Dantrolene (Systemic)

VA CLASSIFICATION
Primary: MS200

Commonly used brand name(s): Dantrium; Dantrium Intravenous.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Malignant hyperthermia therapy adjunct—

Antispastic—

Neuroleptic malignant syndrome therapy adjunct—

Muscle phosphorylase deficiency therapy adjunct—

Duchenne muscular dystrophy therapy adjunct—

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Hyperthermia, malignant (prophylaxis and treatment adjunct)—Intravenous dantrolene is indicated to reverse the symptoms of the malignant hyperthermic crisis syndrome occurring during or following surgery or anesthesia. However, dantrolene is not a substitute for other measures, including discontinuation of possible triggering agents (such as potent inhalation anesthetics, succinylcholine, or stress), management of increased oxygen requirements and metabolic acidosis, institution of cooling, and correction of fluid and electrolyte imbalances. Oral or intravenous dantrolene is indicated as a follow-up to initial intravenous therapy to prevent recurrence of symptoms, but caution in such use is recommended.
—Dantrolene is also indicated for administration prior to surgery or anesthesia to prevent or attenuate the symptoms of the malignant hyperthermic crisis syndrome in patients known or suspected to be at risk for this complication. However, preliminary evidence suggests that prophylactic use of dantrolene is not necessary for most patients, provided that careful patient management procedures are followed (including avoiding known triggering agents during surgery, careful monitoring intra- and postoperatively, and administering intravenous dantrolene if symptoms of malignant hyperthermia develop). Perioperative complications (such as atelectasis, retained secretions, diminished swallow and gag reflexes, impaired postoperative ventilation requiring prolonged endotracheal intubation, and delayed or difficult postoperative ambulation), possibly associated with dantrolene-induced muscle weakness, have been reported following prophylactic use of oral dantrolene and should be considered a possibility following intravenous administration also. Patients with pre-existing myopathy, predisposing neuromuscular disease, or compromised respiratory reserve may be especially at risk for these complications. Although many anesthesiologists advocate prophylactic use of dantrolene, provided that the risk of complications is considered and patients carefully selected, others recommend that dantrolene not be used prophylactically. Patients receiving prophylactic dantrolene should be carefully monitored postoperatively to detect possible prolonged or delayed effects of the medication. The controversy concerning prophylactic use of dantrolene for malignant hyperthermia does not extend to its therapeutic use for other indications.

Spasticity (treatment)—Oral dantrolene is indicated to relieve spasticity caused by upper motor neuron disorders such as spinal cord injury, cerebrovascular accident, cerebral palsy, and multiple sclerosis. It may be especially beneficial for patients whose functional rehabilitation is retarded by the sequelae of spasticity. However, baclofen is now more commonly used for this indication.

[Neuroleptic malignant syndrome (treatment)]¹—Dantrolene is used to relieve the symptoms of neuroleptic malignant syndrome, which are similar to those caused by malignant hyperthermia.

[Pain, exercise-induced, in muscle phosphorylase deficiency (treatment)]¹; or
[Pain, exercise-induced, in Duchenne muscular dystrophy (treatment)]¹—Oral dantrolene is used to relieve exercise-induced pain in patients with these conditions.

[Spasms, flexor (treatment)]¹—Oral dantrolene is used in the management of flexor spasms in patients who are confined to bed or a wheelchair.

Unaccepted
Dantrolene should not be used in patients who require spasticity to sustain upright posture or balance in locomotion, or to obtain increased function.

Dantrolene is not indicated for relief of skeletal muscle spasm caused by rheumatic disorders.

¹ Not included in Canadian product labeling.

Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    399.29 ^{02}

Mechanism of action/Effect:


Malignant hyperthermia therapy adjunct:

By interfering with the release of calcium ion from the sarcoplasmic reticulum, dantrolene prevents or reduces the increase in myoplasmic calcium ion concentration that activates the acute catabolic processes associated with the malignant hyperthermic crisis syndrome.



Antispastic:

Acts directly on skeletal muscle to dissociate excitation-contraction coupling, probably by interfering with the release of calcium ion from the sarcoplasmic reticulum. Dantrolene reduces muscle contractions mediated via both polysynaptic and monosynaptic reflexes. The extent to which any central nervous system (CNS) actions may contribute to the skeletal muscle relaxant effects is unknown.


Biotransformation:

Hepatic; probably by hepatic microsomal enzymes.

Half-life:

Intravenous—4 to 8 hours

Oral—8.7 hours (100-mg dose)

Onset of action:

Spasticity caused by upper motor neuron disorders—1 week or more.

Time to peak concentration:

Oral—5 hours

Peak whole blood concentration

300 to 1100 nanograms per mL following administration of 25 to 100 mg; subject to interpatient variation.

