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DANTROLENE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Dantrolene is a direct-acting skeletal muscle relaxant, affecting the contractile response of the muscle at a site beyond the myoneural junction.

Specific Substances

    1) Dantrolene sodium
    2) F-368 (dantrolene)
    3) F-440 (dantrolene sodium)
    4) Molecular Formula: C14-H9-N4-Na-O5, 3 1/2H2-O
    5) CAS 7261-97-4 (dantrolene)
    6) CAS 14663-23-1 (anhydrous dantrolene sodium)
    7) CAS 24868-20-0 (dantrolene sodium, hemiheptahydrate)
    1.2.1) MOLECULAR FORMULA
    1) C14H9N4NaO5 x 3-1/2H2O

Available Forms Sources

    A) FORMS
    1) Dantrolene is available as 25-mg, 50-mg, and 100-mg capsules, and as 70-mL vials containing 20 mg dantrolene when reconstituted with 60 mL of sterile water for injection (Prod Info Revonto(R) intravenous injection, 2014; Prod Info dantrolene sodium oral capsules, 2013).
    B) USES
    1) Dantrolene is indicated for controlling the manifestations of chronic spasticity from upper motor neuron disorders (eg, spinal cord injury, stroke, cerebral palsy, or multiple sclerosis) (Prod Info Revonto(R) intravenous injection, 2014; Prod Info dantrolene sodium oral capsules, 2013).
    2) Dantrolene is indicated for the management of malignant hyperthermia crises, for the preoperative prophylaxis or attenuation of malignant hyperthermia in malignant hyperthermia-susceptible patients, and for prevention of a recurrence of malignant hyperthermia following the occurrence of a malignant hyperthermic crisis (Prod Info Revonto(R) intravenous injection, 2014; Prod Info dantrolene sodium oral capsules, 2013).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Dantrolene is indicated for controlling the manifestations of chronic spasticity from upper motor neuron disorders (eg, spinal cord injury, stroke, cerebral palsy, or multiple sclerosis). It is also indicated for the management of malignant hyperthermia crises, for the preoperative prophylaxis or attenuation of malignant hyperthermia in malignant hyperthermia-susceptible patients, and for prevention of a recurrence of malignant hyperthermia following the occurrence of a malignant hyperthermic crisis.
    B) PHARMACOLOGY: Dantrolene sodium induces skeletal muscle relaxation by directly affecting the contractile response. It is suggested that its interference with the release of calcium ions from the sarcoplasmic reticulum results in the dissociation of the excitation-contraction coupling in skeletal muscle.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON: Muscle weakness, drowsiness, dizziness, fatigue, confusion, nervousness, nausea, diarrhea, thrombophlebitis, urticaria, erythema, inject site reactions (eg, pain, erythema, swelling) and tissue necrosis secondary to extravasation.
    2) OTHER EFFECTS: Tachycardia, erratic blood pressure, pleural effusion, pericarditis, phlebitis, heart failure, atrioventricular block, acne-like rash, photosensitivity reactions, flushing, pruritus, vomiting, abdominal pain, constipation (rarely progressing into intestinal obstruction), difficulty in swallowing and choking, anorexia, gastrointestinal bleeding, urogenital symptoms (ie, increased urinary frequency, crystalluria, hematuria, difficult erection, urinary incontinence and/or nocturia, difficult urination and/or urinary retention), visual disturbances, excessive tearing, diplopia, aplastic anemia, leukopenia, thrombocytopenia, anaphylaxis, skeletal muscle weakness, myalgias, backache, drowsiness, lightheadedness, dizziness, vertigo, malaise, giddiness, somnolence, insomnia, headache, difficulty speaking, mental depression, dyspnea, eosinophilic pleural effusion, pleural fibrosis, respiratory depression, respiratory failure, and pulmonary edema.
    3) Fatal and non-fatal hepatitis have been reported with prolonged dantrolene therapy. Fatalities appear to be associated with the following factors: patient age over 30 years, duration of use over 2 months, female gender, higher daily doses (300 mg or more), concomitant drugs and disease, and higher bilirubin levels.
    E) WITH POISONING/EXPOSURE
    1) Dantrolene overdose data are limited. Muscular weakness, lethargy, coma, vomiting, diarrhea, and crystalluria may occur in the event of an overdose. In one case series, lethargy was the only adverse effect reported following dantrolene overdose ingestions of 10 to 12 mg/kg.
    0.2.20) REPRODUCTIVE
    A) Dantrolene is classified as FDA pregnancy category C. Dantrolene has been shown to cross the placenta in two studies. Neither study showed adverse effects in the infants following maternal dantrolene use. In a case report, dantrolene IV was associated with uterine atony and hemorrhage requiring a hysterectomy. In animal studies, dantrolene was embryocidal and reduced pup survival. Dantrolene was also detected in the breast milk at low concentrations, but there was no evidence of adverse effects to the nursing infants.
    0.2.21) CARCINOGENICITY
    A) The long-term safety of dantrolene has not been established in humans.

Laboratory Monitoring

    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs and mental status.
    C) Obtain a baseline ECG and institute continuous cardiac monitoring in patients with tachycardia.
    D) Monitor for muscle weakness and respiratory depression.
    E) Monitor CBC with differential, liver enzymes, and renal function after significant overdose.
    F) Monitor serum electrolytes in patients with severe vomiting and/or diarrhea.
    G) Monitor arterial blood gases, pulse oximetry, and pulmonary function tests, and obtain a chest x-ray in any patient with respiratory symptoms.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Administer IV fluids to avoid crystalluria following intravenous exposure. In patients with acute allergic reaction, oxygen therapy, bronchodilators, diphenhydramine, corticosteroids, vasopressors and epinephrine may be required. Correct any significant fluid and/or electrolyte abnormalities in patients with severe diarrhea and/or vomiting. Alterations in heart rhythm and blood pressure may occur. Sinus tachycardia does not generally require treatment unless hemodynamic compromise is present.
    C) DECONTAMINATION
    1) PREHOSPITAL: Prehospital gastrointestinal decontamination is generally not recommended because of the potential for CNS depression and subsequent aspiration.
    2) HOSPITAL: Consider activated charcoal if the overdose is recent, the patient is not vomiting, and is able to maintain airway.
    D) AIRWAY MANAGEMENT
    1) Ensure adequate ventilation and perform endotracheal intubation early in patients with significant CNS depression, severe respiratory distress or allergic reactions.
    E) ANTIDOTE
    1) None.
    F) DYSPNEA
    1) Monitor respiratory function. Assess for evidence of fluid retention (eg, pleural effusion, pulmonary edema). Evaluate and monitor airway patency and adequacy of respiration and oxygenation. Treatment may consist of diuretic therapy to manage fluid retention, as well as supplemental oxygen. If symptoms are severe, endotracheal intubation and assisted ventilation may be indicated. Obtain a baseline chest x-ray in symptomatic patients; repeat as indicated.
    G) ENHANCED ELIMINATION
    1) It is unknown if hemodialysis would be effective in overdose
    H) PATIENT DISPOSITION
    1) HOME CRITERIA: A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    2) OBSERVATION CRITERIA: Patients with a deliberate overdose, and those who are symptomatic, need to be monitored until they are clearly improving and clinically stable.
    3) ADMISSION CRITERIA: Patients with severe symptoms despite treatment should be admitted.
    4) CONSULT CRITERIA: Consult a regional poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    I) PITFALLS
    1) When managing a suspected overdose, the possibility of multidrug involvement should be considered.
    J) PHARMACOKINETICS
    1) Absorption: Following oral administration, dantrolene's absorption is incomplete with approximately 70% of a dose absorbed. Protein binding: Significant amounts of dantrolene are bound to plasma proteins, primarily to albumin. Vd: 0.54 L/kg. Metabolism: Metabolized in the liver by hydroxylation of the hydantoin ring to 5-hydroxy-dantrolene. Excretion: Approximately 20% of an administered oral dose (or 80% of the absorbed dose) is excreted in the urine as metabolites. Elimination half-life: 8.7 hours after ingestion of a 100-mg dose.
    K) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that may cause CNS depression, acute lung injury, or hepatotoxicity.

