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METAXALONE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Metaxalone is a muscle relaxant used to relieve painful musculoskeletal conditions. It has no established mechanism of action but its clinical effect may be associated with general depression of the nervous system. It has no direct effect on the contractile mechanism of striated muscle, the nerve fiber or the motor end plate.

Specific Substances

    1) AHR-438
    2) Metaxalona
    3) Metaxalonum
    4) 5-(3,5-Xylyoxymethyl)oxazolidin-2-one
    5) CAS 1665-48-1
    1.2.1) MOLECULAR FORMULA
    1) C12H15NO3 (Prod Info SKELAXIN(R) oral tablets, 2008)

Available Forms Sources

    A) FORMS
    1) Metaxalone is available in the United States as 800 mg tablets (Prod Info SKELAXIN(R) oral tablets, 2008).
    B) USES
    1) Metaxalone is used as an adjunct to rest and physical therapy in the treatment of painful musculoskeletal conditions (Prod Info SKELAXIN(R) oral tablets, 2008).

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: Metaxalone is used as an adjunct to rest and physical therapy in the treatment of painful musculoskeletal conditions.
    B) PHARMACOLOGY: Metaxalone has no established mechanism of action, but its clinical effect may be associated with general depression of the nervous system. It has no direct effect on the contractile mechanism of striated muscle, the nerve fiber or the motor end plate.
    C) TOXICOLOGY: The toxicity of metaxalone is an extension of its pharmacology, generally causing CNS depression.
    D) EPIDEMIOLOGY: Overdose is rare.
    E) WITH THERAPEUTIC USE
    1) COMMON: Drowsiness, dizziness, headache, nervousness or irritability, nausea, vomiting, and gastrointestinal upset. OTHER EFFECTS: Hypersensitivity reactions, rash with or without pruritus, leukopenia, hemolytic anemia, jaundice, anaphylactoid reactions.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Overdose effects are anticipated to be an extension of adverse effects observed following therapeutic doses. The most common adverse clinical effects following overdose have been drowsiness, agitation, dizziness/vertigo, slurred speech, tremor, nausea, vomiting, and tachycardia. The following adverse effects have also been reported with metaxalone overdose: Bradycardia, hypertension, hypotension, rash, pruritus, abdominal pain, ataxia, confusion, hallucinations/delusions, headache, muscle rigidity, seizures, syncope, mydriasis, urinary retention, diaphoresis, and fever.
    2) SEVERE TOXICITY: An adult with multiple sclerosis developed CNS depression and muscle rigidity after ingesting 90 g of metaxalone, but recovered with supportive care. In a retrospective review of adult metaxalone overdoses, respiratory depression developed in 2 patients. Deaths have been reported in patients ingesting large doses of metaxalone in combination other drugs that cause CNS and respiratory depression (eg, antidepressants, acetaminophen/hydrocodone).
    0.2.3) VITAL SIGNS
    A) WITH POISONING/EXPOSURE
    1) Fever developed in one patient after metaxalone overdose.
    0.2.20) REPRODUCTIVE
    A) At the time of this review, no data were available to assess the teratogenic potential of this agent in humans. Studies conducted in rats did not find evidence of fetal harm when metaxalone was administered (dose not given).
    0.2.21) CARCINOGENICITY
    A) At the time of this review, no human data were available to assess the potential carcinogenic activity of metaxalone.

