Dantrolene Sodium

Dantrolene Sodium

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Questions & Answers

Side Effects & Adverse Reactions

It is important to recognize that fatal and non-fatal liver disorders of an idiosyncratic or hypersensitivity type may occur with dantrolene sodium therapy.

At the start of dantrolene sodium therapy, it is desirable to do liver function studies (SGOT, SGPT, alkaline phosphatase, total bilirubin) for a baseline or to establish whether there is pre-existing liver disease. If baseline liver abnormalities exist and are confirmed, there is a clear possibility that the potential for dantrolene sodium hepatotoxicity could be enhanced, although such a possibility has not yet been established.

Liver function studies (e.g., SGOT or SGPT) should be performed at appropriate intervals during dantrolene sodium therapy. If such studies reveal abnormal values, therapy should generally be discontinued. Only where benefits of the drug have been of major importance to the patient, should reinitiation or continuation of therapy be considered. Some patients have revealed a return to normal laboratory values in the face of continued therapy while others have not.

If symptoms compatible with hepatitis, accompanied by abnormalities in liver function tests or jaundice appear, dantrolene sodium should be discontinued. If caused by dantrolene sodium and detected early, the abnormalities in liver function characteristically have reverted to normal when the drug was discontinued.

Dantrolene sodium therapy has been reinstituted in a few patients who have developed clinical and/or laboratory evidence of hepatocellular injury. If such reinstitution of therapy is done, it should be attempted only in patients who clearly need dantrolene sodium and only after previous symptoms and laboratory abnormalities have cleared. The patient should be hospitalized and the drug should be restarted in very small and gradually increasing doses. Laboratory monitoring should be frequent and the drug should be withdrawn immediately if there is any indication of recurrent liver involvement. Some patients have reacted with unmistakable signs of liver abnormality upon administration of a challenge dose, while others have not.

Dantrolene sodium should be used with particular caution in females and in patients over 35 years of age in view of apparent greater likelihood of drug-induced, potentially fatal, hepatocellular disease in these groups. Spontaneous reports suggest a higher proportion of hepatic events with fatal outcome in elderly patients receiving dantrolene sodium. However, the majority of these cases were complicated with confounding factors such as intercurrent illnesses and/or concomitant potentially hepatotoxic medications (see Geriatric Use subsection).

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term safety of dantrolene sodium in humans has not been established. Chronic studies in rats, dogs, and monkeys at dosages greater than 30 mg/kg/day showed growth or weight depression and signs of hepatopathy and possible occlusion nephropathy, all of which were reversible upon cessation of treatment. Sprague-Dawley female rats fed dantrolene sodium for 18 months at dosage levels of 15, 30, and 60 mg/kg/day showed an increased incidence of benign and malignant mammary tumors compared with concurrent controls. At the highest dose level, there was an increase in the incidence of benign lymphatic neoplasms. In a 30-month study at the same dose levels also in Sprague-Dawley rats, dantrolene sodium produced a decrease in the time of onset of mammary neoplasms. Female rats at the highest dose level showed an increased incidence of hepatic lymphangiomas and hepatic angiosarcomas.

The only drug-related effect seen in a 30-month study in Fischer-344 rats was a dose-related reduction in the time of onset of mammary and testicular tumors. A 24-month study in HaM/ICR mice revealed no evidence of carcinogenic activity. Carcinogenicity in humans cannot be fully excluded, so that this possible risk of chronic administration must be weighed against the benefits of the drug (i.e., after a brief trial) for the individual patient.

Dantrolene sodium has produced positive results in the Ames S. Typhimurium bacterial mutagenesis assay in the presence and absence of a liver activating system.

Pregnancy
Pregnancy Category C

Adequate animal reproduction studies have not been conducted with dantrolene sodium. It is also not known whether dantrolene sodium can cause fatal harm when administered to a pregnant woman or can affect reproduction capacity. Dantronlene sodium should be given to a pregnant woman only if clearly needed.

Labor and Delivery

In one non-randomized open-label study, 21 term pregnant patients received prophylactic oral dantrolene sodium 100 mg per day for 2 to 10 days prior to delivery. Dantrolene readily crossed the placenta with maternal and fetal whole blood levels approximately equal at delivery; neonatal levels then fell approximately 50% per day for 2 days before declining sharply. No neonatal respiratory and neuromuscular side effects were detected at low dose. More data, at higher doses, are needed before more definitive conclusions can be made.

Nursing Mothers

Dantrolene sodium should not be used in nursing mothers.

Usage in Pediatric Patients

The long-term safety of dantrolene sodium in pediatric patients under the age of 5 years has not been established. Because of the possibility that adverse effects of the drug could become apparent only after many years, a benefit-risk consideration of the long-term use of dantrolene sodium is particularly important in pediatric patients.

Geriatric Use

Clinical studies of dantrolene sodium did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience in the literature has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. As with all patients receiving dantrolene sodium, it is recommended that elderly patients receive the lowest dose compatible with the optimal response. Spontaneous reports suggest a higher proportion of hepatic events with fatal outcome in elderly patients receiving dantrolene sodium. However, the majority of these cases were complicated with confounding factors such as intercurrent illnesses and/or concomitant potentially hepatotoxic medications (for hepatotoxicity details and its management see Black Box and Warnings Sections).