Range Of Toxicity

    A) TOXICITY: A specific toxic dose has not been established. Lethargy was the only adverse effect reported following dantrolene overdose ingestions of 10 to 12 mg/kg.
    B) THERAPEUTIC DOSE: Malignant Hyperthermia (Acute): ADULT or PEDIATRIC: 1 mg/kg IV by continuous rapid IV push and continue until symptoms subside or a maximum cumulative dose of 10 mg/kg. Post Crisis Follow-up: ADULT or PEDIATRIC: 4 to 8 mg/kg/day orally in 4 divided doses, for a 1- to 3-day period as indicated. Chronic Spasticity: ADULT: Initial: 25 mg orally once daily then increase to 25 mg 2 to 4 times daily up to 100 mg 2 to 4 times daily if necessary. Rarely should the dose exceed 400 mg/day. PEDIATRIC: Initial: 0.5 mg/kg orally twice daily; increase to 0.5 mg/kg 3 or 4 times daily then by increments of 0.5 mg/kg up to as high as 2 mg/kg 2 to 4 times daily as needed. Do not exceed 400 mg daily. NOTE: For oral use, the manufacturer states that long-term safety has NOT been established in pediatric patients under 5 years of age. For IV use, the manufacturer states that the pediatric weight-based dosing is the same as the adult dose.

Clinical Effects

Summary Of Exposure

    A) USES: Dantrolene is indicated for controlling the manifestations of chronic spasticity from upper motor neuron disorders (eg, spinal cord injury, stroke, cerebral palsy, or multiple sclerosis). It is also indicated for the management of malignant hyperthermia crises, for the preoperative prophylaxis or attenuation of malignant hyperthermia in malignant hyperthermia-susceptible patients, and for prevention of a recurrence of malignant hyperthermia following the occurrence of a malignant hyperthermic crisis.
    B) PHARMACOLOGY: Dantrolene sodium induces skeletal muscle relaxation by directly affecting the contractile response. It is suggested that its interference with the release of calcium ions from the sarcoplasmic reticulum results in the dissociation of the excitation-contraction coupling in skeletal muscle.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON: Muscle weakness, drowsiness, dizziness, fatigue, confusion, nervousness, nausea, diarrhea, thrombophlebitis, urticaria, erythema, inject site reactions (eg, pain, erythema, swelling) and tissue necrosis secondary to extravasation.
    2) OTHER EFFECTS: Tachycardia, erratic blood pressure, pleural effusion, pericarditis, phlebitis, heart failure, atrioventricular block, acne-like rash, photosensitivity reactions, flushing, pruritus, vomiting, abdominal pain, constipation (rarely progressing into intestinal obstruction), difficulty in swallowing and choking, anorexia, gastrointestinal bleeding, urogenital symptoms (ie, increased urinary frequency, crystalluria, hematuria, difficult erection, urinary incontinence and/or nocturia, difficult urination and/or urinary retention), visual disturbances, excessive tearing, diplopia, aplastic anemia, leukopenia, thrombocytopenia, anaphylaxis, skeletal muscle weakness, myalgias, backache, drowsiness, lightheadedness, dizziness, vertigo, malaise, giddiness, somnolence, insomnia, headache, difficulty speaking, mental depression, dyspnea, eosinophilic pleural effusion, pleural fibrosis, respiratory depression, respiratory failure, and pulmonary edema.
    3) Fatal and non-fatal hepatitis have been reported with prolonged dantrolene therapy. Fatalities appear to be associated with the following factors: patient age over 30 years, duration of use over 2 months, female gender, higher daily doses (300 mg or more), concomitant drugs and disease, and higher bilirubin levels.
    E) WITH POISONING/EXPOSURE
    1) Dantrolene overdose data are limited. Muscular weakness, lethargy, coma, vomiting, diarrhea, and crystalluria may occur in the event of an overdose. In one case series, lethargy was the only adverse effect reported following dantrolene overdose ingestions of 10 to 12 mg/kg.

