Dantrolene is a medication primarily used to treat muscle spasticity and muscle spasms. It works by acting directly on skeletal muscles to relax them. Dantrolene is often prescribed for conditions such as multiple sclerosis, cerebral palsy, spinal cord injury, and stroke, where muscle spasticity can be a significant issue.

One of the unique aspects of dantrolene is its mechanism of action. It interferes with the release of calcium ions from the sarcoplasmic reticulum within muscle cells. Calcium ions are crucial for muscle contraction, so by blocking their release, dantrolene effectively reduces muscle tone and spasticity.

Dantrolene (Dantrolen) is a post-synaptic muscle relaxant. It is available as an oral and intravenous formulation.

Dantrolene Uses:

• Chronic spasticity:
  • Oral dantrolene is used in the treatment of spasticity associated with upper motor neuron disorders (eg, spinal cord injury, stroke, cerebral palsy, or multiple sclerosis).
• Malignant hyperthermia:
  • Intravenous administration of dantrolene is recommended in the management of malignant hyperthermia crisis followed by oral or intravenous dose to prevent a recurrence.

Note: Dantrolene is not recommended as a pre-prophylaxis drug in patients who are susceptible to malignant hyperthermia crisis during a surgery, provided non-triggering anesthetic agents are used.

• Off Label Use of Dantrolene in Adults:
  • Neuroleptic malignant syndrome

Dantrolene Dose in Adults

Dantrolene Dosage for the Chronic Treatment of spasticity: 

To treat chronic spasticity with dantrolene in oral form, here's a simplified dosing guide:

• Start with 25 mg once a day for a week.
• Then increase to 25 mg three times a day for a week.
• After that, increase to 50 mg three times a day for another week.
• Finally, increase to 100 mg three times a day. Some patients might need 100 mg four times a day.
• The maximum daily dose is 400 mg.

It's crucial to adjust the dose carefully for each person. If there's no improvement after trying higher doses, it's best to go back to the previous dose level. If there's no benefit seen within 45 days, the treatment should be stopped due to the risk of liver problems.

Dantrolene dose for the treatment of Malignant hyperthermia (MH):

For the treatment of malignant hyperthermia (MH), here's a simplified dosing guide:

During Crisis:

• Initially, administer 2.5 mg/kg of dantrolene through intravenous (IV) injection.
• Continuously monitor the patient's condition.
• If symptoms persist, give additional doses of 1 mg/kg until symptoms subside or a total dose of 10 mg/kg is reached.

Post-Crisis Follow-up and Prevention of Recurrence:

• According to MHAUS protocol recommendation, administer 1 mg/kg of dantrolene every 4 to 6 hours. The route of administration is not specified.
• The manufacturer's labeling suggests oral dosing of 4 to 8 mg/kg per day, divided into four doses, for 1 to 3 days. IV dantrolene may be used if oral therapy is not feasible. The initial dose should be 1 mg/kg or higher, adjusted based on the clinical situation.

Remember to discontinue all MH-triggering agents once the hyperthermia crisis is recognized and provide supportive care. If there's an emergency, contact the MH Hotline provided for immediate assistance.

Dantrolen Dose in the treatment of Neuroleptic malignant syndrome as off-label use:

In the treatment of Neuroleptic Malignant Syndrome (NMS), here's a simplified dosing guide for dantrolene:

Initial Treatment:

• Administer dantrolene intravenously (IV) at a dose of 1 to 2.5 mg/kg initially.
• If rapid improvement in hyperthermia and muscle rigidity is observed, continue with 1 mg/kg every 6 hours.
• The maximum cumulative dose should not exceed 10 mg/kg per day.

Switch to Oral Dosage:

• After achieving stability with IV dantrolene, switch to oral dosage for continued treatment.

Combination Therapy:

• Based on the analysis of case reports, combining dantrolene with other therapies like bromocriptine may be preferred over dantrolene alone. This combination has shown lower mortality rates and longer complete remission periods.

Dantrolene Dose in Childrens

Dantrolene Dose in the treatment of Spasticity:

For treating spasticity with dantrolene orally, here's a simplified dosing guide:

Manufacturer's Labeling:

• Children and Adolescents ≥5 years (Patient weight <50 kg):
  • Start with 0.5 mg/kg/dose once daily for 7 days.
  • Then increase to 0.5 mg/kg/dose three times daily for 7 days.
  • Further increase to 1 mg/kg/dose three times daily for 7 days.
  • Finally, increase to 2 mg/kg/dose three times daily. Some patients may need 2 mg/kg/dose four times daily.
  • The maximum daily dose is 400 mg.
• Children and Adolescents ≥5 years (Patient weight ≥50 kg):
  • Begin with 25 mg once daily for 7 days.
  • Then increase to 25 mg three times daily for 7 days.
  • Progress to 50 mg three times daily for 7 days.
  • Finally, increase to 100 mg three times daily. Some patients may need 100 mg four times daily.
  • The maximum daily dose is 400 mg.

Alternate Dosing:

• Children and Adolescents:
  • Start with 0.5 mg/kg/dose twice daily, up to a maximum of 25 mg per dose.
  • Adjust frequency every 4 to 7 days to achieve desired effects, then increase the dose by 0.5 mg/kg increments weekly.
  • The maximum daily dose is either 12 mg/kg/day or 400 mg/day, whichever is lower.

Remember to titrate the dose to achieve the desired effect. If no further benefit is seen at higher dosages, decrease the dose to the previous level.

Dantrolene Dose in the treatment of Malignant hyperthermia in infants, children, and adolescents:

For the treatment of Malignant Hyperthermia (MH) in infants, children, and adolescents, here's a simplified dosing guide for dantrolene:

Preoperative Prophylaxis:

• Oral: Administer 4 to 8 mg/kg/day in 3 to 4 divided doses for 1 to 2 days before surgery, with the last dose given approximately 3 to 4 hours before the scheduled surgery.
• IV: Give 2.5 mg/kg/dose approximately 1.25 hours before surgery. Administer over at least 1 minute (Ryanodex) or 1 hour (Dantrium, Revonto). Additional doses should be given as needed and individualized.

During Crisis:

• IV:
  • Follow MHAUS protocol recommendation: Administer 2.5 mg/kg, repeating the dose continuously until symptoms subside or a cumulative dose of 10 mg/kg is reached. In rare cases, some patients may require up to 30 mg/kg for initial treatment.
  • Manufacturer's labeling: Start with an initial minimum dose of 1 mg/kg. Repeat dosing with a minimum of 1 mg/kg until symptoms subside or a cumulative dose of 10 mg/kg is reached.

Post-Crisis Follow-up:

• According to MHAUS protocol recommendation:
  • Administer 1 mg/kg every 4 to 6 hours (route not specified), or a continuous IV infusion of 0.25 mg/kg/hour for at least 24 hours. Further doses may be necessary.
• Manufacturer's labeling suggests oral administration of 4 to 8 mg/kg/day in 4 divided doses for 1 to 3 days. IV dantrolene may be used if oral therapy is impractical, starting with a dose of 1 mg/kg or more as deemed appropriate based on the clinical situation.

