VA Class:MS200
Dantrolene sodium is a direct-acting skeletal muscle relaxant.108, 109, 115, 116, 117, 119
Dantrolene sodium is used orally in the management of spasticity resulting from upper motor neuron disorders such as multiple sclerosis, cerebral palsy, spinal cord injury, and stroke. Dantrolene is not indicated for the treatment of muscle spasms resulting from rheumatic disorders or musculoskeletal trauma and is ineffective in the management of amyotrophic lateral sclerosis.
Evidence supporting the use of dantrolene for spasticity 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 receiving the drug.109 In the management of spasticity, the manufacturer states that dantrolene is particularly useful in patients whose functional rehabilitation has been slowed by the sequelae of spasticity.109 For the drug to be beneficial, such patients must have presumably reversible spasticity where relief of spasticity will aid in restoring residual function.109 Although effective doses of dantrolene frequently cause muscle weakness, the patient may feel more confident in the use of his residual strength because of a parallel decrease in involuntary muscle activity. The desirability of long-term dantrolene therapy in ambulatory patients depends on the balance between the weakness and other adverse effects caused by the drug and the benefits obtained from its use. Adverse effects such as weakness may not be as important a consideration in paraplegic patients as in ambulatory patients.
There is presently no method of predicting which patients will benefit from dantrolene therapy; therefore, a therapeutic trial of the drug is necessary to determine the benefits to a specific individual. Many patients with chronic spasticity may not benefit from long-term (several months or longer) dantrolene therapy; however, the benefits may be considerable in some patients. Tolerance to the therapeutic effects of dantrolene apparently does not occur. Although the safety and efficacy of long-term therapy have not been established, long-term administration of dantrolene is considered justifiable if the drug produces a substantial reduction in painful and/or disabling spasticity or a reduction in the intensity of nursing care needed, or if annoying manifestations of spasticity are eliminated as judged by the patient. Subjective impressions of improvement noted by the physician, patient, or persons in close contact with the patient may sometimes be confirmed by withdrawal of the drug for 2-4 days. Observation of the patient for exacerbations of the condition during this time may demonstrate improvements which are otherwise difficult to document. Because of dantrolene's potential for causing liver damage, therapy with the drug should be continued only if it is clearly beneficial.
Compared with other drugs used for spasticity (e.g., baclofen, diazepam, tizanidine), dantrolene is a peripherally acting agent that exhibits direct effects on skeletal muscle; however, few controlled studies have been conducted comparing efficacy and tolerability of the various antispastic agents.48, 49, 109, 123, 124, 126, 127, 128, 129, 131 In one study comparing dantrolene and diazepam in patients with multiple sclerosis, the drugs were about equally effective in relieving spasticity; diazepam was associated with more frequent CNS effects (e.g., drowsiness, incoordination, imbalance), while dantrolene was associated with more muscle weakness.48 Use of dantrolene in combination with other antispastic agents (e.g., diazepam) may produce better control of spasticity in some patients than either drug alone and enable a decrease in the dosage of either or both drugs. However, it should be considered that concomitant therapy may cause additive adverse effects. (See Cautions: Precautions and Contraindications.)
IV dantrolene sodium is used with appropriate supportive measures in the management of fulminant hypermetabolism of skeletal muscle that is characteristic of malignant hyperthermia crisis, a rare inherited condition that can be triggered by certain inhaled anesthetic agents or succinylcholine.108, 113, 115, 116, 117, 121 Dantrolene sodium for injectable suspension (Ryanodex®) has been designated an orphan drug by the FDA for this use.122 As soon as malignant hyperthermia crisis is recognized (i.e., tachycardia, tachypnea, central venous desaturation, hypercarbia, metabolic acidosis, skeletal muscle rigidity, increased utilization of anesthesia circuit carbon dioxide absorber, cyanosis and mottling of the skin, and, in many cases, fever), all anesthetic agents and other potential triggering agents (e.g., succinylcholine) should be discontinued immediately and IV dantrolene therapy initiated.108, 115, 116, 117 IV dantrolene is used in conjunction with supportive measures, which include administering oxygen, treating metabolic acidosis, and instituting cooling procedures if necessary; urinary output and serum electrolytes should be monitored.108, 115, 116, 117 The use of IV dantrolene in the management of malignant hyperthermia crisis is not a substitute for these supportive measures.108, 115, 116
Since the combination of IV dantrolene and a calcium-channel blocking agent (e.g., diltiazem, verapamil) in anesthetized animals resulted in myocardial depression, ventricular fibrillation, and cardiovascular collapse in association with marked hyperkalemia, it is recommended that the combination of IV dantrolene and a calcium-channel blocking agent not be used during the management of malignant hyperthermia crisis. (See Drug Interactions: Calcium-Channel Blocking Agents.) If mannitol is used for the prevention or treatment of late renal complications of malignant hyperthermia, the amount of mannitol administered as part of the IV dantrolene formulation should be considered.108, 115, 116 When using the injectable suspension formulation of dantrolene sodium, a diuretic should be administered to prevent late kidney injury due to myoglobinuria because the amount of mannitol contained in the formulation is insufficient to maintain diuresis.113, 117
Following a malignant hyperthermia crisis, oral dantrolene is used for up to 3 days to prevent recurrence of manifestations of the condition;109 IV dantrolene may be used postoperatively for this purpose when oral therapy is not practical or feasible.108, 115, 116
Dantrolene also has been used orally and/or IV prior to surgery to prevent or attenuate the development of malignant hyperthermia crisis in individuals thought to be at risk;108, 109, 115, 116, 117 however, prophylactic use of dantrolene no longer is recommended because of adverse effects and questionable benefit.114, 119 Vital signs should be monitored in patients receiving dantrolene preoperatively, and the usual precautions associated with surgery in susceptible patients must still be employed since malignant hyperthermia may only be attenuated rather than prevented.