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) BLURRING: Difficulty focusing was reported in subjects receiving 3 mg/kg of dantrolene intravenously (Wedel et al, 1995).
    2) CORNEAL OPACITY: An isolated case of corneal opacity was reported following prolonged therapy. A child treated with 25 mg/day of dantrolene, which was subsequently increased to 50 mg/day for 4 months in the treatment of spasticity, developed a corneal opacity which turned yellow (the color of dantrolene sodium drug) (Wilkie, 1976). The author postulated that the yellow coloration in the cornea may be due to deposition of the drug in connective tissue. However, no data to support this hypothesis was offered.
    3) Visual disturbances, excessive tearing, and diplopia have been reported following dantrolene administration (Prod Info dantrolene sodium oral capsules, 2013).
    3.4.4) EARS
    A) WITH THERAPEUTIC USE
    1) HEARING LOSS: Bilateral sensorineural hearing loss developed after 5 days of dantrolene therapy (25 mg/day, then one 50-mg/day dose) in a patient with previous deficits in one ear. The patient had previously been maintained on baclofen and diazepam for signs of cerebral palsy, and dantrolene was added to this regime (Pace-Balzan & Ramsden, 1988).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) TACHYCARDIA
    1) WITH THERAPEUTIC USE
    a) Tachycardia and erratic blood pressure have been reported with oral dantrolene therapy (Prod Info dantrolene sodium oral capsules, 2013).
    B) PERICARDITIS
    1) WITH THERAPEUTIC USE
    a) Pleural effusion with pericarditis has been reported following dantrolene administration (Prod Info dantrolene sodium oral capsules, 2013; Miller & Haas, 1984).
    b) Eosinophilic pleural effusion with pericarditis is thought to be a hypersensitivity-type reaction to dantrolene therapy. Chronic pleural effusion occurred in three patients, one of whom also developed acute pericarditis. A fourth patient developed both pleural and pericardial effusions. No pulmonary parenchymal involvement was apparent. Although a casual relationship between dantrolene and serosal inflammation remains unproved, this association in 4 patients warrants careful observation of patients receiving long-term dantrolene therapy (Petusevsky et al, 1979).
    C) PHLEBITIS
    1) WITH THERAPEUTIC USE
    a) Phlebitis has been reported with parenteral dantrolene administration (Prod Info dantrolene sodium oral capsules, 2013).
    D) HEART FAILURE
    1) WITH THERAPEUTIC USE
    a) Heart failure has been reported following dantrolene administration (Prod Info dantrolene sodium oral capsules, 2013).
    b) CASE REPORT: A 61-year-old woman, with renal failure, developed cardiac failure with pulmonary edema after receiving incremental doses (25 mg on day 1 to 250 mg on day 8) of oral dantrolene. The patient recovered following cessation of dantrolene therapy (Robillart et al, 1986).
    E) ATRIOVENTRICULAR BLOCK
    1) WITH THERAPEUTIC USE
    a) In one study, atrioventricular block developed in 3% of the 30 healthy volunteers treated with dantrolene sodium (1 mg/kg to 2.5 mg/kg IV infused over the course of 1 minute) as compared with 0% of volunteers treated with an active comparator, containing a different injectable formulation of dantrolene sodium with mannitol (Prod Info RYANODEX(R) intravenous injection suspension, 2014).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) RESPIRATORY FINDING
    1) WITH THERAPEUTIC USE
    a) Decreased respiratory capacity, respiratory muscle weakness, and dyspnea have been reported with dantrolene administration (Prod Info RYANODEX(R) intravenous injection suspension, 2014).
    B) PLEURAL EFFUSION
    1) WITH THERAPEUTIC USE
    a) Eosinophilic pleural effusion and pleural fibrosis have been reported in patients on chronic dantrolene therapy (Prod Info dantrolene sodium oral capsules, 2013; Le-Quang et al, 2004; Felz & Haviland-Foley, 2001; Mahoney & Bachtel, 1994; Miller & Haas, 1984; Petusevsky et al, 1979a).
    C) RESPIRATORY FAILURE
    1) WITH THERAPEUTIC USE
    a) A report by the North American Malignant Hyperthermia Registry of the Malignant Hyperthermia Association of the United States analyzing complications associated with dantrolene therapy between 1987 and 2006 revealed that respiratory failure was reported in 3.8% of patients administered dantrolene (14 out 368). Of these 14 cases, 6 reportedly experienced pulmonary edema and 2 had a low cardiac output associated with dantrolene therapy. One patient who experienced respiratory failure was known to have myopathy prior to initiation of dantrolene therapy (Brandom et al, 2011).
    D) ACUTE LUNG INJURY
    1) WITH THERAPEUTIC USE
    a) Rarely, pulmonary edema has developed with the use of intravenous dantrolene. The diluent volume and mannitol needed may have possibly contributed (Prod Info Revonto(R) intravenous injection, 2014).
    E) DECREASED RESPIRATORY FUNCTION
    1) WITH THERAPEUTIC USE
    a) Respiratory depression has been reported following dantrolene administration (Prod Info Dantrium(R) oral capsules, 2012).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) CENTRAL NERVOUS SYSTEM DEFICIT
    1) WITH THERAPEUTIC USE
    a) Dantrolene is frequently reported to cause CNS depression-like side effects including drowsiness, light-headedness, dizziness, vertigo, malaise, fatigue, giddiness, somnolence, insomnia, confusion, nervousness, headache, incoordination with rubbery legs, difficulty speaking, and a feeling of drunkenness. In most cases these effects are transient although occasionally they may be severe enough, such as in the case of drowsiness that discontinuation of drug therapy may be necessary (Prod Info RYANODEX(R) intravenous injection suspension, 2014; Ketel & Kolb, 1984; Gambi et al, 1983; Luisto et al, 1982; Sheplan & Ishmael, 1975; Steinberg & Ferguson, 1975; Tolosa et al, 1975; Chipman et al, 1974; Ladd et al, 1973; Chyatte & Basmajian, 1973; Chipman & Kaul, 1972; Chyatte et al, 1971a; Chyatte & Birdsong, 1971).
    2) WITH POISONING/EXPOSURE
    a) Lethargy and coma may occur with overdose (Prod Info dantrolene sodium oral capsules, 2013).
    b) A case report describes three oral dantrolene overdoses involving a 20-month-old child and two adults in their early twenties. Dosages ranged from 10 to 12 mg/kg . The child exhibited no symptoms and one of the adults experienced lethargy. The patients were all treated supportively and the episodes resolved uneventfully (Paloucek et al, 1991).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) Nausea, vomiting, and abdominal pain have occurred at therapeutic doses (Prod Info dantrolene sodium oral capsules, 2013; Wedel et al, 1995; Gambi et al, 1983; Chyatte & Basmajian, 1973).
    2) WITH POISONING/EXPOSURE
    a) Vomiting may occur with overdose (Prod Info dantrolene sodium oral capsules, 2013).
    B) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) Diarrhea may frequently occur with dantrolene therapy and may be severe, necessitating temporary withdrawal of dantrolene therapy in some instances (Prod Info dantrolene sodium oral capsules, 2013; Ketel & Kolb, 1984).
    2) WITH POISONING/EXPOSURE
    a) Diarrhea may occur with overdose (Prod Info dantrolene sodium oral capsules, 2013).
    C) GASTROINTESTINAL OBSTRUCTION
    1) WITH THERAPEUTIC USE
    a) Constipation, rarely progressing into intestinal obstruction, has been reported following dantrolene administration (Prod Info dantrolene sodium oral capsules, 2013).
    b) Several cases of bowel obstruction have been reported, usually appearing when dosage was increased. Three patients (age range, 16 to 58 years) were treated for spasticity with 25 to 100 mg four times a day of dantrolene sodium and developed functional small and large bowel obstruction. The first case was a woman who developed constipation, rectal bleeding, and signs of intestinal obstruction following a dose increase of the drug to 100 mg four times a day. The patient was decompressed with a long tube and dantrolene was discontinued until all signs of obstruction disappeared. Rechallenge of dantrolene in this patient at doses less than 50 mg four times a day resulted in no further intestinal problems. The second female patient developed abdominal distention following a dose increase to 75 mg four times a day. Following treatment with an intestinal tube, the patient's symptoms of obstruction rapidly disappeared and dantrolene was discontinued. The third female patient developed abdominal distention following a dose increase to 50 mg four times a day which resolved to normal bowel function following dosage reduction to 25 mg four times a day (Shaivitz, 1974).