Pregnancy Risk Factor C

• In animal studies, adverse effects have been noted during pregnancy with dantrolene.
• The medication crosses the placenta, reaching similar concentrations in the newborn's blood as in the mother's bloodstream during delivery.
• Maternal doses of up to 100 mg/day orally before birth haven't shown adverse effects on newborns.
• However, after delivery, dantrolene injection may lead to uterine atony, possibly due in part to the mannitol in the IV preparation.
• While prophylactic use of dantrolene isn't generally recommended for pregnant women susceptible to malignant hyperthermia (MH) before obstetric surgery, if needed, close monitoring of both mother and newborn is advised.

Dantrolene use during breastfeeding:

• Dantrolene can be found in breast milk, but in small amounts.
• Due to the possibility of serious side effects in nursing infants, the manufacturer advises considering whether to stop breastfeeding or discontinue the medication, considering the importance of treatment for the mother.
• In a case report, the half-life of dantrolene in breast milk was estimated to be 9 hours, with the highest milk concentration reaching 1.2 mcg/mL after a maternal IV dose.
• However, the levels of dantrolene in the mother's blood were not provided.

Dantrolen dose in Renal impairment:

The manufacturer's labeling does not specify any dosage adjustments for individuals with renal impairment.

Dantrolen Dose in liver disease:

• The manufacturer's labeling does not offer any dosage adjustments, and the use of oral dantrolene is contraindicated in patients with active liver disease, such as hepatitis and cirrhosis.

Side effects of Dantrolen:

• Cardiovascular:
  • Flushing
  • Atrioventricular Block
  • Tachycardia
  • Cardiac Failure
  • Phlebitis
  • Variable Blood Pressure
• Central Nervous System:
  • Drowsiness
  • Voice Disorder
  • Feeling Abnormal
  • Dizziness
  • Headache
  • Myasthenia
  • Chills
  • Choking Sensation
  • Confusion
  • Depression
  • Fatigue
  • Insomnia
  • Malaise
  • Nervousness
  • Seizure
  • Speech Disturbance
• Dermatologic:
  • Acneiform Eruption
  • Diaphoresis
  • Eczematous Rash
  • Erythema
  • Hair Disease
  • Pruritus
  • Urticaria
• Gastrointestinal:
  • Dysphagia
  • Nausea
  • Vomiting
  • Abdominal Cramps
  • Anorexia
  • Constipation
  • Diarrhea
  • Dysgeusia
  • Gastric Irritation
  • Gastrointestinal Hemorrhage
  • Sialorrhea
• Genitourinary:
  • Crystalluria
  • Difficulty In Micturition
  • Erectile Dysfunction
  • Hematuria
  • Nocturia
  • Urinary Frequency
  • Urinary Incontinence
  • Urinary Retention
• Hematologic & Oncologic:
  • Anemia
  • Aplastic Anemia
  • Leukopenia
  • Lymphocytic Lymphoma
  • Thrombocytopenia
• Hepatic:
  • Hepatitis
• Hypersensitivity:
  • Anaphylaxis
• Local:
  • Injection Site Reaction
  • Local Tissue Necrosis
• Neuromuscular & Skeletal:
  • Limb Pain
  • Back Pain
  • Myalgia
• Ophthalmic:
  • Blurred Vision
  • Diplopia
  • Epiphora
  • Visual Disturbance
• Respiratory:
  • Dyspnea
  • Pleural Effusion
  • Pulmonary Edema
  • Respiratory Depression
• Miscellaneous:
  • Fever

Contraindications Of Dantrolene:

• Intravenous (IV) administration of dantrolene doesn't have any contraindications listed in the manufacturer's labeling.
• However, for oral use, the medication is contraindicated in individuals with active hepatic disease such as cirrhosis or hepatitis.
• Additionally, oral dantrolene should not be used when spasticity is necessary to maintain upright posture or balance during movement, or when it's needed to achieve or sustain improved function.

Dantrolen Warnings & Precautions

Central Nervous System depression:

• Dantrolene may lead to central nervous system (CNS) depression, potentially affecting both physical and mental capabilities.
• Patients should be warned about engaging in activities requiring mental alertness, such as operating machinery or driving, as their abilities may be impaired while taking this medication.

Hepatotoxicity: [US Boxed Warning]

• Dantrolene carries a significant risk of hepatotoxicity, as highlighted by a boxed warning in the United States.
• Both fatal and nonfatal symptomatic hepatitis cases have been reported.
• Higher doses, even short courses exceeding 800 mg/day, may heighten the risk of severe liver injury, though it can occur at doses below 400 mg/day.
• Hepatitis symptoms are most frequently observed between the third and twelfth month of therapy.
• Females, individuals over 35 years old, and those taking other medications concurrently are at increased risk.
• Fatal liver events are more common in the elderly, possibly influenced by other health conditions and concurrent use of potentially harmful drugs.
• Liver reactions, including hypersensitivity reactions, can be fatal.
• Regular monitoring of liver function is advised during treatment.
• If symptoms of hepatitis or abnormal liver function tests develop, or if there's no improvement within 45 days of therapy initiation for chronic spasticity, treatment should be discontinued.
• Hepatic function typically returns to normal after stopping the medication.
• If re-treatment is necessary, it should be done cautiously with very small and gradual dose increases, preferably under hospital supervision.

Muscle weakness

• Intravenous dantrolene has been associated with muscle weakness, including loss of grip strength, weakness in the legs, difficulty breathing (dyspnea) due to respiratory muscle weakness, difficulty swallowing (dysphagia), and decreased ability to breathe deeply (decreased inspiratory capacity).
• Patients should not attempt to walk without assistance until they have regained normal strength and balance.
• Continuous monitoring for adequate ventilation and signs of swallowing difficulties or choking is essential.

Photosensitivity

• Oral dantrolene therapy can trigger photosensitivity reactions.
• Patients should exercise caution when exposed to sunlight while taking this medication.
• It's advisable to take preventive measures such as wearing protective clothing and using sunscreen to minimize the risk of sun-related skin reactions.

Pleural effusion:

• Dantrolene use may lead to the development of pleural effusion, accompanied by increased levels of eosinophils in the pleural fluid.
• This condition involves the accumulation of fluid in the space surrounding the lungs.

Cardiovascular disease

• Oral dantrolene therapy should be approached with caution in patients with severely impaired cardiac function attributed to myocardial disease.
• Individuals with significant heart conditions may be at increased risk of adverse cardiovascular effects while taking this medication.

Hepatic disease

• Oral dantrolene therapy should be approached cautiously in patients with a history of hepatic disease or dysfunction.
• However, its use is contraindicated in individuals with active hepatic disease, such as cirrhosis or hepatitis.
• Patients with pre-existing liver conditions may be at an increased risk of experiencing adverse effects or exacerbating liver dysfunction while taking this medication.