Neuroleptic Malignant Syndrome
Although the manufacturer states that dantrolene currently is not indicated for the management of neuroleptic malignant syndrome (NMS)†, 108, 109 the drug has been used successfully in a limited number of patients with this syndrome.100, 101, 102, 103, 104, 105, 115, 116 The manufacturer states that fatalities have occurred in patients with NMS despite therapy with the drug.108, 109 Further study is needed to determine the efficacy and optimum dosage and route of administration of the drug in this condition.100, 101, 102, 103, 104, 105
Dantrolene was also reportedly successful for the management of a fulminant hypermetabolic reaction induced by an acute overdosage of phenelzine†.107
In one study, preoperative administration of dantrolene sodium substantially reduced the strength of succinylcholine-induced muscle fasciculations intraoperatively and decreased the incidence of postoperative muscle pain†.
Reconstitution and Administration
Dantrolene sodium is administered orally for the management of spasticity and its sequelae secondary to upper motor neuron disorders, and for prevention of the recurrence of malignant hyperthermia following initial IV therapy.109 For the acute management of malignant hyperthermia crisis, the drug is given by rapid IV injection.108, 115, 116, 117 For preoperative prophylaxis of malignant hyperthermia in patients at risk, dantrolene may be administered orally or as an IV infusion.108, 117
For IV administration, dantrolene sodium is commercially available as a lyophilized drug for injection (e.g., Dantrium®, Revonto®, or generic equivalents) or a lyophilized drug for injectable suspension (Ryanodex®) that must be reconstituted.108, 115, 116, 117 Reconstitution procedures differ based on the preparation; the manufacturer's prescribing information should be consulted for specific instructions on reconstitution, preparation, and administration of the drug.108, 115, 116, 117 Because of the high pH of dantrolene sodium injection and the potential for tissue necrosis, care must be taken to avoid extravasation.108, 115, 116, 117
Dantrolene sodium for injection is reconstituted by adding 60 mL of sterile water for injection to the vial labeled as containing 20 mg of the drug and shaking the vial until the solution is clear.108, 115, 116 Bacteriostatic water for injection, 5% dextrose injection, or 0.9% sodium chloride injection should not be used.108, 115, 116 For IV infusion, the desired volume of reconstituted solution should be transferred to an appropriate-size empty sterile IV plastic bag for administration.108, 115, 116 Reconstituted solutions should not be transferred to large glass containers for prophylactic IV infusion therapy because precipitate formation has been observed with the use of some glass containers as reservoirs.108, 115, 116 Reconstituted and transferred solutions of dantrolene sodium should be inspected visually for particulate matter and discoloration prior to administration.108, 115, 116 Cloudy solutions or those containing a precipitate should not be used. Although reconstituted solutions are stable for 6 hours, it is recommended that IV infusions of the drug be prepared immediately before administration.108, 115, 116 Reconstituted solutions should be protected from light and stored at 15-30°C or 20-25°C depending on the preparation.108, 115, 116
Dantrolene sodium for injectable suspension is reconstituted by adding 5 mL of sterile water for injection to the vial labeled as containing 250 mg of the drug and shaking the vial until an orange-colored uniform suspension is formed.117 No other solutions should be used for reconstitution.117 The reconstituted suspension should not be diluted or transferred to another container.117 After reconstitution, the drug is stable for 6 hours at 20-25°C and must be used within this time period.117 Reconstituted dantrolene sodium suspension may be administered 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, the line should be flushed to assure that there is no residual drug remaining in the catheter.117
