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dantrolene sodium 25 mg cap generic dantrium

In stock Manufacturer PAR PHARM. 49884036201
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Uses

Spasticity

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 syndrome. 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.

In the management of spasticity, dantrolene is particularly useful in patients whose functional rehabilitation has been slowed by the sequelae of spasticity. For the drug to be beneficial, such patients must have presumably reversible spasticity where relief of spasticity will aid in restoring residual function. 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.

There are no well-controlled clinical studies comparing the efficacy of baclofen and dantrolene; baclofen may cause less severe adverse effects than does dantrolene. Dantrolene and diazepam are about equally effective in spasticity caused by various upper motor neuron disorders; however, diazepam causes drowsiness more frequently than does dantrolene and dantrolene causes more muscle weakness than does diazepam. Therefore, dantrolene may be preferred in patients who are easily sedated and have marginal cerebral function whereas diazepam may be preferred in those with borderline muscle strength. Concomitant administration of dantrolene and diazepam has produced better control of spasticity in some patients than either drug alone and enabled a decrease in the dosage of either or both drugs. It should be kept in mind that concomitant therapy with dantrolene and diazepam may cause an additive sedative effect.(See Cautions: Precautions and Contraindications.)

Malignant Hyperthermia Crisis

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. 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 should be discontinued immediately and IV dantrolene therapy initiated. IV dantrolene is used in conjunction with supportive measures which include administering oxygen, treating metabolic acidosis, and instituting cooling procedures if necessary; urinary output should be maintained and serum electrolytes should be monitored. The use of IV dantrolene in the management of malignant hyperthermia crisis is not a substitute for these supportive measures. Since the combination of IV dantrolene and a calcium-channel blocking agent (e.g., diltiazem, verapamil) in anesthetized animals resulted in myocardial depression, in 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.

Following a malignant hyperthermia crisis, oral dantrolene is used for up to 3 days to prevent recurrence of manifestations of the condition; IV dantrolene may be used postoperatively for this purpose when oral therapy is not practical or feasible. Dantrolene may also be administered orally and/or IV preoperatively to prevent or attenuate the manifestations of malignant hyperthermia crisis in individuals thought to be at risk; when administered IV preoperatively, additional IV doses may be necessary intraoperatively if early signs of malignant hyperthermia develop or if surgery is prolonged. 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, the drug has been used successfully in a limited number of patients with this syndrome. The manufacturer states that fatalities have occurred in patients with neuroleptic malignant syndrome despite therapy with the drug. Further study is needed to determine the efficacy and optimum dosage and route of administration of the drug in this condition.

Other Uses

Dantrolene was also reportedly successful for the management of a fulminant hypermetabolic reaction induced by an acute overdosage of phenelzine.

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.

Dosage and Administration

Reconstitution and Administration

Dantrolene sodium is administered orally for the management of spasticity and its sequelae secondary to upper motor neuron disorders, for preoperative prophylaxis of malignant hyperthermia crisis in patients at risk, and to prevent recurrence of the manifestations of malignant hyperthermia following initial IV therapy. For the acute management of malignant hyperthermia crisis, the drug is given by rapid IV injection. For preoperative prophylaxis of malignant hyperthermia crisis in patients at risk, dantrolene may also be given by IV infusion over approximately 1 hour beginning about 1.25 hours before anticipated anesthesia. Because of the high pH of dantrolene sodium injection, care must be taken to avoid extravasation.

For IV administration, dantrolene sodium 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. The resultant solution contains 0.333 mg of dantrolene sodium per mL. Bacteriostatic water for injection, 5% dextrose injection, or 0.9% sodium chloride injection should not be used. For IV infusion, the desired volume of reconstituted solution should be transferred to an appropriate-size empty sterile IV plastic bag for administration. 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. Reconstituted and transferred solutions of dantrolene sodium should be inspected visually for particulate matter and discoloration prior to administration. 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.

A suspension for oral administration of a single dose may be prepared by emptying the contents of an appropriate number of 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 50 mL of Syrup NF. 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 Syrup NF to make 100 mL. The suspension must be mixed thoroughly before use. There are no published data on the stability of this suspension, but it is probably stable for several days when refrigerated; since the preparation does not contain preservatives, care should be taken to avoid contamination. Another extemporaneously prepared suspension of the drug in a methylcellulose-Syrup NF vehicle preserved with sodium benzoate has also been described; however, like the other preparation, there are no published data on the stability of the suspension.

Dosage

Spasticity

Adult Dosage

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. The manufacturer recommends a gradual dosage titration schedule in which each dosage level is maintained for 7 days to determine the patient's response. If no additional benefit is observed at the next higher dosage, dosage should be decreased to the previous lower dosage. 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. 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.

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. Some patients may require up to 100 mg 4 times daily, but dosages exceeding this should not be used.

Pediatric Dosage

For the management of spasticity in children older than 5 years of age, 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. Pediatric dosage should not exceed 100 mg 4 times daily.

Malignant Hyperthermia Crisis

For prevention or attenuation of malignant hyperthermia crisis in adults or children thought to be at risk of developing this condition, oral dantrolene sodium dosages of 4-8 mg/kg daily are 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. Alternatively, a dose of 2.5 mg/kg may be infused IV over a period of approximately 1 hour beginning about 1.25 hours before anticipated anesthesia; additional IV doses, which must be individualized, may be given intraoperatively if necessary.