    D) DYSPHAGIA
    1) WITH POISONING/EXPOSURE
    a) Difficulty in swallowing and choking has reportedly occurred following therapeutic administration of dantrolene (Prod Info RYANODEX(R) intravenous injection suspension, 2014).
    E) LOSS OF APPETITE
    1) WITH THERAPEUTIC USE
    a) Anorexia has been reported following dantrolene administration (Prod Info dantrolene sodium oral capsules, 2013).
    F) GASTROINTESTINAL HEMORRHAGE
    1) WITH THERAPEUTIC USE
    a) Gastrointestinal bleeding has been reported following dantrolene administration (Prod Info dantrolene sodium oral capsules, 2013).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) TOXIC HEPATITIS
    1) WITH THERAPEUTIC USE
    a) A number of cases of hepatitis associated with therapeutic use of dantrolene have been reported (Wilkinson et al, 1979; Lundin et al, 1977; Schneider & Mitchell, 1976).
    b) Hepatotoxicity due to dantrolene may be mild or severe. The incidence of hepatotoxicity induced by dantrolene is 1% overall; however, mortality from liver damage is as high as 10%. Liver toxicity is dose-related. Risk factors for hepatotoxicity include concomitant medications, age greater than 35 years, and female gender (Prod Info dantrolene sodium oral capsules, 2013; Tolman, 1990; Jim, 1989).
    c) Fatal cases were associated with the following: patient age over 30 years, duration of use over 2 months, female gender, higher daily doses (300 mg or more), concomitant drugs and disease, and higher bilirubin levels (Chan, 1990; Utili et al, 1977).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) ATONY OF UTERUS
    1) WITH THERAPEUTIC USE
    a) Postpartum uterine atony occurred in a 26-year-old woman following intravenous administration of dantrolene 220 mg as prophylaxis against malignant hyperthermia following cesarean section. The patient had received an IV infusion of oxytocin just prior to dantrolene, and an oxytocin infusion was continued while the patient was taken to the recovery unit. At this time, an atonic uterus and vaginal bleeding were observed which was unresponsive to uterine massage, IV oxytocin, intramuscular methylergonovine, and prostaglandin F2-alpha. An additional dose of dantrolene 100 mg was administered because of the suspicion of malignant hyperthermia, which may have exacerbated the uterine atony. A hysterectomy was performed and the uterus was atonic (Weingarten et al, 1987a). Based upon the data presented, it is unclear whether dantrolene definitely contributed to the uterine atony in this patient.
    B) UROGENITAL FINDING
    1) WITH THERAPEUTIC USE
    a) Urogenital symptoms that have been reported with dantrolene include increased urinary frequency, crystalluria, hematuria, difficult erection, urinary incontinence and/or nocturia, difficult urination and/or urinary retention (Prod Info dantrolene sodium oral capsules, 2013).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) HEMATOLOGY FINDING
    1) WITH THERAPEUTIC USE
    a) Aplastic anemia, leukopenia, and thrombocytopenia have been reported with oral dantrolene therapy (Prod Info dantrolene sodium oral capsules, 2013).
    B) EOSINOPHILIA
    1) WITH THERAPEUTIC USE
    a) Significant peripheral and pleural eosinophilia with pleural effusion have been reported in several patients who were on chronic dantrolene therapy. The eosinophilia and pleural effusion resolved within months after cessation of dantrolene and, in one case, administration of corticosteroids (Le-Quang et al, 2004; Felz & Haviland-Foley, 2001; Mahoney & Bachtel, 1994; Miller & Haas, 1984; Petusevsky et al, 1979a).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ACNE
    1) WITH THERAPEUTIC USE
    a) Acne-like rash has been reported with dantrolene therapy (Prod Info dantrolene sodium oral capsules, 2013).
    b) Acneform eruptions consisting primarily of darkly pigmented blackheads occurring at sites of pressure and at sites of friction have been reported in 2 women who were receiving dantrolene 150 mg daily and 425 mg daily, respectively (Pembroke et al, 1981).
    B) PHOTOSENSITIVITY
    1) WITH THERAPEUTIC USE
    a) Photosensitivity reactions may develop in patients receiving dantrolene upon exposure to sunlight (Prod Info dantrolene sodium oral capsules, 2013).
    C) URTICARIA
    1) WITH THERAPEUTIC USE
    a) Urticaria and erythema have been rarely reported following intravenous administration of dantrolene (Prod Info Revonto(R) intravenous injection, 2014).
    D) INJECTION SITE REACTION
    1) WITH THERAPEUTIC USE
    a) Injection site reactions (eg, pain, erythema, swelling) and tissue necrosis secondary to extravasation have been reported. In one study, injection site pain developed in 3% of the 30 healthy volunteers treated with dantrolene sodium (1 mg/kg to 2.5 mg/kg IV infused over the course of 1 minute) as compared with 0% of volunteers treated with an active comparator, containing a different injectable formulation of dantrolene sodium with mannitol (Prod Info RYANODEX(R) intravenous injection suspension, 2014).
    E) FLUSHING
    1) WITH THERAPEUTIC USE
    a) In one study, flushing developed in 27% of the 30 healthy volunteers treated with dantrolene sodium (1 mg/kg to 2.5 mg/kg IV infused over the course of 1 minute) as compared with 3% of volunteers treated with an active comparator, containing a different injectable formulation of dantrolene sodium with mannitol (Prod Info RYANODEX(R) intravenous injection suspension, 2014).
    F) ITCHING OF SKIN
    1) WITH THERAPEUTIC USE
    a) Pruritus has been reported following dantrolene administration (Prod Info dantrolene sodium oral capsules, 2013).
    G) PHLEBITIS
    1) WITH THERAPEUTIC USE
    a) Phlebitis has been reported following dantrolene administration (Prod Info dantrolene sodium oral capsules, 2013).
    b) Thrombophlebitis has been reported during postmarketing surveillance (Prod Info RYANODEX(R) intravenous injection suspension, 2014).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) MUSCLE WEAKNESS
    1) WITH THERAPEUTIC USE
    a) Skeletal muscle weakness (ie, loss of grip strength, weakness in legs) has been reported (Prod Info RYANODEX(R) intravenous injection suspension, 2014).
    b) In one study, muscle weakness/asthenia developed in 3% of the 30 healthy volunteers treated with dantrolene sodium (1 mg/kg to 2.5 mg/kg IV infused over the course of 1 minute) as compared with 3% of volunteers treated with an active comparator, containing a different injectable formulation of dantrolene sodium with mannitol (Prod Info RYANODEX(R) intravenous injection suspension, 2014).
    c) CASE REPORT: A 5-year-old child with an underlying neuromuscular disorder developed extreme muscle weakness, atelectasis, difficulty handling airway secretions, and diminished gag and swallow reflexes after oral dantrolene prophylaxis for malignant hyperthermia (Watson et al, 1986).
    d) In a study of 12 patients who received 3 mg/kg of intravenous dantrolene, 6 of whom were thought to be susceptible to malignant hyperthermia, the malignant hyperthermia susceptible group complained of moderate to severe subjective muscle weakness which gradually resolved over 48 hours or longer while the other subjects did not complain of weakness. Minimal to no objective weakness was demonstrated on physical examination (Wedel et al, 1995).
    2) WITH POISONING/EXPOSURE
    a) Muscular weakness may occur with overdose (Prod Info dantrolene sodium oral capsules, 2013).
    B) MUSCLE PAIN
    1) WITH THERAPEUTIC USE
    a) Myalgias and backache have been reported with dantrolene therapy (Prod Info dantrolene sodium oral capsules, 2013). Myoglobin and creatine kinase increased in 100% of 20 patients who received oral dantrolene prior to succinylcholine, but the elevations were significantly lower than for patients who received succinylcholine alone (controls, n=20). Myalgias were also significantly reduced compared with the control group (Laurence & McKean, 1990).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) ANAPHYLAXIS
    1) WITH THERAPEUTIC USE
    a) Anaphylaxis has been reported following dantrolene administration (Prod Info dantrolene sodium oral capsules, 2013).