Laboratory Monitoring

    A) Monitor vital signs and mental status.
    B) Monitor patients with significant CNS depression for respiratory insufficiency.
    C) Monitor serum electrolytes in patients with prolonged vomiting.
    D) Qualitative or quantitative levels of metaxalone in the blood or urine may be obtained by certain labs, but are not useful or generally available for clinical management.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) For mild to moderate exposures, good symptomatic and supportive care is the only necessary treatment. While decontamination may decrease the absorption of metaxalone, it may not be necessary as most patients require little more than supportive care. Manage mild hypotension with IV fluids.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) For severe toxicity, administer intravenous fluids and vasopressors for hypotension, and endotracheal intubation and mechanical ventilation for severe CNS and respiratory depression. For seizures, administer benzodiazepines initially and add propofol or phenobarbital if seizures persist.
    C) DECONTAMINATION
    1) PREHOSPITAL: Prehospital decontamination is not recommended because of the risk of CNS and respiratory depression and subsequent aspiration.
    2) HOSPITAL: Activated charcoal should be considered in patients with large overdoses who present early and are not demonstrating CNS depression and can protect the airway.
    D) AIRWAY MANAGEMENT
    1) Airway management may be an issue after large ingestions, and these patients may require intubation for respiratory depression/airway protection.
    E) ANTIDOTE
    1) None
    F) ENHANCED ELIMINATION
    1) There is no role for dialysis, hemoperfusion, urinary alkalinization, or multiple dose activated charcoal.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: Adults with only mild symptoms who have unintentional ingestions of 2400 mg or less can be observed at home. Children with mild symptoms and unintentional ingestions of 4000 mg or less can be observed at home. ADULTS: In a retrospective review of 142 adult metaxalone ingestions collected by the Texas Poison Center Network during 2000 to 2006, inadvertent ingestion of doses of less than 2400 mg was generally not associated with significant toxicity and could usually be managed at home with telephone follow up. CHILDREN: In a retrospective study of 148 pediatric metaxalone ingestions, children with ingestions of up to 4000 mg or 285.71 mg/kg of metaxalone usually had minor or no effects and could be managed at home.
    2) OBSERVATION CRITERIA: Any patient with a deliberate ingestion or more than mild symptoms should be referred to a healthcare facility for evaluation and treatment. Adults with inadvertent ingestions of more than 2400 mg and children with inadvertent ingestions of more than 4000 mg or more than 285 mg/kg should be referred to a healthcare facility. ADULTS: In a retrospective review of 142 adult metaxalone ingestions collected by the Texas Poison Center Network during 2000 to 2006, metaxalone ingestions of greater than 2400 mg in adults were more likely to be associated with intentional exposure and more serious adverse events. These patients should generally be referred to a health care facility.
    3) ADMISSION CRITERIA: Patients who are symptomatic after a period of observation should be admitted to the hospital. Criteria for discharge should be clear improvement of symptoms (eg, patient is alert and able to ambulate safely).
    4) CONSULT CRITERIA: A medical toxicologist or poison center should be consulted for patients with severe toxicity or unclear diagnosis.
    H) PITFALLS
    1) When managing a suspected metaxalone overdose, the possibility of multidrug involvement should be considered.
    I) PHARMACOKINETICS
    1) Cmax: 983 ng/mL after a single 400 mg oral dose and 1816 ng/mL (1.816 mg/L) after 800 mg dose. Vd: Approximately 800 L. Metabolism: Metabolized by the liver; hepatic cytochrome P450 enzymes (eg, CYP1A2, CYP2D6, CYP2E1, and CYP3A4) play a role in metabolism. Other enzymes with a lesser role include: CYP2C8, CYP2C9, and CYP2C19. Terminal half-life: 8 to 9 +/- 4.8 hours.
    J) DIFFERENTIAL DIAGNOSIS
    1) Differential diagnosis includes other causes of depressed mental status (eg, trauma, infection) as well as other sedating medications (eg, benzodiazepines, opioids).

Range Of Toxicity

    A) TOXICITY: ADULTS: An adult with multiple sclerosis developed CNS depression and muscle rigidity after ingesting 90 g of metaxalone, but recovered with supportive care. In a retrospective review of adults metaxalone ingestions (61 patients with known doses; mean dose, 7732.8 mg; range: 400 to 44,000 mg), ingestion of 2400 mg or less was associated with relatively minor adverse effects. CHILDREN: In a retrospective review of children metaxalone ingestions (80 patients with known doses; mean dose was 655 mg; range: 40 to 4000 mg), ingestion of 4,000 mg (285.71 mg/kg) or less resulted in minor adverse effects. Deaths have been reported in patients ingesting large doses of metaxalone in combination with other drugs that cause respiratory or CNS depression (eg, antidepressants, acetaminophen/hydrocodone). However, the causal relationship was not established. THERAPEUTIC DOSE: ADULTS AND CHILDREN OVER 12 YEARS OF AGE: 800 mg orally 3 or 4 times daily. 12 YEARS AND YOUNGER: Safety and efficacy of metaxalone have not been established.