A suspension for oral administration of a single dose may be prepared by emptying the contents of an appropriate number of dantrolene sodium capsules into fruit juice or any liquid which would serve as a vehicle. For preparation of a suspension containing multiple doses, an appropriate number of capsules may be emptied into an acidic vehicle that has suspending properties. For example, 100 mL of a suspension containing 25 mg of dantrolene sodium per 5 mL can be prepared by suspending the contents of five 100-mg capsules in a small amount of simple syrup NF.118 A solution containing 150 mg of citric acid in 10 mL of water is added to this suspension followed by addition of a sufficient volume of simple syrup NF to make 100 mL.118 The suspension must be mixed thoroughly before use.118 This suspension is stable for 2 days when refrigerated.118 Alternatively, an oral suspension containing 5 mg/mL dantrolene sodium (using ten 50-mg capsules) in citric acid and Syrup BP with or without methyl hydroxybenzoate preservative may be prepared; the suspension is stable for 30 days if protected from light and stored under refrigeration (preferable) or at room temperature.112, 118 Another extemporaneously prepared suspension of the drug in a methylcellulose-Syrup NF vehicle preserved with sodium benzoate has also been described; however, there are no published data on the stability of the suspension.106
Dosage of oral dantrolene sodium for the management of spasticity must be carefully adjusted according to the requirements and response of the patient, using the lowest dosage that produces optimal response without adverse effects.109 The manufacturer recommends a gradual dosage titration schedule in which each dosage level is maintained for 7 days to determine the patient's response.109 If no additional benefit is observed at the next higher dosage, dosage should be decreased to the previous lower dosage.109 Some patients will not respond until higher daily dosage is achieved, and therapy with doses administered 4 times daily may be necessary in some individuals.109 Because of the potential for liver toxicity with long-term use of oral dantrolene sodium, therapy should be discontinued if beneficial effects are not attained within 45 days.109
For the management of spasticity in adults, the manufacturer recommends an initial oral dantrolene sodium dosage of 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 up to 100 mg 4 times daily, but dosages exceeding this should not be used.109
For the management of spasticity in children 5 years of age or older, the manufacturer recommends an initial oral dantrolene sodium dosage of 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 up to 100 mg 4 times daily, but dosages exceeding this should not be used.109
For the management of malignant hyperthermia crisis, the minimum initial adult or pediatric dose of dantrolene sodium is 1 mg/kg administered by rapid IV injection.108, 115, 116, 117 Continuous rapid IV injections should be administered as necessary until physiologic and metabolic abnormalities subside or a maximum total IV dosage of 10 mg/kg is reached.108, 115, 116, 117 Reversal of malignant hyperthermia is usually achieved with an average total IV dosage of 2.5 mg/kg; however, the effective dosage will vary between patients based on their susceptibility to malignant hyperthermia, the amount and time of exposure to the triggering agent, and the rapidity of treatment.108 If physiologic and metabolic abnormalities reappear after initial control, the regimen may be repeated.108, 115, 116, 117 To prevent recurrence of the manifestations of malignant hyperthermia following initial IV therapy for a crisis, the manufacturer states that oral dantrolene sodium dosages of 4-8 mg/kg daily should be administered in 4 divided doses for up to 3 days after the crisis.108, 109, 115, 116 If oral therapy is not practical or feasible postoperatively, the drug may be given IV; the dose must be individualized, starting with 1 mg/kg or more as clinically indicated.108, 115, 116
For the prevention of malignant hyperthermia in adults or children thought to be at risk of developing this condition, oral dantrolene sodium dosages of 4-8 mg/kg daily may be administered in 3 or 4 divided doses for 1-2 days prior to surgery, with the last dose being given approximately 3-4 hours prior to surgery with a small amount of water.109 Dosage may be adjusted within the recommended dosage range if adverse effects (e.g., skeletal muscle weakness, sedation, GI effects) occur.109 Alternatively, an IV dose of 2.5 mg/kg may be administered over a period of approximately 1 hour (if using Dantrium®, Revonto® or generic equivalents) or at least 1 minute (if using Ryanodex®), beginning about 1.25 hours before anticipated anesthesia or surgery; additional IV doses, which must be individualized, may be given intraoperatively if necessary (e.g., appearance of manifestations of malignant hyperthermia, prolonged surgery).108, 115, 116, 117
To reduce succinylcholine-induced muscle fasciculations and postoperative muscle pain†, 100 mg of dantrolene sodium has been given orally 2 hours preoperatively in adults weighing less than 45 kg or 150 mg has been given in those weighing more than 45 kg.