Reproductive

    3.20.1) SUMMARY
    A) Dantrolene is classified as FDA pregnancy category C. Dantrolene has been shown to cross the placenta in two studies. Neither study showed adverse effects in the infants following maternal dantrolene use. In a case report, dantrolene IV was associated with uterine atony and hemorrhage requiring a hysterectomy. In animal studies, dantrolene was embryocidal and reduced pup survival. Dantrolene was also detected in the breast milk at low concentrations, but there was no evidence of adverse effects to the nursing infants.
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) Dantrolene is classified by the manufacturer as FDA pregnancy category C (Prod Info Dantrium(R) IV injection, 2008; Prod Info Dantrium(R) oral capsules, 2008; Prod Info RYANODEX(R) intravenous injection suspension, 2014).
    B) PLACENTAL BARRIER
    1) Dantrolene crosses the placenta with a fetal/maternal ratio of 0.4 (Morison, 1983). Maternal administration prior to delivery appears to have no adverse effects on the infant (Shime et al, 1988).
    2) Oral dantrolene sodium, 100 mg/day, was given prophylactically to term pregnant patients awaiting labor and delivery. Dantrolene crossed the placenta with maternal and fetal whole blood levels equal at delivery. After delivery, neonatal levels decreased approximately 50% per day for 2 days before declining sharply thereafter. No neonatal neuromuscular or respiratory adverse effects occurred following maternal administration of dantrolene (Prod Info Dantrium(R) IV injection, 2008; Prod Info Dantrium(R) oral capsules, 2008; Prod Info RYANODEX(R) intravenous injection suspension, 2014).
    3) Intravenous dantrolene for therapy of mild malignant hyperthermia was associated with uterine atony and hemorrhage requiring hysterectomy (Weingarten et al, 1987).
    C) ANIMAL STUDIES
    1) RATS, RABBITS: Dantrolene appeared to be embryocidal in rabbits and reduced pup survival in rats when given doses 7 times the recommended human dose (Prod Info Dantrium(R) IV injection, 2008; Prod Info RYANODEX(R) intravenous injection suspension, 2014).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) A peak breast milk concentration of dantrolene of 1.2 mcg/mL was detected at 36 hours after giving birth in a mother receiving dantrolene for malignant hyperthermia (MH). The mother developed a MH crisis after anesthesia induction for urgent cesarean section. She received dantrolene 160 mg after the birth and was continued on decreasing doses with 560 mg on day one, 320 mg on day two, and 80 mg on day three. The half-life of dantrolene in breast milk was 9.02 hours. Breastfeeding was determined to be safe for the infant 2 days after the discontinuation of dantrolene (Fricker et al, 1998). During repeat IV administration of dantrolene over 3 days, the drug was detected in human milk at concentrations of less than 2 mcg/mL (Prod Info Dantrium(R) IV injection, 2008; Prod Info RYANODEX(R) intravenous injection suspension, 2014).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) There were no adverse effects on fertility or reproductive performance when male and female rats were given dantrolene at doses up to 45 mg/kg/day (1.4 times the maximum recommended human dose on a body surface area basis) (Prod Info Dantrium(R) IV injection, 2008; Prod Info Dantrium(R) oral capsules, 2008; Prod Info RYANODEX(R) intravenous injection suspension, 2014).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS7261-97-4 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) Not Listed
    3.21.2) SUMMARY/HUMAN
    A) The long-term safety of dantrolene has not been established in humans.
    3.21.3) HUMAN STUDIES
    A) LACK OF INFORMATION
    1) The long-term safety of dantrolene has not been established in humans (Prod Info RYANODEX(R) intravenous injection suspension, 2014; Prod Info Dantrium(R) oral capsules, 2008).
    3.21.4) ANIMAL STUDIES
    A) NEOPLASMS
    1) FEMALE RATS: An increased incidence of benign and malignant mammary tumors occurred in female Sprague-Dawley rats that were given dantrolene sodium for 18 months at dosages of 15, 30, and 60 mg/kg/day as compared with controls. At the highest dosage level, there was also an increased incidence of benign hepatic lymphatic neoplasms (Prod Info RYANODEX(R) intravenous injection suspension, 2014; Prod Info Dantrium(R) IV injection, 2008; Prod Info Dantrium(R) oral capsules, 2008).
    2) FEMALE RATS: An increased incidence of hepatic lymphangiomas and hepatic angiosarcomas occurred in female rats that were given dantrolene sodium for 30 months at the highest dose level. During this same 30-month period, rats given dantrolene sodium at the highest dose level showed a decrease in the time of onset of mammary neoplasms (Prod Info RYANODEX(R) intravenous injection suspension, 2014; Prod Info Dantrium(R) IV injection, 2008; Prod Info Dantrium(R) oral capsules, 2008).
    B) LACK OF EFFECT
    1) MICE: There was no evidence of carcinogenicity when mice were exposed to dantrolene in a 24-month study (Prod Info Dantrium(R) IV injection, 2008; Prod Info Dantrium(R) oral capsules, 2008).

Genotoxicity

    A) Dantrolene sodium tested positive in the Ames S. Typhimurium bacterial mutagenesis assay in the presence and absence of a liver activating system (Prod Info RYANODEX(R) intravenous injection suspension, 2014; Prod Info Dantrium(R) IV injection, 2008; Prod Info Dantrium(R) oral capsules, 2008).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs and mental status.
    C) Obtain a baseline ECG and institute continuous cardiac monitoring in patients with tachycardia.
    D) Monitor for muscle weakness and respiratory depression.
    E) Monitor CBC with differential, liver enzymes, and renal function after significant overdose.
    F) Monitor serum electrolytes in patients with severe vomiting and/or diarrhea.
    G) Monitor arterial blood gases, pulse oximetry, and pulmonary function tests, and obtain a chest x-ray in any patient with respiratory symptoms.