Clinical Effects

Summary Of Exposure

    A) USES: Metaxalone is used as an adjunct to rest and physical therapy in the treatment of painful musculoskeletal conditions.
    B) PHARMACOLOGY: Metaxalone has no established mechanism of action, but its clinical effect may be associated with general depression of the nervous system. It has no direct effect on the contractile mechanism of striated muscle, the nerve fiber or the motor end plate.
    C) TOXICOLOGY: The toxicity of metaxalone is an extension of its pharmacology, generally causing CNS depression.
    D) EPIDEMIOLOGY: Overdose is rare.
    E) WITH THERAPEUTIC USE
    1) COMMON: Drowsiness, dizziness, headache, nervousness or irritability, nausea, vomiting, and gastrointestinal upset. OTHER EFFECTS: Hypersensitivity reactions, rash with or without pruritus, leukopenia, hemolytic anemia, jaundice, anaphylactoid reactions.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Overdose effects are anticipated to be an extension of adverse effects observed following therapeutic doses. The most common adverse clinical effects following overdose have been drowsiness, agitation, dizziness/vertigo, slurred speech, tremor, nausea, vomiting, and tachycardia. The following adverse effects have also been reported with metaxalone overdose: Bradycardia, hypertension, hypotension, rash, pruritus, abdominal pain, ataxia, confusion, hallucinations/delusions, headache, muscle rigidity, seizures, syncope, mydriasis, urinary retention, diaphoresis, and fever.
    2) SEVERE TOXICITY: An adult with multiple sclerosis developed CNS depression and muscle rigidity after ingesting 90 g of metaxalone, but recovered with supportive care. In a retrospective review of adult metaxalone overdoses, respiratory depression developed in 2 patients. Deaths have been reported in patients ingesting large doses of metaxalone in combination other drugs that cause CNS and respiratory depression (eg, antidepressants, acetaminophen/hydrocodone).

Vital Signs

    3.3.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Fever developed in one patient after metaxalone overdose.
    3.3.3) TEMPERATURE
    A) WITH POISONING/EXPOSURE
    1) FEVER: ADULTS: In a retrospective review of 142 adult metaxalone ingestions collected by the Texas Poison Center Network during 2000 to 2006, 2 patients (1.4%) developed fever; of the 61 (43%) cases where the dose ingested was known, fever occurred in 1 patient after ingesting 20,000 mg of metaxalone (Forrester, 2010).

