drug in the elderly.
Dental Health: Effects on Dental Treatment
No significant effects or complications reported
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Effects on Mental Status
Drowsiness is common; may cause insomnia, nervousness, confusion, or depression
Mental Health: Effects on Psychiatric Treatment
Concurrent use with psychotropic may result in additive sedation; use to treat neuroleptic malignant syndrome
Nursing: Physical Assessment/Monitoring
I.V.: Monitor vital signs, cardiac function, respiratory status, and I.V. site (extravasation very irritating to tissues).
Oncology: Vesicant
Because of the high pH (~9.5) of the solution, care should be taken to prevent extravasation; tissue necrosis may result if extravasated.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule, oral, as sodium: 25 mg, 50 mg, 100 mg
Dantrium®: 25 mg, 50 mg, 100 mg
Injection, powder for reconstitution, as sodium:
Dantrium®: 20 mg [contains mannitol 3 g]
Revonto™: 20 mg [contains mannitol 3 g]
Pricing: U.S. (www.drugstore.com)
Capsules (Dantrium)
25 mg (45): $58.98
50 mg (45): $81.99
100 mg (45): $99.99
Capsules (Dantrolene Sodium)
25 mg (30): $34.99
50 mg (45): $63.99
100 mg (45): $76.99
Extemporaneously Prepared
A 5 mg/mL oral suspension may be made with dantrolene capsules, a citric acid solution, and either simple syrup or syrup BP (containing 0.15% w/v methylhydroxybenzoate). Add the contents of five 100 mg dantrolene capsules to a citric acid solution (150 mg citric acid powder in 10 mL water); mix while adding the chosen vehicle in incremental proportions to almost 100 mL. Transfer to a calibrated bottle and add quantity of vehicle sufficient to make 100 mL. Label "shake well" and "refrigerate". Simple syrup suspension is stable for 2 days refrigerated; syrup BP suspension is stable for 30 days refrigerated.
Nahata MC, Pai VB, and Hipple TF, Pediatric Drug Formulations, 5th ed, Cincinnati, OH: Harvey Whitney Books Co, 2004.
References
Britt BA, “Dantrolene,” Can J Anaesth, 1984, 31(1):61-75.
Guerrero RM and Shifrar KA, “Diagnosis and Treatment of Neuroleptic Malignant Syndrome,” Clin Pharm, 1988, 7(9):697-701.
May DC, Morris SW, Stewart RM, et al, “Neuroleptic Malignant Syndrome: Response to Dantrolene Sodium,” Ann Intern Med, 1983, 98(2):183-4.
Nahata MC and Hipple TF, Pediatric Drug Formulations, 1st ed, Harvey Whitney Books Co, 1990.
Paloucek FP, Erickson TE, Lundquist S, et al, “Oral Dantrolene Ingestion: A Case Series (Abstract),” Vet Hum Toxicol, 1991, 33:362.
Rosenberg MR and Green M, “Neuroleptic Malignant Syndrome. Review of Response to Therapy,” Arch Intern Med, 1989, 149(9):1927-31.
Rubin AS and Zablocki AD, “Hyperkalemia, Verapamil, and Dantrolene,” Anesthesiology, 1987, 66(2):248-9.
Strawn JR, Keck PE, Caroff SN, "Neuroleptic Malignant Syndrome," Am J Psychiatry, 2007, 164:870-876.
Susman VL, "Clinical Management of Neuroleptic Malignant Syndrome," Psychiatric Quarterly, 2001, 72(4):325-36.
Tayeb OS, “A Serious Interaction of Dantrolene and Theophylline,” Vet Hum Toxicol, 1990, 32(5):442-3.
Ward A, Chaffman MO, and Sorkin EM, “Dantrolene: A Review of Its Pharmacodynamic and Pharmacokinetic Properties and Therapeutic Use in Malignant Hyperthermia, the Neuroleptic Malignant Syndrome and an Update of Its Use in Muscle Spasticity,” Drugs, 1986, 32(2):130-68.
International Brand Names
Lexi-Comp.com
Last full review/revision March 2012
Content last modified March 2012
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