Drug Interactions

Drowsiness may occur with dantrolene sodium therapy, and the concomitant administration of CNS depressants such as sedatives and tranquilizing agents may result in further drowsiness.

While a definite drug interaction with estrogen therapy has not yet been established, caution should be observed if the two drugs are to be given concomitantly. Hepatotoxicity has occurred more often in women over 35 years of age receiving concomitant estrogen therapy.

Cardiovascular collapse in patients treated simultaneously with verapamil and dantrolene sodium is rare. The combination of therapeutic doses of intravenous dantrolene sodium and verapamil in halothane/α-chloralose anesthetized swine has resulted in ventricular fibrillation and cardiovascular collapse in association with marked hyperkalemia. Until the relevance of these findings to humans is established, the combination of dantrolene sodium and calcium channel blockers is not recommended during the management of malignant hyperthermia.

Administration of dantrolene sodium may potentiate vecuronium-induced neuromuscular block.

Legal Issues

There is currently no legal information available for this drug.

FDA Safety Alerts

There are currently no FDA safety alerts available for this drug.

Manufacturer Warnings

There is currently no manufacturer warning information available for this drug.

FDA Labeling Changes

There are currently no FDA labeling changes available for this drug.

Uses

In Chronic Spasticity

Dantrolene sodium is indicated in controlling the manifestations of clinical spasticity resulting from upper motor neuron disorders (e.g., spinal cord injury, stroke, cerebral palsy, or multiple sclerosis). It is of particular benefit to the patient whose functional rehabilitation has been retarded by the sequelae of spasticity. Such patients must have presumably reversible spasticity where relief of spasticity will aid in restoring residual function. Dantrolene sodium is not indicated in the treatment of skeletal muscle spasm resulting from rheumatic disorders.

If improvement occurs, it will ordinarily occur within the dosage titration (see DOSAGE AND ADMINISTRATION), and will be manifested by a decrease in the severity of spasticity and the ability to resume a daily function not quite attainable without dantrolene sodium.

Occasionally, subtle but meaningful improvement in spasticity may occur with dantrolene sodium therapy. In such instances, information regarding improvement should be solicited from the patient and those who are in constant daily contact and attendance with him. Brief withdrawal of dantrolene sodium for a period of 2 to 4 days will frequently demonstrate exacerbation of the manifestations of spasticity and may serve to confirm a clinical impression.

A decision to continue the administration of dantrolene sodium on a long-term basis is justified if introduction of the drug into the patient's regimen:

 
produces a significant reduction in painful and/or disabling spasticity such as clonus, or
 
permits a significant reduction in the intensity and/or degree of nursing care required, or
 
rids the patient of any annoying manifestation of spasticity considered important by the patient himself.
In Malignant Hyperthermia

Oral dantrolene sodium is also indicated preoperatively to prevent or attenuate the development of signs of malignant hyperthermia in known, or strongly suspect, malignant hyperthermia susceptible patients who require anesthesia and/or surgery. Currently accepted clinical practices in the management of such patients must still be adhered to (careful monitoring for early signs of malignant hyperthermia, minimizing exposure to triggering mechanisms and prompt use of intravenous dantrolene sodium and indicated supportive measures should signs of malignant hyperthermia appear); see also the package insert for Dantrium® (dantrolene sodium) Intravenous.

Oral dantrolene sodium should be administered following a malignant hyperthermic crisis to prevent recurrence of the signs of malignant hyperthermia.

History

There is currently no drug history available for this drug.

Other Information

The chemical formula of dantrolene sodium is hydrated 1-[[[5-(4-nitrophenyl)-2-furanyl]methylene]amino]-2, 4-imidazolidinedione sodium salt. It is an orange powder, slightly soluble in water, but due to its slightly acidic nature the solubility increases somewhat in alkaline solution. The anhydrous salt has a molecular weight of 336. The hydrated salt contains approximately 15% water (3-1/2 moles) and has a molecular weight of 399. The structural formula for the hydrated salt is:

Chemical Structure

Dantrolene sodium is supplied in capsules of 25 mg and 50 mg.

Inactive Ingredients: Each capsule contains edible black ink, FD&C Yellow No. 6, gelatin, lactose, magnesium stearate, starch, synthetic iron oxide red, synthetic iron oxide yellow, talc, and titanium dioxide.

Dantrolene Sodium Manufacturers


  • Jhp Pharmaceuticals, Llc
    Dantrolene Sodium Capsule [Jhp Pharmaceuticals, Llc]
  • Global Pharmaceuticals, Division Of Impax Laboratories Inc.
    Dantrolene Sodium Capsule [Global Pharmaceuticals, Division Of Impax Laboratories Inc.]
  • Attix Pharmaceuticals
    Dantrolene Sodium Powder [Attix Pharmaceuticals]
  • American Health Packaging
    Dantrolene Sodium Capsule [American Health Packaging]
  • Carilion Materials Management
    Dantrolene Sodium Capsule [Carilion Materials Management]

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