Respiratory disease

• Oral dantrolene therapy should be used cautiously in patients with impaired pulmonary function, especially those with obstructive pulmonary disease.
• Individuals with pre-existing respiratory conditions may be more susceptible to respiratory depression or exacerbation of their underlying condition while taking this medication.

Dantrolene: Drug Interaction

Note: Drug Interaction Categories:

• Risk Factor C: Monitor When Using Combination
• Risk Factor D: Consider Treatment Modification
• Risk Factor X: Avoid Concomitant Use

Risk Factor C (Monitor therapy).
Alcohol (Ethyl)	CNS Depressants can increase the CNS depressant effects of Alcohol (Ethyl).
Alizapride	CNS Depressants may increase the CNS depressant effects.
Bosentan	Could lower serum concentrations of CYP3A4 substrates (High Risk with Inducers).
Brexanolone	CNS Depressants can increase the CNS depressant effects of Brexanolone.
Brimonidine (Topical)	CNS Depressants may increase the CNS depressant effects.
Bromopride	CNS Depressants may increase the CNS depressant effects.
Cannabidiol	CNS Depressants may increase the CNS depressant effects.
Cannabis	CNS Depressants may increase the CNS depressant effects.
Chlorphenesin Carbamate	CNS Depressants may have an adverse/toxic effect that can be exacerbated by them.
CNS Depressants	Can increase the toxic/adverse effects of CNS Depressants.
Moderate CYP3A4 Inducers	Could lower serum concentrations of CYP3A4 substrates (High Risk with Inducers).
Deferasirox	Could lower serum concentrations of CYP3A4 substrates (High Risk with Inducers).
Dexketoprofen	Dantrolene may have an adverse/toxic effect.
Dimethindene (Topical).	CNS Depressants may increase the CNS depressant effects.
Doxylamine	CNS Depressants may have a greater CNS depressant effect if taken with other CNS Depressants. Management: The manufacturer of Diclegis (doxylamine/pyridoxine), intended for use in pregnancy, specifically states that use with other CNS depressants is not recommended.
Dronabinol	CNS Depressants may increase the CNS depressant effects.
Erdafitinib	Could lower serum concentrations of CYP3A4 substrates (High Risk with Inducers).
Esketamine	CNS Depressants may increase the CNS depressant effects.
Estrogen Derivatives	Might increase the hepatotoxic effects of Dantrolene.
HydrOXYzine	CNS Depressants may increase the CNS depressant effects.
Ivosidenib	Could lower serum concentrations of CYP3A4 substrates (High Risk with Inducers).
Kava Kava	CNS Depressants may have an adverse/toxic effect that can be exacerbated by them.
Lacidipine	Dantrolene may have an adverse/toxic effect.
Lofexidine	CNS Depressants may have a greater depressant effect on the brain. Management: Separate drug interaction monographs are available for drugs listed as an exception to this monograph.
Magnesium Sulfate	CNS Depressants may increase the CNS depressant effects.
MetyroSINE	MetyroSINE may have a sedative effect that can be enhanced by CNS depressants.
Minocycline	CNS Depressants may increase the CNS depressant effects.
Mirtazapine	CNS Depressants can increase the CNS depressant effects of Mirtazapine.
Nabilone	CNS Depressants may increase the CNS depressant effects.
Piribedil	CNS Depressants could increase the CNS depressant effects of Piribedil.
Pramipexole	Pramipexole may have a greater sedative effect if it is combined with CNS depressants.
ROPINIRole	CNS Depressants can increase the sedative effects of ROPINIRole.
Rotigotine	CNS Depressants can increase the sedative effects of Rotigotine.
Rufinamide	CNS Depressants may have an adverse/toxic effect that can be exacerbated by this. Particularly, dizziness and sleepiness may be increased.
Sarilumab	Could lower serum concentrations of CYP3A4 substrates (High Risk with Inducers).
Selective Serotonin Reuptake inhibitors	CNS Depressants can increase the toxic/adverse effects of Selective Serotonin Resuptake Inhibitors. Particularly, psychomotor impairment could be increased.
Siltuximab	Could lower serum concentrations of CYP3A4 substrates (High Risk with Inducers).
Tetrahydrocannabinol	CNS Depressants may increase the CNS depressant effects.
Tetrahydrocannabinol, and Cannabidiol	CNS Depressants may increase the CNS depressant effects.
Tocilizumab	Could lower serum concentrations of CYP3A4 substrates (High Risk with Inducers).
Trimeprazine	CNS Depressants may increase the CNS depressant effects.
Vecuronium	Dantrolene may enhance the neuromuscular-blocking effect of Vecuronium.
Risk Factor D (Regard therapy modification)
Blonanserin	CNS Depressants can increase the CNS depressant effects of Blonanserin.
Buprenorphine	CNS Depressants can increase the CNS depressant effects of buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Buprenorphine patches (Butrans) should be initiated at 5 mg/hr for adults when taken with other CNS depression drugs.
Chlormethiazole	CNS Depressants may increase the CNS depressant effects. Monitoring: Look out for signs of CNS depression. If a combination of chlormethiazole and other drugs is required, a reduced dose should be used.
Strong CYP3A4 Inducers	May increase metabolism of CYP3A4 substrates (High Risk with Inducers). Management: You may consider a different drug to replace one of the interacting drugs. Some combinations might be contraindicated. Consult appropriate manufacturer labeling.
Dabrafenib	High risk of Inducers causing a decrease in serum CYP3A4 substrates. Management: If possible, seek alternatives to the CYP3A4 substrate. Concomitant therapy should be avoided if possible. Monitor the clinical effects of the substrate carefully (especially therapeutic effects).
Droperidol	CNS Depressants may increase the CNS depressant effects. Management: Droperidol and other CNS agents, such as opioids, may be reduced or used in combination with droperidol. Separate drug interaction monographs provide more detail on exceptions to this monograph.
Enzalutamide	High risk of Inducers causing a decrease in serum concentrations of CYP3A4 substrates. Management: Avoid concurrent use of enzalutamide and CYP3A4 substrates with a narrow therapeutic index. You should exercise caution when using enzalutamide or any other CYP3A4 sub-substance.
Flunitrazepam	CNS Depressants can increase the CNS depressant effects of Flunitrazepam.
HYDROcodone	CNS Depressants can increase the CNS depressant effects of HYDROcodone. When possible, avoid concomitant use with hydrocodone and other CNS depressants. Combining these agents is not recommended unless there are other options. Limit the amount and duration of each drug when combined.
Lorlatinib	High risk of Inducers causing a decrease in serum concentrations of CYP3A4 substrates. Management: Do not use lorlatinib concurrently with any CYP3A4 Substrates. Even a slight decrease in serum concentrations could cause therapeutic failure or serious clinical consequences.
Methotrimeprazine	Methotrimeprazine may have a higher CNS depressant activity than CNS Depressants. Methotrimeprazine can increase the CNS depressant effects of CNS Depressants. Management: Lower the adult dose of CNS Depressants by 50% and start concomitant methotrimeprazine treatment. After clinically proven efficacy of methotrimeprazine, further CNS depressant dose adjustments should only be made.
Mitotane	High risk of Inducers causing a decrease in serum concentrations of CYP3A4 substrates. Treatment: Patients receiving mitotane may require significant adjustments in the dosage of CYP3A4 Substrates.
Opioid Agonists	CNS Depressants can increase the CNS depressant effects of Opioid Aggonists. Management: When possible, avoid concomitant use opioid agonists and other CNS depressants. Combining these agents is not recommended unless there are other options. Limit the amount and duration of each drug when combined.
OxyCODONE	CNS Depressants can increase OxyCODONE's CNS depressant effects. When possible, avoid the simultaneous use of oxycodone and other CNS depressants. Combining these agents is not recommended unless there are other options. Limit the amount and duration of each drug when combined.
Perampanel	CNS Depressants may have a greater CNS depressant effect. Perampanel and any other CNS depressant drug should be used in combination. Patients who take perampanel together with any other drug should not engage in complex or high-risk activities until they have had experience using the combination.
Pitolisant	High risk of Inducers causing a decrease in serum concentrations of CYP3A4 substrates Management: Avoid combining pitolisant and a CYP3A4 substrat with a low therapeutic index. Pitolisant should not be combined with other CYP3A4 sub-substances.
Sodium Oxybate	CNS Depressants may have a greater depressant effect if taken in combination. Management: Look for alternatives to the combination use. If you must combine use, reduce the doses of any one or more drugs. It is not recommended to combine sodium oxybate and alcohol, or any sedative hypnotics.
St John's Wort	High risk of Inducers causing a decrease in serum CYP3A4 Substrates. Management: You may consider a different drug to replace one of the interacting drugs. Some combinations might be contraindicated. Consult appropriate manufacturer labeling.
Suvorexant	CNS Depressants can increase the CNS depressant effects of Suvorexant. Management: Suvorexant or any other CNS depressionant can be reduced in doses. Suvorexant should not be taken with alcohol. It is also not recommended to take suvorexant along with any other drugs for insomnia.
Tapentadol	CNS Depressants may increase the CNS depressant effects. Tapentadol, benzodiazepines and other CNS depressants should be avoided when possible. Combining these agents is not recommended unless there are other options. Limit the amount and duration of each drug when combined.
Zolpidem	CNS Depressants can increase the CNS depressant effects of Zolpidem. Management: For men who also take CNS depressants, reduce the adult Intermezzo brand sublingual Zolpidem dose to 1.75mg. For women, no dose adjustment is advised. Avoid using CNS depressants at night; do not use alcohol.
Risk Factor X (Avoid Combination)
Azelastine (Nasal)	CNS Depressants could increase the CNS depressant effects of Azelastine.
Bromperidol	CNS Depressants may increase the CNS depressant effects.
Calcium Channel Blockers (Nondihydropyridine)	Dantrolene may enhance the hyperkalemic effect of Calcium Channel Blockers (Nondihydropyridine). Dantrolene may enhance the negative inotropic effect of Calcium Channel Blockers (Nondihydropyridine). Management: This interaction was only described in intravenous dantrolene administration.
Orphenadrine	Orphenadrine may be more effective against CNS depression than other drugs.
Oxomemazine	CNS Depressants may increase the CNS depressant effects.
Paraldehyde	Paraldehyde may be enhanced by CNS depressants.
Thalidomide	CNS Depressants can increase Thalidomide's CNS depressant effects.

