Adult: In combination with appropriate supportive measures (e.g. administration of oxygen, treatment of metabolic acidosis, cooling procedures): Initially, 1 mg/kg via continuous rapid IV push. Continue administration until symptoms subside or if the Max total dose of 10 mg/kg is reached. An average dose of 2.5 mg/kg is usually effective in the reversal of malignant hyperthermia. If recurrence of symptoms occurs, the regimen may be repeated. Dosage and treatment recommendations may vary among countries (refer to latest local or country-specific product guidelines). Child: Same as adult dose.
Intravenous Prophylaxis of malignant hyperthermia
Adult: For preoperative use in patients suspected to be at risk: 2.5 mg/kg given over approx 1 hour (solution for inj) or at least 1 minute (susp for inj), starting approx 75 minutes prior to anaesthesia or surgery. For postoperative use to prevent or diminish the recurrence of symptoms when oral treatment is not feasible: Initially, 1 mg/kg or more as clinically indicated. Dosage and treatment recommendations may vary among countries (refer to latest local or country-specific product guidelines).
Oral Severe chronic spasticity
Adult: For spasticity resulting from upper motor neuron disorders (e.g. multiple sclerosis, cerebral palsy, spinal cord injury, stroke): Initially, 25 mg once daily, gradually increase at intervals of 7 days over approx 7 weeks. Max: 100 mg 4 times daily. Suggested titration schedule: Initially, 25 mg once daily for 7 days, then increase to 25 mg tid for 7 days, then increase to 50 mg tid for 7 days and then increase to 100 mg tid; some patients may need a dose of 100 mg 4 times daily. Doses must be individualised and titrated slowly for maximum effect. Use the lowest effective dose. If no further benefit is observed at the higher dose level, dose must be reduced to the previous lower dose level. Discontinue use if no benefit is observed within 45 days. Dosage and treatment recommendations may vary among countries (refer to latest local or country-specific product guidelines). Child: ≥5 years For spasticity resulting from upper motor neuron disorders (e.g. multiple sclerosis, cerebral palsy, spinal cord injury, stroke): Initially, 0.5 mg/kg once daily or bid for 7 days, then increase to 0.5 mg/kg tid for 7 days, then increase to 1 mg/kg tid for 7 days and then increase to 2 mg/kg tid. Some patients may need a dose of 100 mg 4 times daily, but doses higher than this must not be used. Doses must be individualised and titrated slowly for maximum effect. Use the lowest effective dose. If no further benefit is observed at the higher dose level, dose must be reduced to the previous lower dose level. Discontinue use if no benefit is observed within 45 days. Dosage and treatment recommendations may vary among countries (refer to latest local or country-specific product guidelines).
Oral Prophylaxis of malignant hyperthermia
Adult: For pre-operative use: 4-8 mg/kg daily in 3 or 4 divided doses for 1-2 days prior to surgery, with the last dose given approx 3-4 hours before surgery. For prevention of recurrence following malignant hyperthermia crisis: 4-8 mg/kg daily in 4 divided doses for 1-3 days. Treatment recommendations may vary among countries (refer to latest local or country-specific product guidelines).
Administration
May be taken with or without food.
Reconstitution
Powder for solution for inj: Reconstitute vial labelled as 20 mg by adding 60 mL sterile water for inj (without bacteriostatic agent). Shake the vial to dissolve until the solution is clear. Powder for susp for inj: Reconstitute vial labelled as 250 mg by adding 5 mL of sterile water for inj (without bacteriostatic agent). Shake the vial until an orange-coloured suspension is formed. Instructions on reconstitution may vary between individual products (refer to specific product guidelines).
Incompatibility
Solution for inj: Incompatible with NaCl 0.9%, dextrose 5% and other acidic solutions.
Contraindications
Oral: Active hepatic disease (e.g. cirrhosis, hepatitis). In cases when spasticity is used to maintain upright posture and balance in locomotion or to obtain or maintain increased body function. Lactation.
Special Precautions
Patient with severely impaired cardiac function due to myocardial disease, impaired pulmonary function (particularly in obstructive pulmonary disease), and history of hepatic disease or dysfunction (oral). Female patients and patients >30 years old (oral). Not indicated for the treatment of skeletal muscle spasms resulting from rheumatic disorders. Avoid extravasation during IV inj. Children. Pregnancy.
Adverse Reactions
Significant: CNS depression, pleural effusion with eosinophilia. Oral: Photosensitivity reaction, elevated liver enzymes. IV: Muscle weakness (e.g. loss of grip strength, leg weakness, dyspnoea, respiratory muscle weakness, dysphagia, decreased inspiratory capacity). Cardiac disorders: Tachycardia. Eye disorders: Visual disturbances, diplopia (oral). Gastrointestinal disorders: Diarrhoea, abdominal cramps, nausea, vomiting, constipation, gastrointestinal bleeding. General disorders and administration site conditions: Asthenia, fatigue. Malaise, fever, chills (oral); inj site reactions such as pain, erythema, and swelling (IV). Metabolism and nutrition disorders: Decreased appetite (oral); hyperkalaemia (IV). Musculoskeletal and connective tissue disorders: Myalgia, back pain (oral). Nervous system disorders: Dizziness, drowsiness, headache, speech disturbances, seizures. Psychiatric disorders: Confusion, depression, insomnia, nervousness (oral). Renal and urinary disorders: Crystalluria, haematuria, urinary incontinence (oral). Skin and subcutaneous tissue disorders: Rash (often acneiform), erythema, urticaria, hyperhidrosis. Vascular disorders: Thrombophlebitis (IV). Potentially Fatal: Oral: Hepatotoxicity (e.g. symptomatic hepatitis, liver disorders of idiosyncratic and hypersensitivity type).