Methods

    A) CHROMATOGRAPHY
    1) A high performance liquid chromatography method for measuring dantrolene concentrations in plasma and urine has been reported (Wuis et al, 1986).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients with severe symptoms despite treatment should be admitted.
    6.3.1.2) HOME CRITERIA/ORAL
    A) A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a regional poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with a deliberate overdose, and those who are symptomatic, need to be monitored until they are clearly improving and clinically stable.

Monitoring

    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs and mental status.
    C) Obtain a baseline ECG and institute continuous cardiac monitoring in patients with tachycardia.
    D) Monitor for muscle weakness and respiratory depression.
    E) Monitor CBC with differential, liver enzymes, and renal function after significant overdose.
    F) Monitor serum electrolytes in patients with severe vomiting and/or diarrhea.
    G) Monitor arterial blood gases, pulse oximetry, and pulmonary function tests, and obtain a chest x-ray in any patient with respiratory symptoms.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Prehospital gastrointestinal decontamination is generally not recommended because of the potential for CNS depression and subsequent aspiration. Decontamination is not indicated following parenteral exposure.
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) MANAGEMENT OF MILD TO MODERATE TOXICITY
    a) Treatment is symptomatic and supportive.
    2) MANAGEMENT OF SEVERE TOXICITY
    a) Treatment is symptomatic and supportive. Administer IV fluids to avoid crystalluria following intravenous exposure. In patients with acute allergic reaction, oxygen therapy, bronchodilators, diphenhydramine, corticosteroids, vasopressors and epinephrine may be required. Correct any significant fluid and/or electrolyte abnormalities in patients with severe diarrhea and/or vomiting. Alterations in heart rhythm and blood pressure may occur. Sinus tachycardia does not generally require treatment unless hemodynamic compromise is present.
    B) MONITORING OF PATIENT
    1) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    2) Monitor vital signs and mental status.
    3) Obtain a baseline ECG and institute continuous cardiac monitoring in patients with tachycardia.
    4) Monitor for muscle weakness and respiratory depression.
    5) Monitor CBC with differential, liver enzymes, and renal function after significant overdose.
    6) Monitor serum electrolytes in patients with severe vomiting and/or diarrhea.
    7) Monitor arterial blood gases, pulse oximetry, and pulmonary function tests, and obtain a chest x-ray in any patient with respiratory symptoms.
    C) ACUTE ALLERGIC REACTION
    1) SUMMARY
    a) Mild to moderate allergic reactions may be treated with antihistamines with or without inhaled beta adrenergic agonists, corticosteroids or epinephrine. Treatment of severe anaphylaxis also includes oxygen supplementation, aggressive airway management, epinephrine, ECG monitoring, and IV fluids.
    2) BRONCHOSPASM
    a) ALBUTEROL
    1) ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007). CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 mg/kg (up to 10 mg) every 1 to 4 hours as needed, or 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).
    3) CORTICOSTEROIDS
    a) Consider systemic corticosteroids in patients with significant bronchospasm.
    b) PREDNISONE: ADULT: 40 to 80 milligrams/day. CHILD: 1 to 2 milligrams/kilogram/day (maximum 60 mg) in 1 to 2 divided doses divided twice daily (National Heart,Lung,and Blood Institute, 2007).
    4) MILD CASES
    a) DIPHENHYDRAMINE
    1) SUMMARY: Oral diphenhydramine, as well as other H1 antihistamines can be used as indicated (Lieberman et al, 2010).
    2) ADULT: 50 milligrams orally, or 10 to 50 mg intravenously at a rate not to exceed 25 mg/min or may be given by deep intramuscular injection. A total of 100 mg may be administered if needed. Maximum daily dosage is 400 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
    3) CHILD: 5 mg/kg/24 hours or 150 mg/m(2)/24 hours. Divided into 4 doses, administered intravenously at a rate not exceeding 25 mg/min or by deep intramuscular injection. Maximum daily dosage is 300 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
    5) MODERATE CASES
    a) EPINEPHRINE: INJECTABLE SOLUTION: It should be administered early in patients by IM injection. Using a 1:1000 (1 mg/mL) solution of epinephrine. Initial Dose: 0.01 mg/kg intramuscularly with a maximum dose of 0.5 mg in adults and 0.3 mg in children. The dose may be repeated every 5 to 15 minutes, if no clinical improvement. Most patients respond to 1 or 2 doses (Nowak & Macias, 2014).
    6) SEVERE CASES
    a) EPINEPHRINE
    1) INTRAVENOUS BOLUS: ADULT: 1 mg intravenously as a 1:10,000 (0.1 mg/mL) solution; CHILD: 0.01 mL/kg intravenously to a maximum single dose of 1 mg given as a 1:10,000 (0.1 mg/mL) solution. It can be repeated every 3 to 5 minutes as needed. The dose can also be given by the intraosseous route if IV access cannot be established (Lieberman et al, 2015). ALTERNATIVE ROUTE: ENDOTRACHEAL ADMINISTRATION: If IV/IO access is unavailable. DOSE: ADULT: Administer 2 to 2.5 mg of 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube. CHILD: DOSE: 0.1 mg/kg to a maximum of 2.5 mg administered as a 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube (Lieberman et al, 2015).
    2) INTRAVENOUS INFUSION: Intravenous administration may be considered in patients poorly responsive to IM or SubQ epinephrine. An epinephrine infusion may be prepared by adding 1 mg (1 mL of 1:1000 (1 mg/mL) solution) to 250 mL D5W, yielding a concentration of 4 mcg/mL, and infuse this solution IV at a rate of 1 mcg/min to 10 mcg/min (maximum rate). CHILD: A dosage of 0.01 mg/kg (0.1 mL/kg of a 1:10,000 (0.1 mg/mL) solution up to 10 mcg/min (maximum dose 0.3 mg) is recommended for children (Lieberman et al, 2010). Careful titration of a continuous infusion of IV epinephrine, based on the severity of the reaction, along with a crystalloid infusion can be considered in the treatment of anaphylactic shock. It appears to be a reasonable alternative to IV boluses, if the patient is not in cardiac arrest (Vanden Hoek,TLet al,null).
    7) AIRWAY MANAGEMENT
    a) OXYGEN: 5 to 10 liters/minute via high flow mask.
    b) INTUBATION: Perform early if any stridor or signs of airway obstruction.
    c) CRICOTHYROTOMY: Use if unable to intubate with complete airway obstruction (Vanden Hoek,TLet al,null).
    d) BRONCHODILATORS are recommended for mild to severe bronchospasm.
    e) ALBUTEROL: ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007).
    f) ALBUTEROL: CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 milligram/kilogram (maximum 10 milligrams) every 1 to 4 hours as needed OR administer 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).
    8) MONITORING
    a) CARDIAC MONITOR: All complicated cases.
    b) IV ACCESS: Routine in all complicated cases.
    9) HYPOTENSION
    a) If hypotensive give 500 to 2000 milliliters crystalloid initially (20 milliliters/kilogram in children) and titrate to desired effect (stabilization of vital signs, mentation, urine output); adults may require up to 6 to 10 L/24 hours. Central venous or pulmonary artery pressure monitoring is recommended in patients with persistent hypotension.
    1) VASOPRESSORS: Should be used in refractory cases unresponsive to repeated doses of epinephrine and after vigorous intravenous crystalloid rehydration (Lieberman et al, 2010).
    2) DOPAMINE: Initial Dose: 2 to 20 micrograms/kilogram/minute intravenously; titrate to maintain systolic blood pressure greater than 90 mm Hg (Lieberman et al, 2010).
    10) H1 and H2 ANTIHISTAMINES
    a) SUMMARY: Antihistamines are second-line therapy and are used as supportive therapy and should not be used in place of epinephrine (Lieberman et al, 2010).
    1) DIPHENHYDRAMINE: ADULT: 25 to 50 milligrams via a slow intravenous infusion or IM. PEDIATRIC: 1 milligram/kilogram via slow intravenous infusion or IM up to 50 mg in children (Lieberman et al, 2010).
    b) RANITIDINE: ADULT: 1 mg/kg parenterally; CHILD: 12.5 to 50 mg parenterally. If the intravenous route is used, ranitidine should be infused over 10 to 15 minutes or diluted in 5% dextrose to a volume of 20 mL and injected over 5 minutes (Lieberman et al, 2010).
    c) Oral diphenhydramine, as well as other H1 antihistamines, can also be used as indicated (Lieberman et al, 2010).
    11) DYSRHYTHMIAS
    a) Dysrhythmias and cardiac dysfunction may occur primarily or iatrogenically as a result of pharmacologic treatment (epinephrine) (Vanden Hoek,TLet al,null). Monitor and correct serum electrolytes, oxygenation and tissue perfusion. Treat with antiarrhythmic agents as indicated.
    12) OTHER THERAPIES
    a) There have been a few reports of patients with anaphylaxis, with or without cardiac arrest, that have responded to vasopressin therapy that did not respond to standard therapy. Although there are no randomized controlled trials, other alternative vasoactive therapies (ie, vasopressin, norepinephrine, methoxamine, and metaraminol) may be considered in patients in cardiac arrest secondary to anaphylaxis that do not respond to epinephrine (Vanden Hoek,TLet al,null).
    D) DYSPNEA
    1) Monitor respiratory function. Assess for evidence of fluid retention (eg, pleural effusion, pulmonary edema). Evaluate and monitor airway patency and adequacy of respiration and oxygenation. Treatment may consist of diuretic therapy to manage fluid retention, as well as supplemental oxygen. If symptoms are severe, endotracheal intubation and assisted ventilation may be indicated. Obtain a baseline chest x-ray in symptomatic patients; repeat as indicated.