Adverse effects occur quite commonly in patients who receive dantrolene, and it should be considered that the long-term safety and efficacy of dantrolene have not been established. The serious adverse effects occurring occasionally with long-term oral dantrolene therapy (e.g., hepatitis, seizures, pleural effusion with pericarditis) have not been reasonably associated with short-term IV use of the drug to date.108, 115, 116
The most common adverse effect of dantrolene is muscle weakness which rarely may result in slurring of speech, drooling, and enuresis. Other common adverse effects are drowsiness,108, 109, 115, 116, 117 dizziness,108, 109, 115, 116, 117 lightheadedness,108, 115, 116 diarrhea,109 nausea,109, 117 malaise,109 and fatigue.109 These adverse effects are usually transient, lasting up to 4 days after the initiation of oral therapy or up to 2 days after IV administration of the drug, and are generally related to the rate of increase in dosage and total daily dosage. Severe weakness and/or diarrhea may necessitate decreasing the dosage or discontinuing the drug. If diarrhea recurs after reinstitution of dantrolene at a lower dosage, the drug should probably be discontinued permanently. Thrombophlebitis, tissue necrosis secondary to extravasation, urticaria and erythema, and injection site reactions (e.g., pain, erythema, swelling) also have occurred with IV administration of the drug.108, 115, 116, 117 Adverse effects associated with the injectable suspension formulation of the drug (Ryanodex®) generally are similar to those experienced with other IV formulations; although results of a study in healthy individuals identified several adverse effects that were more frequent with Ryanodex® than with an older IV formulation of dantrolene sodium (Dantrium®), this finding was not considered to be clinically important.113, 117, 121
Oral dantrolene therapy has caused abnormal liver function test results such as increased serum AST (SGOT), ALT (SGPT), alkaline phosphatase, LDH, BUN, and total serum bilirubin concentrations which, if detected early, return to normal when the drug is discontinued. In some patients, these abnormalities may be transient even when dantrolene is continued. Fatal or nonfatal hepatitis has occurred in patients receiving dantrolene and is apparently an idiosyncratic reaction.109 In about 60% of the cases, nausea, anorexia, vomiting, and abdominal discomfort precede the onset of hepatitis. Hepatomegaly and, rarely, splenomegaly also may occur.
Symptomatic hepatitis (fatal and nonfatal) has been reported at various dosages and following various durations of dantrolene therapy.108, 109 Dantrolene-induced hepatitis occurs most frequently in patients receiving more than 300 mg daily for longer than 2 months, but even intermittent short courses of therapy with 800 mg or more daily markedly increase the risk of hepatotoxicity. Overt hepatitis has been observed most frequently between the third and twelfth month of therapy.108 The risk of dantrolene-induced hepatotoxicity is greatest in females, in patients older than 35 years of age, and in patients receiving other drugs (particularly estrogens) concomitantly. The risk of dantrolene-induced hepatotoxicity possibly may be increased in patients with baseline liver function test abnormalities and in geriatric patients.109 (See Cautions: Geriatric Precautions.)
IV dantrolene therapy is associated with skeletal muscle weakness (e.g., loss of grip strength, leg weakness).108, 117 Dysphagia also has been reported.108, 117
In addition to diarrhea, other adverse GI effects that have been reported with oral dantrolene include anorexia, nausea, vomiting, gastric irritation, abdominal cramps, constipation (which rarely progresses to signs of intestinal obstruction), difficulty in swallowing, and GI bleeding.109 Severe constipation has occasionally resulted in abdominal distention and signs of bowel obstruction. These symptoms usually have responded to reduction of dosage and/or discontinuance of the drug. Although a causal relationship to dantrolene was not established, adynamic ileus and death occurred in one patient receiving the drug.
Adverse nervous system effects of oral dantrolene include speech disturbance, headache, visual disturbances including diplopia, alteration of taste, mental depression, confusion, auditory and visual hallucinations, increased nervousness, insomnia, drooling, and exacerbation or precipitation of seizures. In addition, drowsiness and dizziness have been associated with IV administration of dantrolene in healthy individuals.108, 115, 116, 117 Concomitant use of dantrolene and other CNS depressants may cause additive CNS effects.109, 117 (See Drug Interactions: CNS Depressants.)