Monitor:

Monitoring for Therapeutic Outcomes:

• Assess motor performance regularly to evaluate treatment effectiveness.
• Monitor for common side effects such as nausea and vomiting.
• Conduct baseline liver function tests before starting treatment and periodically thereafter to watch for potential liver problems.
• For intravenous administration, closely monitor cardiac function, blood pressure, and respiratory status.

Malignant Hyperthermia Management:

• During and Post-Acute Phase:
  • Adhere to MHAUS protocol, ensuring patient observation in an ICU for at least 24 hours due to the possibility of recrudescence.
  • Monitor for arrhythmias and other cardiac complications.
  • Keep a close watch on vital signs, including core temperature.
  • Check electrolyte levels, arterial blood gases (ABG), and creatine kinase (CK) levels.
  • Utilize end-tidal CO2 (EtCO2) monitoring or capnography.
  • Monitor urine output and urine myoglobin levels for signs of muscle breakdown.

Administration of Dantrolene:

IV Administration:

• Therapeutic or emergency doses can be given rapidly as a continuous IV push.
• Subsequent doses should be administered over at least 1 minute (for Ryanodex) or 1 hour (for Dantrium, Revonto) to minimize adverse effects.

Vesicant Precautions:

• Dantrolene is a vesicant, so ensure proper needle or catheter placement before and during infusion to prevent extravasation.
• Take precautions to avoid extravasation during administration.

Extravasation Management:

• If extravasation occurs, halt the infusion immediately and disconnect the line, but leave the needle or cannula in place.
• Gently aspirate any extravasated solution without flushing the line.
• Remove the needle or cannula and elevate the affected extremity to minimize swelling and discomfort.

Mechanism of action of Dantrolene (Dantrolen):

• Dantrolene works directly on skeletal muscles by interfering with the release of calcium ions from the sarcoplasmic reticulum.
• This action helps prevent or reduce the increase in calcium ion concentration within muscle cells.
• By doing so, dantrolene inhibits the activation of acute catabolic processes associated with malignant hyperthermia, a condition characterized by dangerously high body temperatures and muscle rigidity triggered by certain medications used during anesthesia.

Absorption:

• Oral dantrolene is absorbed to about 70% from the gastrointestinal tract.

Distribution:

• Volume of distribution (V): Approximately 36.4 ± 11.7 liters.

Metabolism:

• Dantrolene is metabolized in the liver.
• Major metabolites include 5-hydroxy dantrolene and an acetylamino metabolite of dantrolene.

Half-life Elimination:

• Neonates (at birth): Around 20 hours.
• Children aged 2 to 7 years: Approximately 10 hours, with a range of 8.1 to 14.8 hours.
• Adults: Typically between 4 to 11 hours.

Time to Peak:

• Intravenous administration: Dantrolene reaches peak levels 1 minute post-dose, while its major metabolite, 5-hydroxy dantrolene, peaks 24 hours post-dose.

Excretion:

• Dantrolene and its metabolites are primarily excreted via feces (45% to 50%).
• About 25% of the drug and its metabolites are excreted unchanged in urine.

International Brands of Dantrolene:

• Dantrium
• Revonto
• Ryanodex
• Anorex
• Dantamacrin
• Dantrelax
• Dantrium
• Dantrolen
• Dantromove
• Degison
• Mobicont
• Relaxo
• Ryanorelax

Dantrolene Brands in Pakistan:

No Brands Available in Pakistan.