Therapeutic serum concentration

100 to 600 nanograms per mL; subject to interpatient variation.

Elimination:
    Renal, as metabolites. Small amounts may also be excreted unchanged.


Precautions to Consider

Carcinogenicity/Tumorigenicity

An increased incidence of nonmalignant and malignant mammary tumors occurred with chronic (18 months) administration of dantrolene in doses of 15, 30, or 60 mg per kg of body weight (mg/kg) per day to female Sprague-Dawley rats. Also, an increased incidence of hepatic lymphangiomas and angiosarcomas occurred with chronic administration of 60 mg/kg per day. However, dantrolene did not produce these effects in other studies when administered for 2 years to mice or 21/2 years to rats. The risk of carcinogenicity in humans is not known; therefore, risk-benefit with chronic therapy must be considered.

Pregnancy/Reproduction

Pregnancy—
Problems in humans have not been documented.

Breast-feeding

Dantrolene should not be used in nursing mothers ^{{06} {07}}.

Pediatrics

Appropriate studies performed to date have not demonstrated pediatrics-specific problems that would limit the usefulness of dantrolene in children. However, long-term studies have not been done in children <5 years of age.


Geriatrics


No information is available on the relationship of age to the effects of dantrolene in geriatric patients.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.


For short-term (up to 3 days) or chronic use
» CNS depression–producing medications (See Appendix II )    (concurrent use with dantrolene may result in increased CNS depressant effects; caution is recommended and dosage of one or both agents should be reduced)


For chronic oral use only
» Hepatotoxic medications, other (See Appendix II )    (concurrent use of these medications with dantrolene may increase the risk of hepatotoxicity; females over 35 years of age may be especially at risk with concurrent use of estrogens)


For intravenous use in treating malignant hyperthermia only
Calcium channel blockers    (concurrent administration of therapeutic doses of verapamil with intravenous dantrolene to halothane/alpha-chloralose anesthetized swine has caused ventricular fibrillation and cardiovascular collapse associated with severe hypokalemia; although the relevance of these findings to humans has not been determined, it is recommended that calcium channel blockers not be used concurrently with intravenous dantrolene in the management of a malignant hyperthermic crisis)



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Liver function tests    (abnormalities may occur indicating hepatotoxicity)


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Note: The following precautions do not apply to short-term intravenous use of dantrolene for treatment of a malignant hyperthermic crisis, unless otherwise specified.


Except under special circumstances, this medication should not be used when the following medical problem exists:
» Hepatic disease, active, such as hepatitis or cirrhosis    (increased risk of hepatotoxicity)


Risk-benefit should be considered when the following medical problems exist
Cardiac function impairment, especially if due to myocardial disease    (dantrolene may cause pleural effusion and pericarditis)


Hepatic function impairment or history of    (possible increased risk of hepatotoxicity)


Myopathy, pre-existing or
Neuromuscular disease predisposing to respiratory insufficiency    (increased risk of perioperative complications when dantrolene is used as prophylaxis against malignant hyperthermia)


Pulmonary function impairment, especially obstructive pulmonary disease    (dantrolene may cause respiratory depression, possibly associated with muscle weakness, or pleural effusion)


Sensitivity to dantrolene
Caution is also recommended in patients older than 35 years of age, especially females, because of the increased risk of hepatotoxicity.

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Blood cell counts and
Renal function determinations    (may be required at periodic intervals during chronic therapy)


» Hepatic function determinations, including:
Alanine aminotransferase (ALT [SGPT]), serum
Alkaline phosphatase
Aspartate aminotransferase (AST [SGOT]), serum
Bilirubin, total
Gammaglutamyl transpeptidase (GGTP)    (may be required before initiation of chronic therapy to determine baseline values and to identify pre-existing hepatic dysfunction or disease and at periodic intervals during chronic therapy)




Side/Adverse Effects

Note: Dantrolene-induced hepatotoxicity may be caused by an idiosyncratic or allergic reaction to the medication. The risk of hepatotoxicity appears greater with females, patients over 35 years of age, and patients concurrently taking other medications. In particular, females over 35 years of age who are receiving estrogen therapy have an increased frequency of hepatotoxicity. Hepatotoxicity may be less likely to occur in patients taking up to 400 mg per day than in those taking 800 mg or more per day. Even short-term administration of the larger doses within a treatment regimen may increase the risk of hepatotoxicity. Overt hepatitis occurs most frequently between the third and twelfth months of chronic therapy.

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence less frequent
With short-term (up to 3 days) or chronic oral use
    
Diarrhea, severe
    
respiratory depression (shortness of breath or slow or troubled breathing)
Note: Severe diarrhea may necessitate temporary discontinuation of therapy. If severe diarrhea recurs when therapy is resumed, therapy should probably be discontinued permanently.