Adverse urogenital effects of oral dantrolene include increased urinary frequency, urinary incontinence and/or nocturia, difficult urination and/or urinary retention, crystalluria, hematuria, and difficult erection.109
Dermatologic and Sensitivity Reactions
Adverse dermatologic effects of oral dantrolene include abnormal hair growth, acneiform rash, eczematoid eruption, pruritus, urticaria, and sweating.109 There have also been rare reports of urticaria and erythema possibly associated with IV dantrolene.108 Injection site reactions (pain, erythema, swelling), commonly due to extravasation, also have been reported with IV dantrolene.108, 115, 116, 117 Pleural effusions with associated eosinophilia or with pericarditis have been reported with oral dantrolene, 109 and anaphylaxis has been reported with both IV and oral dantrolene.108, 109, 115, 116, 117
Adverse cardiovascular effects of oral dantrolene include tachycardia, erratic blood pressure, phlebitis, and heart failure.109
Dantrolene therapy has been associated with respiratory depression, a feeling of suffocation, dyspnea, respiratory muscle weakness, and decreased inspiratory capacity.109, 117 Rarely, pulmonary edema has developed during the treatment of malignant hyperthermia crisis in which the diluent volume and amount of mannitol associated with the IV dantrolene sodium dose may have contributed.108, 115, 116
Adverse hematologic effects of oral dantrolene include aplastic anemia, anemia, leukopenia, lymphocytic lymphoma, and thrombocytopenia.109
Other reported adverse effects of oral dantrolene include backache, myalgia, excessive tearing, chills, and fever.109
Chronic administration of high doses of dantrolene has caused reversible growth or weight depression and possible nephrotoxicity in some animal species.109
Precautions and Contraindications
Since dantrolene may cause severe hepatotoxicity, the manufacturer states that the drug should not be used in patients with conditions other than those for which such therapy is recommended.109 Serum AST (SGOT), ALT (SGPT), alkaline phosphatase, and total serum bilirubin concentrations should be determined prior to oral dantrolene therapy, and tests should be repeated periodically during therapy or whenever symptoms of hepatitis occur. If liver function test abnormalities occur alone, dantrolene should usually be discontinued; the drug should be continued or reinstituted only if major benefits occurred during dantrolene therapy. If symptoms of hepatitis are accompanied by liver function test abnormalities or jaundice, dantrolene should be discontinued. Dantrolene therapy has been resumed in a few patients who developed clinical and/or laboratory evidence of hepatotoxicity; if therapy is reinstituted, it should only be in patients who clearly need dantrolene and only after symptoms and laboratory abnormalities have cleared. The patient should be hospitalized and therapy should be initiated with very small doses and gradually increased with frequent monitoring of liver function; dantrolene should be discontinued immediately if signs of liver abnormality recur. Dantrolene should be used with particular caution in females, in patients older than 35 years of age, and in those receiving other drugs (especially estrogens) concomitantly, since the risk of hepatotoxicity may be increased in these groups of patients. The drug should be used with caution in patients with a history of previous liver disease or dysfunction.
Dantrolene should be used with caution in patients with severely impaired cardiac function due to myocardial disease or with impaired pulmonary function (particularly those with obstructive pulmonary disease). Patients should be monitored for adequate ventilation since respiratory muscle weakness and other respiratory effects may occur.117 Patients who engage in potentially hazardous activities requiring mental alertness or physical coordination such as operating machinery or driving a motor vehicle should be warned about possible weakness, drowsiness, or dizziness; since these effects may persist for up to 2 days following IV administration of dantrolene, patients should not drive a motor vehicle or engage in other potentially hazardous activities during such a time period. The drug should be administered with caution in patients receiving other drugs that can produce drowsiness (e.g., diazepam). Patients should be advised that decreased grip strength and leg muscle weakness, particularly upon walking down stairs, may be expected to occur postoperatively. Patients should not ambulate without assistance until normal strength and balance return.117 Caution should be employed at meals during the day(s) of dantrolene administration since choking and difficulty in swallowing have been reported. Dantrolene may cause photosensitivity reactions, so patients should be warned against excessive or unnecessary exposure to sunlight.
Dantrolene is contraindicated in patients who must utilize spasticity to maintain upright posture and balance in moving or when spasticity is utilized to obtain or maintain increased body function. The drug is also contraindicated in patients with upper motor neuron disorders and active hepatic disease such as hepatitis and cirrhosis. There are no contraindications to the use of IV dantrolene sodium in the prophylaxis or management of malignant hyperthermia crisis.
The long-term safety of orally administered dantrolene sodium in children younger than 5 years of age has not been established.109 Before initiating long-term oral therapy in pediatric patients, the possibility that adverse effects may only become evident after many years should be weighed against the potential benefit to the patient.109
Clinical studies of dantrolene did not include sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger patients.108, 109, 115, 116, 117 While other clinical experience has not revealed age-related differences in response or tolerance, dosage generally should be titrated carefully in geriatric patients, usually initiating therapy at the low end of the dosage range.108, 109, 115, 116, 117 The greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly also should be considered.108, 115, 116, 117 Spontaneous reports suggest that geriatric patients receiving oral dantrolene may have a higher risk of hepatic events with fatal outcomes; however, the majority of these reports were complicated by confounding factors (e.g., comorbid illnesses, concomitant use of hepatotoxic drugs).109
Mutagenicity and Carcinogenicity