For the management of malignant hyperthermia crisis, the minimum initial adult or pediatric dose of dantrolene sodium is 1 mg/kg administered rapidly IV. The initial dose may be repeated as necessary until physiologic and metabolic abnormalities subside or a maximum total IV dosage of 10 mg/kg is reached. Reversal of malignant hyperthermia is usually achieved with an average total IV dosage of 2.5 mg/kg. If physiologic and metabolic abnormalities reappear after initial control, the regimen may be repeated. To prevent recurrence of the manifestations of malignant hyperthermia following initial IV therapy for a crisis, oral dantrolene sodium dosages of 4-8 mg/kg daily are administered in 4 divided doses for up to 3 days after the crisis. 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.

Other Uses

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.

Cautions

Adverse effects occur quite commonly in patients who receive dantrolene, and it should be kept in mind 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.

The most common adverse effect of dantrolene sodium is muscle weakness which rarely may result in slurring of speech, drooling, and enuresis. Other common adverse effects are drowsiness, dizziness, lightheadedness, diarrhea, nausea, malaise, and fatigue. 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.

Hepatic Effects

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. 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. 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. 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.

GI Effects

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. 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.

Nervous System Effects

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, loss of grip strength, weakness in the legs, drowsiness, and dizziness have been associated with IV administration of dantrolene in healthy individuals.

Urogenital Effects

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.

Dermatologic and Sensitivity Reactions

Adverse dermatologic effects of oral dantrolene include abnormal hair growth, acneiform rash, eczematoid eruption, pruritus, urticaria, and sweating. There have also been rare reports of urticaria and erythema possibly associated with IV dantrolene. In addition, pleural effusion with pericarditis has been reported with oral dantrolene, and anaphylaxis has been reported with both IV and oral dantrolene.

Cardiovascular Effects

Adverse cardiovascular effects of oral dantrolene include tachycardia, erratic blood pressure, phlebitis, and heart failure.

Hematologic Effects

Adverse hematologic effects of oral dantrolene include aplastic anemia, anemia, leukopenia, lymphocytic lymphoma, and thrombocytopenia.

Other Adverse Effects

Other reported adverse effects of oral dantrolene include backache, myalgia, excessive tearing, chills and fever, respiratory depression, and a feeling of suffocation. Thrombophlebitis has occurred with IV dantrolene. 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 dose may have contributed.

Chronic administration of high doses of dantrolene has caused reversible growth or weight depression and possible nephrotoxicity in some animal species.

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. 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 sodium 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 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). It will sometimes be appropriate to tell patients who receive IV dantrolene that decreased grip strength and leg muscle weakness, particularly upon walking down stairs, can be expected to occur postoperatively. 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 sodium 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.

Pediatric Precautions

The long-term safety of orally administered dantrolene sodium in children younger than 5 years of age has not been established. 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.

Geriatric Precautions

Clinical studies of IV dantrolene did not include sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger patients. While other clinical experience has not revealed age-related differences in response or tolerance, drug dosage generally should be titrated carefully in geriatric patients, usually initiating therapy at the low end of the dosage range. 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.

Mutagenicity and Carcinogenicity

Dantrolene sodium has produced positive results in microbial mutagen (Ames) tests using Salmonetta typhimurium with and without liver metabolic activation.

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/m basis) an increased incidence of hepatic lymphangiomas and angiosarcomas. The only drug-related effect seen in 30-month carcinogenicity studies in 2 strains of rats was a dose-related decrease in the time of onset of mammary and/or testicular tumors. Carcinogenic effects were not seen in mice receiving the drug. The relevance of these findings to human toxicity is not known.

Pregnancy, Fertility, and Lactation

Pregnancy

Safe use of dantrolene during pregnancy has not been clearly established. 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. There are no adequate and well-controlled studies using dantrolene in pregnant women. The drug 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 in neonates born to these women. Further studies are needed, particularly with higher dosages. Dantrolene should not be used in women who are or may become pregnant unless the possible benefits outweigh the potential risks to the fetus.

Fertility

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/m basis) showed no adverse effects on fertility or general reproductive performance.

Lactation

Dantrolene should not be administered to nursing women.

Drug Interactions

Calcium-Channel Blocking Agents

Cardiovascular collapse following concomitant use of dantrolene and verapamil is rare. 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. 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. Consequently, concomitant use of IV dantrolene and a calcium-channel blocking agent during the management of malignant hyperthermia crisis is not recommended by the manufacturer.

Vecuronium Bromide

Dantrolene reportedly potentiates vecuronium bromide-induced neuromuscular blockade.

CNS Depressants

Dantrolene may be additive with, or may potentiate the action of, other CNS depressants such as sedatives and tranquilizing agents. When dantrolene is used concomitantly with other CNS depressants, caution should be used to avoid excessive sedation.

Estrogens

Hepatotoxicity has occurred more frequently in women over 35 years of age receiving concomitant dantrolene and estrogen therapy. 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.

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. However, neither phenobarbital nor diazepam appears to affect dantrolene metabolism.

Protein-Bound Drugs

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, phenytoin, or phenylbutazone (no longer commercially available in the US).

Pharmacokinetics

Absorption

An average of about 35% of an oral dose of dantrolene sodium is absorbed from the GI tract. 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.

Distribution

Substantial amounts of dantrolene are bound to plasma proteins, principally albumin. The drug readily crosses the placenta.

Elimination

The plasma half-life of dantrolene in healthy adults is reported to be about 8.7 hours after a single 100-mg oral dose. In a study in children with chronic spasticity, the estimated plasma half-life was 7.3 hours after a single dose.

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 may also undergo hydrolysis and subsequent oxidation to form nitrophenylfuroic acid. The manufacturer states that metabolism of dantrolene does not appear to be affected by concurrent administration of phenobarbital or diazepam. Dantrolene is excreted in urine, mainly as metabolites.

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