Dantrolene is a medication primarily used to treat muscle spasticity and muscle spasms. It works by acting directly on skeletal muscles to relax them. Dantrolene is often prescribed for conditions such as multiple sclerosis, cerebral palsy, spinal cord injury, and stroke, where muscle spasticity can be a significant issue.

One of the unique aspects of dantrolene is its mechanism of action. It interferes with the release of calcium ions from the sarcoplasmic reticulum within muscle cells. Calcium ions are crucial for muscle contraction, so by blocking their release, dantrolene effectively reduces muscle tone and spasticity.

Dantrolene (Dantrolen) is a post-synaptic muscle relaxant. It is available as an oral and intravenous formulation.

Dantrolene Uses:

• Chronic spasticity:
  • Oral dantrolene is used in the treatment of spasticity associated with upper motor neuron disorders (eg, spinal cord injury, stroke, cerebral palsy, or multiple sclerosis).
• Malignant hyperthermia:
  • Intravenous administration of dantrolene is recommended in the management of malignant hyperthermia crisis followed by oral or intravenous dose to prevent a recurrence.

Note: Dantrolene is not recommended as a pre-prophylaxis drug in patients who are susceptible to malignant hyperthermia crisis during a surgery, provided non-triggering anesthetic agents are used.

• Off Label Use of Dantrolene in Adults:
  • Neuroleptic malignant syndrome

Dantrolene Dose in Adults

Dantrolene Dosage for the Chronic Treatment of spasticity: 

To treat chronic spasticity with dantrolene in oral form, here's a simplified dosing guide:

• Start with 25 mg once a day for a week.
• Then increase to 25 mg three times a day for a week.
• After that, increase to 50 mg three times a day for another week.
• Finally, increase to 100 mg three times a day. Some patients might need 100 mg four times a day.
• The maximum daily dose is 400 mg.

It's crucial to adjust the dose carefully for each person. If there's no improvement after trying higher doses, it's best to go back to the previous dose level. If there's no benefit seen within 45 days, the treatment should be stopped due to the risk of liver problems.

Dantrolene dose for the treatment of Malignant hyperthermia (MH):

For the treatment of malignant hyperthermia (MH), here's a simplified dosing guide:

During Crisis:

• Initially, administer 2.5 mg/kg of dantrolene through intravenous (IV) injection.
• Continuously monitor the patient's condition.
• If symptoms persist, give additional doses of 1 mg/kg until symptoms subside or a total dose of 10 mg/kg is reached.

Post-Crisis Follow-up and Prevention of Recurrence:

• According to MHAUS protocol recommendation, administer 1 mg/kg of dantrolene every 4 to 6 hours. The route of administration is not specified.
• The manufacturer's labeling suggests oral dosing of 4 to 8 mg/kg per day, divided into four doses, for 1 to 3 days. IV dantrolene may be used if oral therapy is not feasible. The initial dose should be 1 mg/kg or higher, adjusted based on the clinical situation.

Remember to discontinue all MH-triggering agents once the hyperthermia crisis is recognized and provide supportive care. If there's an emergency, contact the MH Hotline provided for immediate assistance.

Dantrolen Dose in the treatment of Neuroleptic malignant syndrome as off-label use:

In the treatment of Neuroleptic Malignant Syndrome (NMS), here's a simplified dosing guide for dantrolene:

Initial Treatment:

• Administer dantrolene intravenously (IV) at a dose of 1 to 2.5 mg/kg initially.
• If rapid improvement in hyperthermia and muscle rigidity is observed, continue with 1 mg/kg every 6 hours.
• The maximum cumulative dose should not exceed 10 mg/kg per day.

Switch to Oral Dosage:

• After achieving stability with IV dantrolene, switch to oral dosage for continued treatment.

Combination Therapy:

• Based on the analysis of case reports, combining dantrolene with other therapies like bromocriptine may be preferred over dantrolene alone. This combination has shown lower mortality rates and longer complete remission periods.

Dantrolene Dose in Childrens

Dantrolene Dose in the treatment of Spasticity:

For treating spasticity with dantrolene orally, here's a simplified dosing guide:

Manufacturer's Labeling:

• Children and Adolescents ≥5 years (Patient weight <50 kg):
  • Start with 0.5 mg/kg/dose once daily for 7 days.
  • Then increase to 0.5 mg/kg/dose three times daily for 7 days.
  • Further increase to 1 mg/kg/dose three times daily for 7 days.
  • Finally, increase to 2 mg/kg/dose three times daily. Some patients may need 2 mg/kg/dose four times daily.
  • The maximum daily dose is 400 mg.
• Children and Adolescents ≥5 years (Patient weight ≥50 kg):
  • Begin with 25 mg once daily for 7 days.
  • Then increase to 25 mg three times daily for 7 days.
  • Progress to 50 mg three times daily for 7 days.
  • Finally, increase to 100 mg three times daily. Some patients may need 100 mg four times daily.
  • The maximum daily dose is 400 mg.

Alternate Dosing:

• Children and Adolescents:
  • Start with 0.5 mg/kg/dose twice daily, up to a maximum of 25 mg per dose.
  • Adjust frequency every 4 to 7 days to achieve desired effects, then increase the dose by 0.5 mg/kg increments weekly.
  • The maximum daily dose is either 12 mg/kg/day or 400 mg/day, whichever is lower.

Remember to titrate the dose to achieve the desired effect. If no further benefit is seen at higher dosages, decrease the dose to the previous level.

Dantrolene Dose in the treatment of Malignant hyperthermia in infants, children, and adolescents:

For the treatment of Malignant Hyperthermia (MH) in infants, children, and adolescents, here's a simplified dosing guide for dantrolene:

Preoperative Prophylaxis:

• Oral: Administer 4 to 8 mg/kg/day in 3 to 4 divided doses for 1 to 2 days before surgery, with the last dose given approximately 3 to 4 hours before the scheduled surgery.
• IV: Give 2.5 mg/kg/dose approximately 1.25 hours before surgery. Administer over at least 1 minute (Ryanodex) or 1 hour (Dantrium, Revonto). Additional doses should be given as needed and individualized.

During Crisis:

• IV:
  • Follow MHAUS protocol recommendation: Administer 2.5 mg/kg, repeating the dose continuously until symptoms subside or a cumulative dose of 10 mg/kg is reached. In rare cases, some patients may require up to 30 mg/kg for initial treatment.
  • Manufacturer's labeling: Start with an initial minimum dose of 1 mg/kg. Repeat dosing with a minimum of 1 mg/kg until symptoms subside or a cumulative dose of 10 mg/kg is reached.

Post-Crisis Follow-up:

• According to MHAUS protocol recommendation:
  • Administer 1 mg/kg every 4 to 6 hours (route not specified), or a continuous IV infusion of 0.25 mg/kg/hour for at least 24 hours. Further doses may be necessary.
• Manufacturer's labeling suggests oral administration of 4 to 8 mg/kg/day in 4 divided doses for 1 to 3 days. IV dantrolene may be used if oral therapy is impractical, starting with a dose of 1 mg/kg or more as deemed appropriate based on the clinical situation.