Dantrolene sodium has produced positive results in microbial mutagen (Ames) tests using Salmonella typhimurium with and without liver metabolic activation.108, 109, 115, 116, 117
One strain of female rats receiving oral dantrolene sodium dosages of 15, 30, and 60 mg/kg daily for 18 months showed an increased incidence of malignant and nonmalignant mammary tumors and, at the highest dosage level (approximately equal to the maximum recommended human daily dosage on a mg/m2 basis) an increased incidence of hepatic lymphangiomas and angiosarcomas.108, 109, 115, 116, 117 The only drug-related effect seen in 30-month carcinogenicity studies in rats was a dose-related decrease in the time of onset of mammary and/or testicular tumors.108, 109, 115, 116, 117 Carcinogenic effects were not seen in mice receiving the drug.108, 109, 115, 116, 117 The relevance of these findings to human toxicity is not known.108, 109, 115, 116, 117
Pregnancy, Fertility, and Lactation
There are no adequate and well-controlled studies of dantrolene in pregnant women.108, 109, 115, 116, 117 The drug has been shown to be embryocidal in rabbits and to decrease pup survival in rats when given at doses 7 times the human oral dose.108, 115, 116, 117 Dantrolene sodium readily crosses the placenta but, when given to pregnant women at term in a dosage of 100 mg daily, no adverse respiratory or neuromuscular effects were detected at low dose in neonates born to these women.108, 109, 115, 116 Further studies are needed, particularly with higher dosages.108, 109, 115, 116, 117 Dantrolene should not be used in women who are or may become pregnant unless the possible benefits outweigh the potential risks to the fetus.108, 109, 115, 116, 117
Dantrolene sodium administered to male and female rats at dose levels up to 45 mg/kg daily (approximately 1.4 times the maximum recommended human daily dosage on a mg/m2 basis) showed no adverse effects on fertility or general reproductive performance.108, 115, 116, 117
Dantrolene is distributed into human milk.108, 115, 116, 117 Because of the potential for serious adverse effects in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.108, 115, 116, 117
Drugs Affecting Hepatic Microsomal Enzymes
Dantrolene is metabolized by the liver, and it is theoretically possible that its metabolism may be enhanced by drugs known to induce hepatic microsomal enzymes.108, 109, 115, 116, 117 However, neither phenobarbital nor diazepam appears to affect dantrolene metabolism.108, 109, 115, 116, 117
Calcium-Channel Blocking Agents
While cardiovascular collapse following concomitant use of dantrolene and verapamil is rare,109 it has been reported in patients receiving such concomitant therapy.108, 115, 116, 117 In anesthetized animals (e.g., swine, dogs), IV administration of dantrolene and a calcium-channel blocking agent (e.g., diltiazem, verapamil) has resulted in myocardial depression, ventricular fibrillation, and cardiovascular collapse in association with marked hyperkalemia.109, 110 In addition, metabolic changes (i.e., hyperglycemia, hyperkalemia) accompanied by decreased cardiac output and metabolic acidosis have been reported following preoperative administration of IV dantrolene in at least one diabetic patient already receiving oral verapamil therapy.110, 111 Consequently, concomitant use of dantrolene and a calcium-channel blocking agent during the management of malignant hyperthermia is not recommended by the manufacturers.108, 109, 115, 116, 117
Dantrolene may be additive with, or may potentiate the action of, other CNS depressants such as sedatives and tranquilizing agents.109, 117 When dantrolene is used concomitantly with other CNS depressants, caution should be used to avoid excessive sedation.109
Hepatotoxicity has occurred more frequently in women over 35 years of age receiving concomitant dantrolene and estrogen therapy.109 Although the potential for an interaction between these agents has not been clearly established, caution should be observed if the 2 drugs are used concomitantly.109
Concomitant use of dantrolene and muscle relaxants may potentiate the neuromuscular block.117
Plasma protein binding of dantrolene is increased by tolbutamide and is decreased by warfarin and clofibrate, but does not appear to be substantially affected by diazepam or phenytoin.108, 115, 116, 117
Dantrolene reportedly potentiates vecuronium bromide-induced neuromuscular blockade.108, 109, 115, 116
Overdosage of dantrolene produces symptoms that include muscular weakness and alterations in the state of consciousness (e.g., lethargy, coma), vomiting, diarrhea, and crystalluria.108, 109, 115, 116, 117
Overdosage of oral dantrolene sodium should be treated conservatively with supportive measures, gastric lavage, and close observation of the patient. An adequate airway should be maintained and artificial respiration facilities should be readily available. ECG monitoring and large quantities of IV fluids to avoid crystalluria should be instituted. The efficacy of dialysis in the treatment of dantrolene sodium overdosage is unknown.108, 109, 115, 116, 117
Dantrolene causes skeletal muscle relaxation through a direct effect on skeletal muscle.108, 109, 115, 116, 117, 119 In vitro experiments on animal tissue indicate that the drug may act by reducing the release of calcium from the sarcoplasmic reticulum by the muscle action potential, resulting in a decreased response of the muscle to the action potential and a decreased muscle contraction. Therefore, in patients with upper motor neuron disorders, dantrolene decreases muscle contractions caused by direct stimulation as well as those mediated through monosynaptic and polysynaptic reflexes. In patients with anesthesia-induced malignant hyperthermia, the drug's interference with the release of calcium from the sarcoplasmic reticulum to the myoplasm may prevent the increase in myoplasmic calcium which activates the acute catabolism in the skeletal muscle cell.108, 115, 116, 117 The drug has no effect on the electrical activity at the myoneural junction or within the muscle, nor does it affect the rate of acetylcholine synthesis or release. The extent of CNS involvement in muscle relaxation produced by dantrolene is not known. It has been postulated that adverse CNS effects such as drowsiness and dizziness may be caused indirectly as a result of decreased skeletal muscle activity. Dantrolene has little or no effect on the contraction of cardiac or intestinal smooth muscle, except possibly with higher concentrations than those required for effects on skeletal muscle contraction.