Enhanced Elimination

    A) HEMODIALYSIS
    1) It is unknown if hemodialysis would be effective in overdose (Prod Info dantrolene sodium oral capsules, 2004).

Range Of Toxicity

Summary

    A) TOXICITY: A specific toxic dose has not been established. Lethargy was the only adverse effect reported following dantrolene overdose ingestions of 10 to 12 mg/kg.
    B) THERAPEUTIC DOSE: Malignant Hyperthermia (Acute): ADULT or PEDIATRIC: 1 mg/kg IV by continuous rapid IV push and continue until symptoms subside or a maximum cumulative dose of 10 mg/kg. Post Crisis Follow-up: ADULT or PEDIATRIC: 4 to 8 mg/kg/day orally in 4 divided doses, for a 1- to 3-day period as indicated. Chronic Spasticity: ADULT: Initial: 25 mg orally once daily then increase to 25 mg 2 to 4 times daily up to 100 mg 2 to 4 times daily if necessary. Rarely should the dose exceed 400 mg/day. PEDIATRIC: Initial: 0.5 mg/kg orally twice daily; increase to 0.5 mg/kg 3 or 4 times daily then by increments of 0.5 mg/kg up to as high as 2 mg/kg 2 to 4 times daily as needed. Do not exceed 400 mg daily. NOTE: For oral use, the manufacturer states that long-term safety has NOT been established in pediatric patients under 5 years of age. For IV use, the manufacturer states that the pediatric weight-based dosing is the same as the adult dose.

Therapeutic Dose

    7.2.1) ADULT
    A) SPECIFIC DISEASE STATE
    1) CHRONIC SPASTICITY
    a) ORAL: The initial recommended dose of oral dantrolene is 25 mg/day for 7 days. This dose may be increased to 25 mg 3 times daily for 7 days, then to 50 mg 3 times daily for 7 days, and then up to 100 mg 3 times daily as needed. Before beginning therapy, a therapeutic goal should be identified with doses increased accordingly. Therapy should be stopped if benefits are not seen within 45 days. Doses higher than 100 mg 4 times per day should NOT be used (Prod Info Dantrium(R) oral capsules, 2012).
    2) MALIGNANT HYPERTHERMIA
    a) IV: The recommended dose of IV dantrolene is 1 mg/kg by continuous rapid intravenous push continued until symptoms subside or to a MAXIMUM CUMULATIVE DOSE of 10 mg/kg (Prod Info RYANODEX(R) intravenous injection suspension, 2014). In addition, all malignant hyperthermia-triggering anesthetic agents should be discontinued (Prod Info RYANODEX(R) intravenous injection suspension, 2014).
    3) PREOPERATIVE MALIGNANT HYPERTHERMIA PROPHYLAXIS
    a) ORAL: 4 to 8 mg/kg/day in 3 to 4 divided doses for 1 to 2 days prior to surgery, with the last dose given approximately 3 to 4 hours before surgery with a minimum of water (Prod Info Dantrium(R) oral capsules, 2012)
    b) IV: 2.5 mg/kg infused over at least 1 minute, starting approximately 75 minutes before surgery (Prod Info RYANODEX(R) intravenous injection suspension, 2014).
    4) MALIGNANT HYPERTHERMIA POST-CRISIS FOLLOW-UP
    a) ORAL: The recommended oral dantrolene dose is 4 to 8 mg/kg/day in 4 divided doses, for a 1- to 3-day period to prevent recurrence of the manifestations of malignant hyperthermia (Prod Info Dantrium(R) oral capsules, 2012).
    7.2.2) PEDIATRIC
    A) NOTE: For oral use, the manufacturer states that long-term safety has NOT been established in pediatric patients under 5 years of age (Prod Info Dantrium(R) oral capsules, 2012). For IV use, the manufacturer states that the pediatric weight-based dosing is the same as the adult dose (Prod Info RYANODEX(R) intravenous injection suspension, 2014).
    B) SPECIFIC DISEASE STATE
    1) CHRONIC SPASTICITY
    a) UNDER 5 YEARS OF AGE: Long-term safety of the oral capsules has not been established (Prod Info Dantrium(R) oral capsules, 2012).
    b) 5 YEARS OF AGE AND OLDER: The initial recommended dose of oral dantrolene is 0.5 mg/kg/day. This dose may be increased to 0.5 mg/kg 3 times daily for 7 days, then to 1 mg/kg 3 times daily for 7 days, and then up to 2 mg/kg 3 times daily as needed. Doses higher than 100 mg 4 times per day should NOT be used (Prod Info Dantrium(R) oral capsules, 2012).
    2) MALIGNANT HYPERTHERMIA
    a) UP TO 18 YEARS OF AGE: IV: The recommended dose of IV dantrolene is 1 mg/kg by continuous IV push continued until symptoms subside or to a MAXIMUM CUMULATIVE DOSE of 10 mg/kg (Prod Info RYANODEX(R) intravenous injection suspension, 2014). In addition, all malignant hyperthermia-triggering anesthetic agents should be discontinued (Prod Info RYANODEX(R) intravenous injection suspension, 2014).
    3) PREOPERATIVE MALIGNANT HYPERTHERMIA PROPHYLAXIS
    a) UP TO 18 YEARS OF AGE: IV: 2.5 mg/kg infused over at least 1 minute, starting approximately 75 minutes before surgery (Prod Info RYANODEX(R) intravenous injection suspension, 2014).
    b) 5 YEARS OF AGE AND OLDER: ORAL: 4 to 8 mg/kg/day in 3 to 4 divided doses for 1 to 2 days prior to surgery with the last dose given approximately 3 to 4 hours before surgery with a minimum of water (Prod Info Dantrium(R) oral capsules, 2012).
    c) UNDER 5 YEARS OF AGE: Long-term safety of oral capsules has not been established (Prod Info Dantrium(R) oral capsules, 2012).
    4) MALIGNANT HYPERTHERMIA POST-CRISIS FOLLOW-UP
    a) 5 YEARS OF AGE AND OLDER: ORAL: The recommended oral dantrolene dose is 4 to 8 mg/kg/day in 4 divided doses for 1 to 3 days to prevent recurrence (Prod Info Dantrium(R) oral capsules, 2012).
    b) UNDER 5 YEARS OF AGE: Long-term safety of oral capsules has not been established (Prod Info Dantrium(R) oral capsules, 2012).