Pregnancy Risk Factor C

• In animal studies, adverse effects have been noted during pregnancy with dantrolene.
• The medication crosses the placenta, reaching similar concentrations in the newborn's blood as in the mother's bloodstream during delivery.
• Maternal doses of up to 100 mg/day orally before birth haven't shown adverse effects on newborns.
• However, after delivery, dantrolene injection may lead to uterine atony, possibly due in part to the mannitol in the IV preparation.
• While prophylactic use of dantrolene isn't generally recommended for pregnant women susceptible to malignant hyperthermia (MH) before obstetric surgery, if needed, close monitoring of both mother and newborn is advised.

Dantrolene use during breastfeeding:

• Dantrolene can be found in breast milk, but in small amounts.
• Due to the possibility of serious side effects in nursing infants, the manufacturer advises considering whether to stop breastfeeding or discontinue the medication, considering the importance of treatment for the mother.
• In a case report, the half-life of dantrolene in breast milk was estimated to be 9 hours, with the highest milk concentration reaching 1.2 mcg/mL after a maternal IV dose.
• However, the levels of dantrolene in the mother's blood were not provided.

Dantrolen dose in Renal impairment:

The manufacturer's labeling does not specify any dosage adjustments for individuals with renal impairment.

Dantrolen Dose in liver disease:

• The manufacturer's labeling does not offer any dosage adjustments, and the use of oral dantrolene is contraindicated in patients with active liver disease, such as hepatitis and cirrhosis.

Side effects of Dantrolen:

• Cardiovascular:
  • Flushing
  • Atrioventricular Block
  • Tachycardia
  • Cardiac Failure
  • Phlebitis
  • Variable Blood Pressure
• Central Nervous System:
  • Drowsiness
  • Voice Disorder
  • Feeling Abnormal
  • Dizziness
  • Headache
  • Myasthenia
  • Chills
  • Choking Sensation
  • Confusion
  • Depression
  • Fatigue
  • Insomnia
  • Malaise
  • Nervousness
  • Seizure
  • Speech Disturbance
• Dermatologic:
  • Acneiform Eruption
  • Diaphoresis
  • Eczematous Rash
  • Erythema
  • Hair Disease
  • Pruritus
  • Urticaria
• Gastrointestinal:
  • Dysphagia
  • Nausea
  • Vomiting
  • Abdominal Cramps
  • Anorexia
  • Constipation
  • Diarrhea
  • Dysgeusia
  • Gastric Irritation
  • Gastrointestinal Hemorrhage
  • Sialorrhea
• Genitourinary:
  • Crystalluria
  • Difficulty In Micturition
  • Erectile Dysfunction
  • Hematuria
  • Nocturia
  • Urinary Frequency
  • Urinary Incontinence
  • Urinary Retention
• Hematologic & Oncologic:
  • Anemia
  • Aplastic Anemia
  • Leukopenia
  • Lymphocytic Lymphoma
  • Thrombocytopenia
• Hepatic:
  • Hepatitis
• Hypersensitivity:
  • Anaphylaxis
• Local:
  • Injection Site Reaction
  • Local Tissue Necrosis
• Neuromuscular & Skeletal:
  • Limb Pain
  • Back Pain
  • Myalgia
• Ophthalmic:
  • Blurred Vision
  • Diplopia
  • Epiphora
  • Visual Disturbance
• Respiratory:
  • Dyspnea
  • Pleural Effusion
  • Pulmonary Edema
  • Respiratory Depression
• Miscellaneous:
  • Fever

Contraindications Of Dantrolene:

• Intravenous (IV) administration of dantrolene doesn't have any contraindications listed in the manufacturer's labeling.
• However, for oral use, the medication is contraindicated in individuals with active hepatic disease such as cirrhosis or hepatitis.
• Additionally, oral dantrolene should not be used when spasticity is necessary to maintain upright posture or balance during movement, or when it's needed to achieve or sustain improved function.

Dantrolen Warnings & Precautions

Central Nervous System depression:

• Dantrolene may lead to central nervous system (CNS) depression, potentially affecting both physical and mental capabilities.
• Patients should be warned about engaging in activities requiring mental alertness, such as operating machinery or driving, as their abilities may be impaired while taking this medication.

Hepatotoxicity: [US Boxed Warning]

• Dantrolene carries a significant risk of hepatotoxicity, as highlighted by a boxed warning in the United States.
• Both fatal and nonfatal symptomatic hepatitis cases have been reported.
• Higher doses, even short courses exceeding 800 mg/day, may heighten the risk of severe liver injury, though it can occur at doses below 400 mg/day.
• Hepatitis symptoms are most frequently observed between the third and twelfth month of therapy.
• Females, individuals over 35 years old, and those taking other medications concurrently are at increased risk.
• Fatal liver events are more common in the elderly, possibly influenced by other health conditions and concurrent use of potentially harmful drugs.
• Liver reactions, including hypersensitivity reactions, can be fatal.
• Regular monitoring of liver function is advised during treatment.
• If symptoms of hepatitis or abnormal liver function tests develop, or if there's no improvement within 45 days of therapy initiation for chronic spasticity, treatment should be discontinued.
• Hepatic function typically returns to normal after stopping the medication.
• If re-treatment is necessary, it should be done cautiously with very small and gradual dose increases, preferably under hospital supervision.

Muscle weakness

• Intravenous dantrolene has been associated with muscle weakness, including loss of grip strength, weakness in the legs, difficulty breathing (dyspnea) due to respiratory muscle weakness, difficulty swallowing (dysphagia), and decreased ability to breathe deeply (decreased inspiratory capacity).
• Patients should not attempt to walk without assistance until they have regained normal strength and balance.
• Continuous monitoring for adequate ventilation and signs of swallowing difficulties or choking is essential.

Photosensitivity

• Oral dantrolene therapy can trigger photosensitivity reactions.
• Patients should exercise caution when exposed to sunlight while taking this medication.
• It's advisable to take preventive measures such as wearing protective clothing and using sunscreen to minimize the risk of sun-related skin reactions.

Pleural effusion:

• Dantrolene use may lead to the development of pleural effusion, accompanied by increased levels of eosinophils in the pleural fluid.
• This condition involves the accumulation of fluid in the space surrounding the lungs.

Cardiovascular disease

• Oral dantrolene therapy should be approached with caution in patients with severely impaired cardiac function attributed to myocardial disease.
• Individuals with significant heart conditions may be at increased risk of adverse cardiovascular effects while taking this medication.

Hepatic disease

• Oral dantrolene therapy should be approached cautiously in patients with a history of hepatic disease or dysfunction.
• However, its use is contraindicated in individuals with active hepatic disease, such as cirrhosis or hepatitis.
• Patients with pre-existing liver conditions may be at an increased risk of experiencing adverse effects or exacerbating liver dysfunction while taking this medication.