With chronic oral use only
    
Bloody or dark urine
    
confusion
    
constipation, severe — may cause abdominal distention or other symptoms of bowel obstruction
    
convulsions
    
dermatitis, allergic (skin rash, hives, or itching)
    
difficult urination
    
hepatotoxicity (yellow eyes or skin)—may be preceded by gastrointestinal symptoms such as nausea, vomiting, anorexia, and abdominal discomfort
    
mental depression
    
phlebitis (pain, tenderness, changes in skin color, or swelling of foot or leg)
    
pleural effusion with pericarditis (chest pain)




Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
With short-term (up to 3 days) or chronic oral use
    
Diarrhea, mild
    
dizziness or lightheadedness
    
drowsiness
    
general feeling of discomfort or illness
    
muscle weakness not affecting muscles of respiration
    
nausea or vomiting
    
unusual tiredness
Incidence less frequent
    
Abdominal or stomach cramps or discomfort



With chronic oral use only
Incidence less frequent
    
Blurred or double vision or any change in vision
    
chills and fever
    
constipation, mild
    
difficulty in swallowing
    
frequent urge to urinate or uncontrolled urination
    
headache
    
loss of appetite
    
slurring of speech or other speech problems
    
sudden decrease in amount of urine
    
trouble in sleeping
    
unusual nervousness






Overdose
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Treatment of overdose
To decrease absorption—Removing unabsorbed dantrolene (if ingested orally) via induction of emesis or gastric lavage.

Monitoring—May include monitoring the electrocardiogram (ECG), carefully observing the patient, and instituting supportive treatment of observed symptoms.

Supportive care—Administering large quantities of intravenous fluids to prevent crystalluria.

Maintaining an adequate airway, with equipment for artificial resuscitation at hand. Patients in whom intentional overdose is known or suspected should be referred to for psychiatric consultation.

Note: The possible value of dialysis in treating overdosage has not been determined.



Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Dantrolene (Systemic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Other medications, especially CNS depression-producing medications and other hepatotoxic medications

Other medical problems, especially hepatic disease.

Proper use of this medication
Mixing contents of capsule with fruit juice or other liquid if unable to swallow capsule; drinking immediately after mixing

» Not taking more medication than the amount prescribed, to minimize risk of hepatotoxicity or other adverse effects

» Proper dosing
Missed dose: Taking if remembered within an hour or so; not taking if not remembered within an hour; not doubling doses

» Proper storage

Precautions while using this medication
Regular visits to physician to check progress during long-term therapy; possibility of blood tests to check for side effects

» Avoiding alcohol or other CNS depressants during therapy unless prescribed or otherwise approved by physician

» Caution if drowsiness, dizziness or lightheadedness, vision disturbances, or muscle weakness occurs


Side/adverse effects
Signs of potential side effects, especially bloody or dark urine; confusion; constipation, severe; convulsions; allergic dermatitis; diarrhea, severe; difficult urination; hepatitis; mental depression; phlebitis; pleural effusion with pericarditis; and respiratory depression


General Dosing Information
Side effects such as drowsiness, dizziness, weakness, tiredness, or gastrointestinal irritation may be minimized by initiating therapy with a low dose and gradually increasing the dosage until maximal benefit is achieved.

If no benefit is observed after 45 days of therapy, the medication should be discontinued.

Dantrolene should be discontinued if a patient develops symptoms of hepatitis during therapy. If hepatic function test abnormalities without symptoms of overt hepatitis occur, the medication should probably be discontinued; however, in some patients, hepatic function test values have returned to normal despite continuation of therapy. Reinstitution or continuation of therapy should be considered only for patients receiving major benefit from the medication. Reinstitution of therapy following dantrolene-induced hepatitis should be attempted only after the symptoms and hepatic function test abnormalities have cleared. The patient should be hospitalized. Therapy should be resumed with very small and gradually increasing doses. Liver function tests should be performed frequently and the medication withdrawn immediately if any abnormalities occur.

For parenteral dosage form only
Extravasation of the intravenous solution into surrounding tissues should be avoided because of the high pH of the solution.


Oral Dosage Forms

DANTROLENE SODIUM CAPSULES

Usual adult and adolescent dose
Malignant hyperthermic crisis prophylaxis
Oral, 4 to 8 mg per kg of body weight per day in three or four divided doses for one to two days prior to surgery. The last dose should be given three to four hours prior to scheduled surgery with a minimum of water.

Post-malignant hyperthermic crisis treatment (as a follow-up to intravenous therapy)
Oral, 4 to 8 mg per kg of body weight per day in four divided doses for one to three days.

Antispastic
Oral, 25 mg once a day, initially; total daily dose may be increased by 25 mg every four to seven days until optimal response is achieved or until a dosage of 100 mg four times a day is reached. Medication should be administered in four divided daily doses whenever possible.