Maximum Tolerated Exposure

    A) A case series describes three oral dantrolene overdoses involving a 20-month-old child and two adults in their early twenties. Dosages ranged from 10 to 12 mg/kg . The child exhibited no symptoms and one of the adults experienced lethargy. The patients were all treated supportively and the episodes resolved uneventfully (Paloucek et al, 1991).

Workplace Standards

    A) ACGIH TLV Values for CAS7261-97-4 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    B) NIOSH REL and IDLH Values for CAS7261-97-4 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    C) Carcinogenicity Ratings for CAS7261-97-4 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    D) OSHA PEL Values for CAS7261-97-4 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Toxicity Information

    7.7.1) TOXICITY VALUES

Pharmacology Toxicology

Pharmacologic Mechanism

    A) SPASTICITY
    1) Dantrolene is unique among muscle relaxants in having a direct action on skeletal muscle. Dantrolene has no effect on the transmission of nerve impulses to the muscle, the transmembrane potential, or the release of acetylcholine at the myoneuronal junction. It was demonstrated in paraplegic subjects that dantrolene inhibited tendon jerks without affecting electroexcitability of the muscle (Herman et al, 1972).
    2) According to the proposed mechanism of action, normal depolarization of the muscle membrane takes place, but dantrolene causes a decrease in the amount of calcium released from the sarcoplastic reticulum stores within the muscle cell which decreases the force of muscle contraction (Van Winkle, 1976). Dantrolene may act by inhibiting inward movement of the activator calcium current across the cell membrane, thus less calcium is available to trigger release of calcium from stores within the cell (Putney & Bianchi, 1973).
    3) The inhibition of contraction caused by dantrolene is specific for skeletal muscle. Except in higher concentrations than those required for therapeutic effect, dantrolene has little effect on cardiac and smooth muscle (Butterfield & Ellis, 1973). While the effect of dantrolene is on all skeletal muscle, voluntary contractions are much less inhibited than spastic tension or reflex contractions (Monster et al, 1973). However, the effect on voluntary muscle is substantial enough to require up to a two-fold increase in voluntary effort in order to maintain similar muscle tension (Herman et al, 1972). Dantrolene does not produce complete muscle paralysis. Dose-response studies in animals show a maximum of less than 50% muscle contraction inhibition (Ellis et al, 1973).
    B) MALIGNANT HYPERTHERMIA
    1) In anesthetic-induced malignant hyperthermia, the triggering agent produces a change within the cell resulting in elevated myoplasmic calcium. This then activates an acute cellular catabolic process that cascades to malignant hyperthermia crisis. The addition of dantrolene reestablishes a normal level of ionized calcium in the myoplasm. Dantrolene inhibits calcium release from the sarcoplasmic reticulum, reestablishes the myoplasmic calcium equilibrium and increases the percentage of bound calcium. Thus the changes associated with malignant hyperthermia may be reversed or attenuated (Prod Info Revonto(R) intravenous injection, 2014).

Physicochemical

Physical Characteristics

    A) Dantrolene sodium is an orange powder that is slightly soluble in water with an increase in its solubility in alkaline solutions due to its slightly acidic nature (Prod Info Dantrium(R) oral capsules, 2008).

Ph

    A) Dantrolene sodium: approximately 9.5 (Prod Info Dantrium(R) IV injection, 2008); approximately 10.3 when reconstituted with sterile water for injection (Prod Info RYANODEX(R) intravenous injection suspension, 2014)

Molecular Weight

    A) Dantrolene sodium: 399 (hydrated salt); 336 (anhydrous salt) (Prod Info RYANODEX(R) intravenous injection suspension, 2014)

References

General Bibliography

    1) 40 CFR 372.28: Environmental Protection Agency - Toxic Chemical Release Reporting, Community Right-To-Know, Lower thresholds for chemicals of special concern. National Archives and Records Administration (NARA) and the Government Printing Office (GPO). Washington, DC. Final rules current as of Apr 3, 2006.
    2) 40 CFR 372.65: Environmental Protection Agency - Toxic Chemical Release Reporting, Community Right-To-Know, Chemicals and Chemical Categories to which this part applies. National Archives and Records Association (NARA) and the Government Printing Office (GPO), Washington, DC. Final rules current as of Apr 3, 2006.
    3) 49 CFR 172.101 - App. B: Department of Transportation - Table of Hazardous Materials, Appendix B: List of Marine Pollutants. National Archives and Records Administration (NARA) and the Government Printing Office (GPO), Washington, DC. Final rules current as of Aug 29, 2005.
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