Respiratory disease

• Oral dantrolene therapy should be used cautiously in patients with impaired pulmonary function, especially those with obstructive pulmonary disease.
• Individuals with pre-existing respiratory conditions may be more susceptible to respiratory depression or exacerbation of their underlying condition while taking this medication.

Dantrolene: Drug Interaction

Note: Drug Interaction Categories:

• Risk Factor C: Monitor When Using Combination
• Risk Factor D: Consider Treatment Modification
• Risk Factor X: Avoid Concomitant Use

Risk Factor C (Monitor therapy).
Alcohol (Ethyl)	CNS Depressants can increase the CNS depressant effects of Alcohol (Ethyl).
Alizapride	CNS Depressants may increase the CNS depressant effects.
Bosentan	Could lower serum concentrations of CYP3A4 substrates (High Risk with Inducers).
Brexanolone	CNS Depressants can increase the CNS depressant effects of Brexanolone.
Brimonidine (Topical)	CNS Depressants may increase the CNS depressant effects.
Bromopride	CNS Depressants may increase the CNS depressant effects.
Cannabidiol	CNS Depressants may increase the CNS depressant effects.
Cannabis	CNS Depressants may increase the CNS depressant effects.
Chlorphenesin Carbamate	CNS Depressants may have an adverse/toxic effect that can be exacerbated by them.
CNS Depressants	Can increase the toxic/adverse effects of CNS Depressants.
Moderate CYP3A4 Inducers	Could lower serum concentrations of CYP3A4 substrates (High Risk with Inducers).
Deferasirox	Could lower serum concentrations of CYP3A4 substrates (High Risk with Inducers).
Dexketoprofen	Dantrolene may have an adverse/toxic effect.
Dimethindene (Topical).	CNS Depressants may increase the CNS depressant effects.
Doxylamine	CNS Depressants may have a greater CNS depressant effect if taken with other CNS Depressants. Management: The manufacturer of Diclegis (doxylamine/pyridoxine), intended for use in pregnancy, specifically states that use with other CNS depressants is not recommended.
Dronabinol	CNS Depressants may increase the CNS depressant effects.
Erdafitinib	Could lower serum concentrations of CYP3A4 substrates (High Risk with Inducers).
Esketamine	CNS Depressants may increase the CNS depressant effects.
Estrogen Derivatives	Might increase the hepatotoxic effects of Dantrolene.
HydrOXYzine	CNS Depressants may increase the CNS depressant effects.
Ivosidenib	Could lower serum concentrations of CYP3A4 substrates (High Risk with Inducers).
Kava Kava	CNS Depressants may have an adverse/toxic effect that can be exacerbated by them.
Lacidipine	Dantrolene may have an adverse/toxic effect.
Lofexidine	CNS Depressants may have a greater depressant effect on the brain. Management: Separate drug interaction monographs are available for drugs listed as an exception to this monograph.
Magnesium Sulfate	CNS Depressants may increase the CNS depressant effects.
MetyroSINE	MetyroSINE may have a sedative effect that can be enhanced by CNS depressants.
Minocycline	CNS Depressants may increase the CNS depressant effects.
Mirtazapine	CNS Depressants can increase the CNS depressant effects of Mirtazapine.
Nabilone	CNS Depressants may increase the CNS depressant effects.
Piribedil	CNS Depressants could increase the CNS depressant effects of Piribedil.
Pramipexole	Pramipexole may have a greater sedative effect if it is combined with CNS depressants.
ROPINIRole	CNS Depressants can increase the sedative effects of ROPINIRole.
Rotigotine	CNS Depressants can increase the sedative effects of Rotigotine.
Rufinamide	CNS Depressants may have an adverse/toxic effect that can be exacerbated by this. Particularly, dizziness and sleepiness may be increased.
Sarilumab	Could lower serum concentrations of CYP3A4 substrates (High Risk with Inducers).
Selective Serotonin Reuptake inhibitors	CNS Depressants can increase the toxic/adverse effects of Selective Serotonin Resuptake Inhibitors. Particularly, psychomotor impairment could be increased.
Siltuximab	Could lower serum concentrations of CYP3A4 substrates (High Risk with Inducers).
Tetrahydrocannabinol	CNS Depressants may increase the CNS depressant effects.
Tetrahydrocannabinol, and Cannabidiol	CNS Depressants may increase the CNS depressant effects.
Tocilizumab	Could lower serum concentrations of CYP3A4 substrates (High Risk with Inducers).
Trimeprazine	CNS Depressants may increase the CNS depressant effects.
Vecuronium	Dantrolene may enhance the neuromuscular-blocking effect of Vecuronium.
Risk Factor D (Regard therapy modification)
Blonanserin	CNS Depressants can increase the CNS depressant effects of Blonanserin.
Buprenorphine	CNS Depressants can increase the CNS depressant effects of buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Buprenorphine patches (Butrans) should be initiated at 5 mg/hr for adults when taken with other CNS depression drugs.
Chlormethiazole	CNS Depressants may increase the CNS depressant effects. Monitoring: Look out for signs of CNS depression. If a combination of chlormethiazole and other drugs is required, a reduced dose should be used.
Strong CYP3A4 Inducers	May increase metabolism of CYP3A4 substrates (High Risk with Inducers). Management: You may consider a different drug to replace one of the interacting drugs. Some combinations might be contraindicated. Consult appropriate manufacturer labeling.
Dabrafenib	High risk of Inducers causing a decrease in serum CYP3A4 substrates. Management: If possible, seek alternatives to the CYP3A4 substrate. Concomitant therapy should be avoided if possible. Monitor the clinical effects of the substrate carefully (especially therapeutic effects).
Droperidol	CNS Depressants may increase the CNS depressant effects. Management: Droperidol and other CNS agents, such as opioids, may be reduced or used in combination with droperidol. Separate drug interaction monographs provide more detail on exceptions to this monograph.
Enzalutamide	High risk of Inducers causing a decrease in serum concentrations of CYP3A4 substrates. Management: Avoid concurrent use of enzalutamide and CYP3A4 substrates with a narrow therapeutic index. You should exercise caution when using enzalutamide or any other CYP3A4 sub-substance.
Flunitrazepam	CNS Depressants can increase the CNS depressant effects of Flunitrazepam.
HYDROcodone	CNS Depressants can increase the CNS depressant effects of HYDROcodone. When possible, avoid concomitant use with hydrocodone and other CNS depressants. Combining these agents is not recommended unless there are other options. Limit the amount and duration of each drug when combined.
Lorlatinib	High risk of Inducers causing a decrease in serum concentrations of CYP3A4 substrates. Management: Do not use lorlatinib concurrently with any CYP3A4 Substrates. Even a slight decrease in serum concentrations could cause therapeutic failure or serious clinical consequences.
Methotrimeprazine	Methotrimeprazine may have a higher CNS depressant activity than CNS Depressants. Methotrimeprazine can increase the CNS depressant effects of CNS Depressants. Management: Lower the adult dose of CNS Depressants by 50% and start concomitant methotrimeprazine treatment. After clinically proven efficacy of methotrimeprazine, further CNS depressant dose adjustments should only be made.
Mitotane	High risk of Inducers causing a decrease in serum concentrations of CYP3A4 substrates. Treatment: Patients receiving mitotane may require significant adjustments in the dosage of CYP3A4 Substrates.
Opioid Agonists	CNS Depressants can increase the CNS depressant effects of Opioid Aggonists. Management: When possible, avoid concomitant use opioid agonists and other CNS depressants. Combining these agents is not recommended unless there are other options. Limit the amount and duration of each drug when combined.
OxyCODONE	CNS Depressants can increase OxyCODONE's CNS depressant effects. When possible, avoid the simultaneous use of oxycodone and other CNS depressants. Combining these agents is not recommended unless there are other options. Limit the amount and duration of each drug when combined.
Perampanel	CNS Depressants may have a greater CNS depressant effect. Perampanel and any other CNS depressant drug should be used in combination. Patients who take perampanel together with any other drug should not engage in complex or high-risk activities until they have had experience using the combination.
Pitolisant	High risk of Inducers causing a decrease in serum concentrations of CYP3A4 substrates Management: Avoid combining pitolisant and a CYP3A4 substrat with a low therapeutic index. Pitolisant should not be combined with other CYP3A4 sub-substances.
Sodium Oxybate	CNS Depressants may have a greater depressant effect if taken in combination. Management: Look for alternatives to the combination use. If you must combine use, reduce the doses of any one or more drugs. It is not recommended to combine sodium oxybate and alcohol, or any sedative hypnotics.
St John's Wort	High risk of Inducers causing a decrease in serum CYP3A4 Substrates. Management: You may consider a different drug to replace one of the interacting drugs. Some combinations might be contraindicated. Consult appropriate manufacturer labeling.
Suvorexant	CNS Depressants can increase the CNS depressant effects of Suvorexant. Management: Suvorexant or any other CNS depressionant can be reduced in doses. Suvorexant should not be taken with alcohol. It is also not recommended to take suvorexant along with any other drugs for insomnia.
Tapentadol	CNS Depressants may increase the CNS depressant effects. Tapentadol, benzodiazepines and other CNS depressants should be avoided when possible. Combining these agents is not recommended unless there are other options. Limit the amount and duration of each drug when combined.
Zolpidem	CNS Depressants can increase the CNS depressant effects of Zolpidem. Management: For men who also take CNS depressants, reduce the adult Intermezzo brand sublingual Zolpidem dose to 1.75mg. For women, no dose adjustment is advised. Avoid using CNS depressants at night; do not use alcohol.
Risk Factor X (Avoid Combination)
Azelastine (Nasal)	CNS Depressants could increase the CNS depressant effects of Azelastine.
Bromperidol	CNS Depressants may increase the CNS depressant effects.
Calcium Channel Blockers (Nondihydropyridine)	Dantrolene may enhance the hyperkalemic effect of Calcium Channel Blockers (Nondihydropyridine). Dantrolene may enhance the negative inotropic effect of Calcium Channel Blockers (Nondihydropyridine). Management: This interaction was only described in intravenous dantrolene administration.
Orphenadrine	Orphenadrine may be more effective against CNS depression than other drugs.
Oxomemazine	CNS Depressants may increase the CNS depressant effects.
Paraldehyde	Paraldehyde may be enhanced by CNS depressants.
Thalidomide	CNS Depressants can increase Thalidomide's CNS depressant effects.