Usual pediatric dose
Antispastic
Oral, 500 mcg (0.5 mg) per kg of body weight two times a day, initially; total daily dose may be increased by 500 mcg (0.5 mg) per kg of body weight every four to seven days until optimal response is achieved or until a dosage of 3 mg per kg of body weight four times a day is reached. Medication should be administered in four divided daily doses whenever possible.


Note: The maximum recommended pediatric dosage is 400 mg a day.


Strength(s) usually available
U.S.—
^{04}

25 mg (Rx) [Dantrium (lactose)]


50 mg (Rx) [Dantrium (lactose)]


100 mg (Rx) [Dantrium (lactose)]

Canada—
^{04}

25 mg (Rx) [Dantrium (lactose)]


100 mg (Rx) [Dantrium (lactose)]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), in a well-closed container, unless otherwise specified by manufacturer.

Preparation of dosage form:
For patients who cannot take oral solids

Single dose: Immediately prior to use, add the contents of the required number of capsules to fruit juice or other liquid and stir to mix.

Multiple dose: Empty 5 capsules (100 mg each) into 50 mL of Syrup NF; add 150 mg of citric acid dissolved in 10 mL of water; add enough Syrup NF to make 100 mL of suspension. This suspension will contain 25 mg of dantrolene sodium per 5 mL. Although the stability of such an extemporaneous preparation is unknown, it is thought to be stable for several days when refrigerated. However, since it contains no preservative, care must be taken to avoid contamination.


Auxiliary labeling:
   • May cause drowsiness.
   • Avoid alcoholic beverages.



Parenteral Dosage Forms

DANTROLENE SODIUM FOR INJECTION

Usual adult and adolescent dose
Malignant hyperthermia therapy adjunct
Prophylactic¹: ^{03} Intravenous infusion, 2.5 mg per kg of body weight, administered over a one-hour period prior to anesthesia.

Therapeutic: Intravenous, by continuous rapid push, at least 1 mg per kg of body weight, initially, with administration being continued until the symptoms subside or until the maximum cumulative dose of 10 mg per kg of body weight has been reached. Administration may be repeated if symptoms recur.

Note: For treatment of a malignant hyperthermic crisis, some anesthesiologists recommend an initial dose of 2.5 to 3 mg per kg of body weight.



Usual pediatric dose
See Usual adult and adolescent dose.

Size(s) usually available:
U.S.—


20 mg (Rx) [Dantrium Intravenous]

Canada—


20 mg (Rx) [Dantrium Intravenous]

Packaging and storage:
Prior to reconstitution, store below 30 °C (86 °F), protected from prolonged exposure to light, unless otherwise specified by manufacturer.

Preparation of dosage form:
60 mL of sterile water for injection without a bacteriostatic agent should be added to the vial containing 20 mg of dantrolene sodium and shaken until the solution is clear. The solution will contain 333 mcg (0.33 mg) per mL.

Stability:
After reconstitution, protect from temperatures below 15 °C (59 °F) or above 30 °C (86 °F). Protect from direct light. Use within 6 hours following reconstitution.

Precipitate formation has occurred after transfer of reconstituted dantrolene solutions to large glass bottles for preparation of an intravenous infusion. It is recommended that intravenous infusions be prepared in sterile plastic bags, immediately prior to the time of anticipated use. Also, the prepared infusion should be inspected for cloudiness and/or precipitation prior to use, and discarded if either is present. ^{05}

Incompatibilities:
Dantrolene is incompatible with acidic solutions, including 5% dextrose injection and 0.9% sodium chloride injection. Acidic solutions should not be used for reconstituting the medication. ^{05}

Revised: 05/10/1993

References

1. Dantrium capsules product monograph (Norwich Eaton—US), PDR 1987, Rev 1/85.
   

2. Fleeger CA, editor. USAN 1993. USAN and the USP dictionary of drug names. Rockville, MD: The United States Pharmacopeial Convention, Inc., 1992.
   

3. Company announcement, Norwich Eaton, indicating prophylactic use of IV dantrolene now FDA-approved and recommended dose, Rec 6/87.
   

4. For 1990 revision: Information on inactive ingredients obtained from package inserts: Dantrium Capsules (Norwich Eaton—US), Rev 1/85, Rec 11/88; Dantrium Intravenous (Norwich Eaton—US), Rev 5/87, Rec 11/88; and Dantrium Capsules (Norwich Eaton—Canada), CPS 1988.
   

5. Dantrium Intravenous product monograph (Norwich Eaton—US), PDR 1990: 1533, Rev 2/89.
   

6. Dantrium product monograph (Norwich Eaton—Canada), CPS 1992: 284-5.
   

7. Dantrium product monograph (Procter & Gamble—US), PDR 1993: 1870-2, Rev 5/92.