In patients with upper motor neuron disorders, the drug produces generalized, mild weakness of skeletal muscles, decreases the force of reflex muscle contractions, and decreases hyperreflexia, clonus, muscle stiffness, spasticity, and phasic involuntary movements. Improvement in motor performance of the upper extremities may occur as evidenced by decreased resistance to passive motion and increased active and passive range of motion.
Oral bioavailability of dantrolene sodium is 70%.119, 120 The absorption half-life has been reported to average 1.1 hours in adults and 1.4 hours in children. In patients with upper motor neuron disorders, beneficial effects of dantrolene may not become apparent for a week or more after institution of therapy in the usual initial oral dosage. Therapeutically effective blood concentrations of dantrolene and its metabolites appear to vary with the individual, but have been reported to range from 100-600 ng/mL or more. The blood concentration which is attained after oral administration varies widely among patients, but peak concentrations are usually attained about 5 hours after oral administration. In a study in 6 patients who received a single 100-mg oral dose, peak blood concentrations ranged from 0.7-1.45 mcg/mL. When dantrolene is administered IV as recommended for prophylaxis, blood concentrations of the drug remain at approximately steady-state levels for 3 or more hours after the infusion is completed.108, 115, 116, 117
Substantial amounts of dantrolene are bound to plasma proteins, principally albumin.108, 115, 116, 117 The drug readily crosses the placenta.108, 109, 115, 116, 117
The plasma half-life of dantrolene in adults is 8.7 hours after a single 100-mg dose.109 In a study in children with chronic spasticity, the estimated plasma half-life was 7.3 hours after a single dose. The mean plasma half-life of IV dantrolene is variable (range: 4-11.4 hours) depending on the preparation.108, 115, 116, 117
Dantrolene is metabolized in the liver primarily to the 5-hydroxy derivative which is less active than the parent drug. Dantrolene is also metabolized by reductive pathways to the amino derivative which has considerably less skeletal muscle relaxant effect than does dantrolene; the amino derivative is acetylated to the acetamido derivative. Dantrolene also may undergo hydrolysis and subsequent oxidation to form nitrophenylfuroic acid.108, 115, 116, 117 Dantrolene and its metabolites are excreted mainly in urine and bile.119
Dantrolene sodium is a hydantoin derivative which is chemically and pharmacologically unrelated to other skeletal muscle relaxants. Dantrolene sodium, which is commercially available as the hydrate, occurs as an orange powder and is slightly soluble in water. Dantrolene is a weak acid with a pKa of about 7.5. The sodium salt of the drug hydrolyzes in aqueous solution to form a precipitate of dantrolene.
Sodium hydroxide is added during manufacture of the commercially available lyophilized powder for injection to adjust the pH.108, 115, 116 Each 20-mg vial of dantrolene sodium for injection also contains 3 g of mannitol.108, 115, 116 When reconstituted with 60 mL of sterile water for injection, the injection has a pH of about 9.5.108, 115, 116
Sodium hydroxide or hydrochloric acid is added during manufacture of the commercially available lyophilized powder for injectable suspension to adjust the pH.117 Each 250-mg vial of dantrolene sodium for injectable suspension contains 125 mg of mannitol.117 When reconstituted with 5 mL of sterile water for injection, the suspension has a pH of about 10.3.117
Dantrolene sodium capsules should be stored at a controlled room temperature of 20-25°C.109 The powder for injection should be stored at controlled room temperature between 20-25°C, and the powder for injectable suspension should be stored at 20-25°C, but may be exposed to 15-30°C; prolonged exposure to light should be avoided.108, 115, 116, 117
Following reconstitution with 60 mL of sterile water for injection, dantrolene sodium injection (Dantrium®) is stable for 6 hours when stored at 15-30°C; Revonto® and generic equivalents are stable for 6 hours when stored at 20-25°C after reconstitution.108, 115, 116 Following reconstitution with 5 mL of sterile water for injection, dantrolene sodium injectable suspension (Ryanodex®) is stable for 6 hours when stored at 20-25°C.117 The reconstituted IV solution or suspension should be protected from direct light and used within 6 hours after reconstitution.108, 115, 116, 117
Dantrolene sodium injection is not compatible with 5% dextrose or 0.9% sodium chloride injection;108, 115, 116 however, the injectable suspension formulation of the drug is compatible with small amounts of 5% dextrose or 0.9% sodium chloride injection when administered into the IV catheter of a freely running IV infusion of these solutions.113, 117
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.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Capsules | 25 mg* | ||
Dantrolene Sodium Capsules | ||||
50 mg* | Dantrium® | Par | ||
Dantrolene Sodium Capsules | ||||
100 mg* | Dantrium® | Par | ||
Dantrolene Sodium Capsules | ||||
Parenteral | For injection | 20 mg* | Dantrium® Intravenous | Par |
For injectable suspension | 250 mg |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Only references cited for selected revisions after 1984 are available electronically.