Monitor:

Monitoring for Therapeutic Outcomes:

• Assess motor performance regularly to evaluate treatment effectiveness.
• Monitor for common side effects such as nausea and vomiting.
• Conduct baseline liver function tests before starting treatment and periodically thereafter to watch for potential liver problems.
• For intravenous administration, closely monitor cardiac function, blood pressure, and respiratory status.

Malignant Hyperthermia Management:

• During and Post-Acute Phase:
  • Adhere to MHAUS protocol, ensuring patient observation in an ICU for at least 24 hours due to the possibility of recrudescence.
  • Monitor for arrhythmias and other cardiac complications.
  • Keep a close watch on vital signs, including core temperature.
  • Check electrolyte levels, arterial blood gases (ABG), and creatine kinase (CK) levels.
  • Utilize end-tidal CO2 (EtCO2) monitoring or capnography.
  • Monitor urine output and urine myoglobin levels for signs of muscle breakdown.

Administration of Dantrolene:

IV Administration:

• Therapeutic or emergency doses can be given rapidly as a continuous IV push.
• Subsequent doses should be administered over at least 1 minute (for Ryanodex) or 1 hour (for Dantrium, Revonto) to minimize adverse effects.

Vesicant Precautions:

• Dantrolene is a vesicant, so ensure proper needle or catheter placement before and during infusion to prevent extravasation.
• Take precautions to avoid extravasation during administration.

Extravasation Management:

• If extravasation occurs, halt the infusion immediately and disconnect the line, but leave the needle or cannula in place.
• Gently aspirate any extravasated solution without flushing the line.
• Remove the needle or cannula and elevate the affected extremity to minimize swelling and discomfort.

Mechanism of action of Dantrolene (Dantrolen):

• Dantrolene works directly on skeletal muscles by interfering with the release of calcium ions from the sarcoplasmic reticulum.
• This action helps prevent or reduce the increase in calcium ion concentration within muscle cells.
• By doing so, dantrolene inhibits the activation of acute catabolic processes associated with malignant hyperthermia, a condition characterized by dangerously high body temperatures and muscle rigidity triggered by certain medications used during anesthesia.

Absorption:

• Oral dantrolene is absorbed to about 70% from the gastrointestinal tract.

Distribution:

• Volume of distribution (V): Approximately 36.4 ± 11.7 liters.

Metabolism:

• Dantrolene is metabolized in the liver.
• Major metabolites include 5-hydroxy dantrolene and an acetylamino metabolite of dantrolene.

Half-life Elimination:

• Neonates (at birth): Around 20 hours.
• Children aged 2 to 7 years: Approximately 10 hours, with a range of 8.1 to 14.8 hours.
• Adults: Typically between 4 to 11 hours.

Time to Peak:

• Intravenous administration: Dantrolene reaches peak levels 1 minute post-dose, while its major metabolite, 5-hydroxy dantrolene, peaks 24 hours post-dose.

Excretion:

• Dantrolene and its metabolites are primarily excreted via feces (45% to 50%).
• About 25% of the drug and its metabolites are excreted unchanged in urine.

International Brands of Dantrolene:

• Dantrium
• Revonto
• Ryanodex
• Anorex
• Dantamacrin
• Dantrelax
• Dantrium
• Dantrolen
• Dantromove
• Degison
• Mobicont
• Relaxo
• Ryanorelax

Dantrolene Brands in Pakistan:

Not available.