Dantrolene

Registered South African indications:

• Malignant hyperthermia
• Spasticity

Contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Hepatic impairment (cap)
• In patients where spasticity is utilised to sustain upright posture and balance in locomotion (cap)
• In patients where spasticity is utilised to obtain or maintain increased function (cap)
• Acute skeletal muscle spasms (cap)
• Galactose intolerance (cap)
• Lapp lactase deficiency (cap)
• Glucose-galactose malabsorption (cap)

Cautions

• Pregnancy
• Breastfeeding
• Hepatic impairment (inj)
• Elderly
• Risk factors for hepatotoxicity (cap)
  - Higher daily doses (>400mg/dly) (cap)
  - Duration of therapy (2-12 months of treatment) (cap)
  - Female gender (cap)
  - >30 years (cap)
  - Prior history of liver disease/dysfunction (cap)
  - Other hepatotoxic therapies (cap)
• Re-introduction of dantrolene therapy (cap)
• Cardiovascular disease(cap)
• Impaired respiratory function (cap)
• Obstructive pulmonary disease (cap)
• Central nervous system depressant use (tranquillising agents and alcohol) (cap)
• May impair the ability to drive and operate machinery

Forms avail. in SA and covered in this monograph: inj, cap

Malignant hyperthermia
- Treatment

• IV: Initial: 1mg/kg, as a bolus; Repeat until symptoms subside; Max: 10mg/kg

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Stop all anaesthetic agents as soon as malignant hyperthermia is recognised

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If a relapse or recurrence occurs, dantrolene IV should be readministered at the last effective dose

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Clinical experience has shown that the average dose of dantrolene IV required to reverse the manifestations of malignant hyperthermia has been 2.5mg/kg

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Dantrolene is not a substitute for other supportive measures. It will be necessary to discontinue the suspect triggering agents, attend to increased oxygen requirements and manage the metabolic acidosis. When necessary institute cooling, attend to urinary output and monitor for electrolyte imbalance

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When mannitol is used for prevention or treatment of renal complication of malignant hyperthermia, the 3 grams of mannitol present as an excipient in each 20mg vial of intravenous dantrolene sodium should be taken into consideration when calculating total mannitol dose to be administered

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Because of the high pH of the intravenous formulation of dantrolene and potential for tissue necrosis, care must be taken to prevent extravasation of the intravenous solution into the surrounding tissues

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Use of the filtration device when drawing up the solution is required at all times

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Chronic, severe spasticity of skeletal muscle 

• Oral (cap): Week 1: 25mg, dly; Week 2: 25mg, 12hrly; Week 3: 50mg, 12hrly; Week 4: 50mg, 8hrly; Week 5: 75mg, 8hrly; Week 6: 75mg, 6hrly; Week 7: 100mg, 6hrly; Max: 400mg/24hrs

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Lowest dose compatible with optimal response recommended

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Each dosage level should be maintained for 7 days to determine the patient's response

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If no observable benefit is derived from administration of dantrium capsules after a total of 6-8 weeks, therapy should be discontinued

Not recommended for children (tab)

No information available (inj)

Pregnancy 

• Caution
• Although teratological studies in animals have proved satisfactory, dantrolene sodium does cross the placenta and therefore the use of dantrolene is not advised during pregnancy and should be given only when the potential benefits have been weighed against the possible risk to mother and child

Breastfeeding 

• Caution; not recommended
• Dantrolene has been detected in human milk at low concentrations (<2μg/ml) during repeat intravenous administration. Dantrolene IV should be used by breastfeeding mothers only if the potential benefit justifies the potential risk to the infant
• Dantrolene sodium (cap) has been detected in human milk. Therefore the use of dantrolene is not advised in breastfeeding mothers

Fertility

• There is no data on the effects of dantrolene on human fertility

Renal Impairment 

• Caution; no information available

Hepatic Impairment 

• Caution; no information available (inj)
• Contraindicated (cap)

Elderly 

• Caution; no dose adjustment recommended
  Higher proportion of hepatic events with fatal outcomes reported in elderly patients

Porphyria Information

• Not yet classified (NC)

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Seizure
• Visual disturbances
• Speech disturbances
• Headache
• Dizziness
• Somnolence
• Convulsion speech disorder
• Mental depression
• Mental confusion
• Insomnia
• Nervousness

Cardiovascular Disorders

• Cardiac failure
• Bradycardia
• Tachycardia
• Pericarditis
• Exacerbation of pre-existing cardiac insufficiency
• Labile blood pressure

Respiratory Disorders

• Pleural effusion (with associated eosinophilia)
• Respiratory depression
• Dyspnoea
• Pulmonary oedema
• Respiratory failure

Gastrointestinal Disorders

• Abdominal pain
• Nausea and vomiting
• Gastrointestinal bleeding
• Dysphagia
• Constipation (rarely progressing to signs of intestinal obstruction)

Hepatobiliary Disorders

• Hepatic dysfunction  
  - Fatal hepatic failure
• Jaundice
• Hepatitis
• Hepatotoxicity
• liver function test disturbances

Genitourinary Disorders

• Crystalluria
• Incontinence
• Increased urinary frequency
• Urinary retention
• Haematuria

Endocrine and Metabolic Disorders 

• Anorexia

Skin and Subcutaneous Disorders

• Hyperhidrosis
• Acne-like rash
• Rash
• Sweating
• Erythema
• Localised pain
• Thrombophlebitis

Immune, Blood and Lymphatic System Disorders

• Chills
• Fever

• Calcium channel blockers
  - Verapamil
• Non-depolarizing muscle relaxants

• Hepatic function
• Motor performance
• Cardiac function
• Respiratory function
• Blood pressure

Additional observations (Malignant hyperthermia)

• Observation in ICU for 24 hours to monitor for recurrence
• Monitor for arrhythmias
• Vital signs
• Core temperature
• Electrolytes
• Arterial blood gas
• Creatinine kinase
• End tidal CO2 (EtCO2)/capnography
• Urine output
• Urine myoglobin

The receptor molecule for dantrolene sodium has not been identified. Radiolabelled dantrolene sodium binds to specific components of the striated muscle cell, namely the t-tubules and the sarcoplasmic reticulum; however the kinetics of binding varies between these two organelles. Whatever the molecular mechanism, the cardinal property of dantrolene sodium is that it lowers intracellular calcium concentration in skeletal muscle. Fast fibres may be more sensitive than slow fibres to the action of dantrolene sodium. Elevation of intracellular, free calcium ion concentration is an obligatory step in excitation-contraction coupling of skeletal muscle. Dantrolene sodium, therefore, acts as a muscle relaxant by a peripheral mechanism which is quite different, and easily distinguishable from neuromuscular junction blocking drugs. In contrast with compounds that relax skeletal muscle by acting principally on the central nervous system, dantrolene sodium acts directly on skeletal muscle cells.

Capsule 25mg

• Dantrium (Pharmaco) originator

Injection (per vial) 20mg

• Dantrium IV (Meda) originator

Injection (per vial)  3000mg

• Dantrium IV (Pharmaco) originator