48. Schmidt RT, Lee RH, Spehlmann R. Comparison of dantrolene sodium and diazepam in the treatment of spasticity. J Neurol Neurosurg Psychiatry . 1976; 39:350-6. [PubMed 778344]
49. Glass A, Hannah A. A comparison of dantrolene sodium and diazepam in the treatment of spasticity. Paraplegia . 1974; 12:170-4. [PubMed 4616209]
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. [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. [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. [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. [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. [PubMed 3944965]
108. Par Pharmaceutical. Dantrium® IV (dantrolene sodium) for injection prescribing information. Chestnut Ridge, NY; 2016 Jul.
109. Par Pharmaceutical. Dantrium® (dantrolene sodium) capsules prescribing information. Chestnut Ridge, NY; 2015 Oct.
110. Rubin AS, Zablocki AD. Hyperkalemia, verapamil, and dantrolene. Anesthesiology . 1987; 66:246-9. [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.
112. Fawcett JP, Stark G, Tucker IG et al. Stability of dantrolene oral suspension prepared from capsules. J Clin Pharm Ther . 1994; 19:349-53. [PubMed 7876365]
113. Food and Drug Administration. Center for Drug Evaluation and Research: Application number 205579Orig1s000: summary review. From FDA website. [Web]
114. Malignant Hyperthermia Association of the United States. FAQs: Should MHS patients be pretreated with Dantrolene?. From MHAUS website. Accessed 2018 Jan 17. [Web]
115. Westward Pharmaceuticals. Dantrolene sodium for injection prescribing information. Eatontown, NJ; 2017 Oct.
116. US WorldMeds. Revonto® (dantrolene sodium) for injection prescribing information. Louisville, KY; 2016 Oct.
117. Eagle Pharmaceuticals. Ryanodex® (dantrolene sodium) for injectable suspension prescribing information. Woodcliff Lake, NJ; 2016 Oct.
118. Nahata MC, Pai VB. Pediatric drug formulations. 6th ed., revised. Cincinnati, Ohio: Harvey Whitney Books Company; 2014.
119. Krause T, Gerbershagen MU, Fiege M et al. Dantrolene--a review of its pharmacology, therapeutic use and new developments. Anaesthesia . 2004; 59:364-73. [PubMed 15023108]
120. Allen GC, Cattran CB, Peterson RG et al. Plasma levels of dantrolene following oral administration in malignant hyperthermia-susceptible patients. Anesthesiology . 1988; 69:900-4. [PubMed 3057938]
121. . Ryanodex--A New Dantrolene Formulation for Malignant Hyperthermia. Med Lett Drugs Ther . 2015; 57:100. [PubMed 26147894]
122. Food and Drug Administration. FDA Application: Search Orphan Drug Designations and Approvals. Silver Spring, MD. From FDA website. Accessed 2017 Dec 18. [Web]
123. Taricco M, Pagliacci MC, Telaro E et al. Pharmacological interventions for spasticity following spinal cord injury: results of a Cochrane systematic review. Eura Medicophys . 2006; 42:5-15. [PubMed 16565680]
124. Thompson AJ, Jarrett L, Lockley L et al. Clinical management of spasticity. J Neurol Neurosurg Psychiatry . 2005; 76:459-63. [PubMed 15774425]
125. Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society, Delgado MR, Hirtz D et al. Practice parameter: pharmacologic treatment of spasticity in children and adolescents with cerebral palsy (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology . 2010; 74:336-43. [PubMed 20101040]
126. Chang E, Ghosh N, Yanni D et al. A Review of Spasticity Treatments: Pharmacological and Interventional Approaches. Crit Rev Phys Rehabil Med . 2013; 25:11-22. [PubMed 25750484]
127. Abbruzzese G. The medical management of spasticity. Eur J Neurol . 2002; 9 Suppl 1:30-4; discussion 53-61. [PubMed 11918647]
128. Shakespeare DT, Boggild M, Young C. Anti-spasticity agents for multiple sclerosis. Cochrane Database Syst Rev . 2003; :CD001332. [PubMed 14583932]
129. Elbasiouny SM, Moroz D, Bakr MM et al. Management of spasticity after spinal cord injury: current techniques and future directions. Neurorehabil Neural Repair . 2010; 24:23-33. [PubMed 19723923]
130. Taricco M, Adone R, Pagliacci C et al. Pharmacological interventions for spasticity following spinal cord injury. Cochrane Database Syst Rev . 2000; :CD001131. [PubMed 10796750]
131. Francisco GE, McGuire JR. Poststroke spasticity management. Stroke . 2012; 43:3132-6. [PubMed 22984012]