This drug may cause dizziness, drowsiness, and weakness, if affected, do not drive or operate machinery. Oral: Avoid exposure to sunlight; wear protective clothing and use sunscreen when going outdoors.
Monitoring Parameters
Monitor motor performance and LFTs (at baseline, periodically during treatment or whenever symptoms of hepatitis occur). IV: Monitor blood pressure, cardiac function, pulmonary status, vital signs and IV site. Assess for adequacy of ventilation or for difficulty swallowing and choking.
Overdosage
Symptoms: Muscular weakness, vomiting, diarrhoea, crystalluria, tachycardia, hypotension, troubling hypotonia, diplopia, fatigue, dizziness, hypertension, pruritus, hepatotoxic reactions, alteration in state of consciousness (e.g. lethargy, coma). Management: Supportive treatment. Employ gastric lavage immediately. Maintain adequate airway and artificial resuscitation equipment should be readily available. Administer IV fluid in fairly large quantities to avoid crystalluria. Institute ECG monitoring.
Drug Interactions
Increased risk of adverse reactions, particularly CNS depressant effect and muscle weakness, with CNS depressants (e.g. tranquillisers, sedatives). May increase the risk of liver damage with estrogens or other hepatotoxic drugs. May potentiate the effect of non-depolarising muscle relaxants (e.g. vecuronium bromide). Concomitant use of IV dantrolene and Ca channel blockers (e.g. diltiazem, verapamil) in patients predisposed to malignant hyperthermia may result in hyperkalaemia and myocardial depression.
Food Interaction
May enhance the CNS depressant effect of alcohol.
Action
Description: Mechanism of Action: Dantrolene, a direct-acting skeletal muscle relaxant, uncouples muscular contraction from excitation probably by interfering with the release of Ca ions in the sarcoplasmic reticulum. In malignant hyperthermia, it prevents the increase in myoplasmic Ca ion concentration that activates the acute catabolism in skeletal muscle cell. Pharmacokinetics: Absorption: Slowly and almost completely absorbed from the gastrointestinal tract. Bioavailability: 70% (oral). Time to peak plasma concentration: Approx 5 hours (oral); 1 minute (IV). Distribution: Crosses the placenta and enters breast milk. Volume of distribution: 36.4 ± 11.7 L. Extensively bound to plasma proteins, mainly to albumin. Metabolism: Metabolised in the liver mainly to 5-hydroxy dantrolene (active metabolite) and via reductive pathways to form the amino derivative, then acetylated to form the acetamido derivative. May also undergo hydrolysis and then oxidation to form nitrophenylfuroic acid. Excretion: Via faeces (45-50%); urine (25% as unchanged drug and metabolites). Elimination half-life: 4-11 hours.
Chemical Structure
Dantrolene Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 6914273, Dantrolene. https://pubchem.ncbi.nlm.nih.gov/compound/Dantroleno. Accessed Sept. 30, 2024.
Storage
Cap/Intact IV vial: Store between 20-25°C. Reconstituted IV solution/susp: Store between 15-25°C and use within 6 hours. Do not refrigerate or freeze. Protect from direct light. Storage recommendations may vary among countries and between individual products (refer to specific product guidelines).
M03CA01 - dantrolene ; Belongs to the class of dantrolene and derivatives agents. Used as directly-acting muscle relaxants.
References
Anon. Dantrolene. AHFS Clinical Drug Information [online]. Bethesda, MD. American Society of Health-System Pharmacists, Inc. https://www.ahfscdi.com. Accessed 13/08/2024.Brayfield A, Cadart C (eds). Dantrolene Sodium. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 13/08/2024.Dantrium 25 mg Capsules (Norgine Pharmaceuticals Limited). MHRA. https://products.mhra.gov.uk. Accessed 10/05/2024.Dantrium IV 20 mg (Norgine Pharmaceuticals Limited). MHRA. https://products.mhra.gov.uk. Accessed 10/05/2024.Dantrolene Sodium Capsule (Bryant Ranch Prepack). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed. Accessed 10/05/2024.Dantrolene Sodium Injection (Par Pharmaceutical, Inc.). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed. Accessed 10/05/2024.Dantrolene. UpToDate Lexidrug, Lexi-Drugs Multinational Online. Waltham, MA. UpToDate, Inc. https://online.lexi.com. Accessed 13/08/2024.Joint Formulary Committee. Dantrolene Sodium. British National Formulary [online]. London. BMJ Group and Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 10/05/2024.Pfizer New Zealand Limited. Dantrium Capsule 25 mg and 50 mg data sheet 4 February 2019. Medsafe. http://www.medsafe.govt.nz. Accessed 10/05/2024.Pfizer New Zealand Limited. Dantrium IV 20 mg Powder for Injection data sheet 22 December 2020. Medsafe. http://www.medsafe.govt.nz. Accessed 10/05/2024.Ryanodex Injection, Suspension (Eagle Pharmaceuticals, Inc.). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed. Accessed 13/08/2024.
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