Dantrium^® (Lyophilisate) Instructions for Use

Marketing Authorization Holder

LANTSET, JSC (Russia)

Manufactured By

Wasserburger Arzneimittelwerk, GmbH (Germany)

ATC Code

M03CA01 (Dantrolene)

Active Substance

Dantrolene (Rec.INN registered by WHO)

Dosage Form

Dantrium®

Lyophilizate for preparation of solution for intravenous administration 20 mg

Dosage Form, Packaging, and Composition

Lyophilizate for preparation of solution for intravenous administration

20 mg – vials (12 pcs.) – cardboard packs – By prescription
20 mg – vials (36 pcs.) – cardboard packs – By prescription

Pharmacotherapeutic Group

Direct-acting muscle relaxants

Pharmacological Action

Direct-acting muscle relaxant. The molecular receptor for dantrolene has not been identified. Radioactively labeled dantrolene sodium binds to specific structures of striated muscle fiber, namely the t-tubules and sarcoplasmic reticulum, although the binding kinetics to these two organelles vary. It is believed that ryanodine competes for calcium binding in these organelles; additional evidence for binding specificity is that dantrolene inhibits the binding of ryanodine to heavy vesicles of the sarcoplasmic reticulum of rabbit skeletal muscle.

Under certain conditions, dantrolene will reduce resting sarcoplasmic calcium concentrations. This may be more important in pathologically altered muscle (e.g., in malignant hyperthermia syndrome in humans and in stress syndrome in experimental animals) than in normally functioning muscle.

Dantrolene does not bind to the same sites as calcium channel blocking drugs such as nitrendipine or calmodulin. There is no electrophysiological evidence that dantrolene impedes the entry of calcium from the extracellular fluid into the muscle fiber. A possible reason for the lack of reports of paralysis in animals or humans under the influence of dantrolene is the presence of alternative calcium sources in the muscle cell that are not affected by dantrolene.

Regardless of the molecular mechanism, the main property of dantrolene sodium is that it reduces the intracellular calcium concentration in skeletal muscle fibers.

Calcium concentrations may decrease both at rest and as a result of reduced calcium release from the sarcoplasmic reticulum in response to a standard stimulus. This effect has been observed in striated muscle fibers of some animal species and is not observed in the myocardium. It is possible that fast-twitch fibers are more sensitive to the action of dantrolene sodium than slow-twitch fibers.

Pharmacokinetics

Dantrolene sodium is an extremely lipophobic substance. Furthermore, it is not hydrophilic. Dantrolene sodium binds in vitro to human serum albumin in a molar ratio from 0.95 to 1.68. The in vitro association constant ranges from 2.3 to 5.4×10^-5 mol^-1. In vitro, dantrolene sodium can be displaced from albumin binding by warfarin, clofibrate, and tolbutamide. Information about this interaction has not been confirmed in humans. After a single intravenous administration, the primary V_d is about 15 L. The T_1/2 from plasma in most people is from 5 to 9 hours, although there are reports of a range of recorded T_1/2 after a single IV dose of 12.1±1.9 hours. Inactivation occurs primarily through metabolism in the liver. There are two alternative metabolic pathways. Most of the active substance is hydroxylated to 5-hydroxydantrolene. An auxiliary metabolic pathway involves nitro-reduction to aminodantrolene, which is then acetylated (compound F-490). The 5-hydroxy metabolite is a muscle relaxant with almost the same specific activity as the original molecule and may have a longer half-life than the parent compound. Compound F-490 has much lower specific activity and is probably inactive at concentrations achieved in clinical samples. Metabolites are subsequently excreted in the urine. The proportion of the active substance excreted in the feces is dose-dependent.

Indications

Treatment of malignant hyperthermia syndrome.

ICD codes

Dosage Regimen

Intravenous.

The initial dose is 1 mg/kg. If physiological and metabolic abnormalities persist or recur, this dose can be repeated up to a cumulative dose of 10 mg/kg. According to current clinical experience, the average dose of dantrolene required to resolve manifestations of malignant hyperthermia is 2.5 mg/kg. In case of recurrence, Dantrolene should be re-administered at the last effective dose.

Adverse Reactions

Nervous system disorders frequency unknown – dizziness, drowsiness, stuttering.

Cardiovascular system disorders: frequency unknown – heart failure, bradycardia, tachycardia.

Respiratory system disorders frequency unknown – pulmonary edema (the mannitol and solvent used to prepare the reconstituted solution may lead to adverse reactions), pleural effusion, respiratory failure, respiratory depression.

Gastrointestinal disorders frequency unknown – abdominal pain, nausea, vomiting, gastrointestinal bleeding.

Hepatobiliary disorders frequency unknown – impaired liver function, including fatal liver failure, jaundice, hepatitis.

Skin and subcutaneous tissue disorders frequency unknown – hyperhidrosis.

Renal and urinary disorders frequency unknown – crystalluria.

Local reactions frequency unknown – rash, erythema, pain at the injection site, thrombophlebitis.

Contraindications

Hypersensitivity to dantrolene.

Use in Pregnancy and Lactation

The safety of dantrolene use in pregnant women has not been established. Dantrolene crosses the placental barrier and should be used only in cases where the potential benefit outweighs the possible risk to the mother and child. Dantrolene has been detected in human breast milk in low concentrations.

Use in Hepatic Impairment

There are reports of impaired liver function during dantrolene therapy, including cases of hepatitis and fatal liver failure. Despite the short-term use of the drug, the risk of liver dysfunction may increase with increasing dose and duration of treatment, in accordance with the experience of using dantrolene in the oral dosage form. However, in some patients, liver damage is of an idiosyncratic or hypersensitivity reaction nature and can occur after a single administration.

Special Precautions

The use of dantrolene for the management of malignant hyperthermia is not a substitute for supportive treatment. The administration of triggering agents should be discontinued, the increased oxygen demand should be monitored, and symptomatic therapy should be provided if metabolic acidosis develops. If necessary, the patient should be cooled, urine output should be assessed, and emerging electrolyte imbalances should be corrected.

There are reports of impaired liver function during dantrolene therapy, including cases of hepatitis and fatal liver failure. Despite the short-term use of the drug, the risk of liver dysfunction may increase with increasing dose and duration of treatment, in accordance with the experience of using dantrolene in the oral dosage form. However, in some patients, liver damage is of an idiosyncratic or hypersensitivity reaction nature and can occur after a single administration.

Effect on ability to drive and operate machinery

In the postoperative period, symptoms such as reduced hand strength, lower limb muscle weakness (especially when walking downstairs), and dizziness may occur. Since these symptoms may persist for up to 48 hours, patients should not drive a car or engage in other potentially hazardous activities during this time.

Drug Interactions

Combined use of therapeutic doses of dantrolene sodium and verapamil in experimental animal studies under halothane/alpha-chloralose anesthesia led to ventricular fibrillation and collapse combined with severe hyperkalemia. There are rare reports of hyperkalemia and collapse in patients predisposed to malignant hyperthermia syndrome receiving intravenous Dantrolene in combination with calcium channel blockers. The combination of intravenous dantrolene and calcium channel blockers, such as verapamil, is not recommended for the management of recurrent malignant hyperthermia syndrome until the significance of these changes in humans is determined.

Administration of dantrolene may potentiate the effect of vecuronium.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.