Heent

    3.4.3) EYES
    A) WITH POISONING/EXPOSURE
    1) MYDRIASIS: ADULTS: In a retrospective review of 142 adult metaxalone ingestions collected by the Texas Poison Center Network during 2000 to 2006, 1 patient developed mydriasis after ingesting 20,000 mg of metaxalone (Forrester, 2010).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) SHOCK
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 32-year-old woman was found unconscious at home. Despite supportive care, she died about 27 hours after presentation from circulatory shock with hypotension, tachycardia, acidosis, respiratory failure, and disseminated intravascular coagulation (DIC). Laboratory results revealed a blood metaxalone concentration of 37.4 mcg/mL on admission day (Curtis et al, 2015).
    B) TACHYCARDIA
    1) WITH POISONING/EXPOSURE
    a) ADULTS: In a retrospective review of 142 adult metaxalone ingestions collected by the Texas Poison Center Network during 2000 to 2006, 13 (9.2%) patients developed tachycardia; of the 61 (43%) cases where the dose ingested was known, tachycardia occurred in 4 patients after ingesting metaxalone (mean dose: 10,400 mg; range: 4800 to 20,000 mg)(Forrester, 2010).
    b) CHILDREN: In a retrospective review of 148 children (5 years or younger) metaxalone ingestions collected by the Texas Poison Center Network during 2000 to 2007, tachycardia developed in 1 patient after ingesting 800 mg of metaxalone (Forrester, 2010a).
    C) BRADYCARDIA
    1) WITH POISONING/EXPOSURE
    a) ADULTS: In a retrospective review of 142 adult metaxalone ingestions collected by the Texas Poison Center Network during 2000 to 2006, bradycardia occurred in 1 patient (Forrester, 2010).
    D) HYPERTENSIVE EPISODE
    1) WITH POISONING/EXPOSURE
    a) ADULTS: In a retrospective review of 142 adult metaxalone ingestions collected by the Texas Poison Center Network during 2000 to 2006, hypertension occurred in 2 (1.4%) patients (Forrester, 2010).
    E) HYPOTENSIVE EPISODE
    1) WITH POISONING/EXPOSURE
    a) ADULTS: In a retrospective review of 142 adult metaxalone ingestions collected by the Texas Poison Center Network during 2000 to 2006, hypotension occurred in 1 patient (Forrester, 2010).
    F) SYNCOPE
    1) WITH POISONING/EXPOSURE
    a) ADULTS: In a retrospective review of 142 adult metaxalone ingestions collected by the Texas Poison Center Network during 2000 to 2006, syncope occurred in 1 patient (Forrester, 2010).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) DECREASED RESPIRATORY FUNCTION
    1) WITH POISONING/EXPOSURE
    a) ADULTS: In a retrospective review of 142 adult metaxalone ingestions collected by the Texas Poison Center Network during 2000 to 2006, respiratory depression requiring intubation occurred in 2 (1.4%) patients (Forrester, 2010).
    b) ANIMAL STUDY: In animal studies, progressive sedation, hypnosis, and respiratory failure were observed in rats and mice when obtaining metaxalone LD50 (1200 +/- 173 mg/kg) (Gruszecki et al, 2003; Prod Info SKELAXIN(R) oral tablets, 2008).
    3.6.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) In animal studies, progressive sedation, hypnosis, and respiratory failure were observed in rats and mice when obtaining metaxalone LD50 (1200 +/- 173 mg/kg) (Gruszecki et al, 2003; Prod Info SKELAXIN(R) oral tablets, 2008).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) DROWSY
    1) WITH THERAPEUTIC USE
    a) Drowsiness has been frequently reported following metaxalone use (Prod Info SKELAXIN(R) oral tablets, 2008).
    2) WITH POISONING/EXPOSURE
    a) ADULTS: In a retrospective review of 142 adult metaxalone ingestions collected by the Texas Poison Center Network during 2000 to 2006, drowsiness/lethargy occurred in 42 (29.6%) patients; of the 61 (43%) cases where the dose ingested was known, drowsiness/lethargy occurred in 17 (27.9%) patients after ingesting metaxalone (mean dose: 10,823.5 mg; range: 1200 to 36,000 mg) (Forrester, 2010).
    b) CHILDREN: In a retrospective review of 148 children (5 years or younger) metaxalone ingestions collected by the Texas Poison Center Network during 2000 to 2007, drowsiness occurred in 11 (7.4%) patients; of the 80 (54.1%) cases where the dose ingested was known, drowsiness occurred in 9 (11.3%) patients after ingesting metaxalone (mean dose, 964.4 mg; range, 80 to 4000 mg) (Forrester, 2010a).
    B) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) Dizziness has been frequently reported following metaxalone use (Prod Info SKELAXIN(R) oral tablets, 2008).
    2) WITH POISONING/EXPOSURE
    a) ADULTS: In a retrospective review of 142 adult metaxalone ingestions collected by the Texas Poison Center Network during 2000 to 2006, dizziness/vertigo occurred in 4 (2.8%) patients; of the 61 (43%) cases where the dose ingested was known, dizziness/vertigo occurred in 3 (4.9%) patients after ingesting metaxalone (mean dose: 3066.7 mg; range: 1600 to 6000 mg) (Forrester, 2010).
    C) HEADACHE
    1) WITH THERAPEUTIC USE
    a) Headache has been frequently reported following metaxalone use (Prod Info SKELAXIN(R) oral tablets, 2008).
    2) WITH POISONING/EXPOSURE
    a) Headache has been reported with metaxalone overdose (Dent & Ervin, 1975) .
    b) ADULTS: In a retrospective review of 142 adult metaxalone ingestions collected by the Texas Poison Center Network during 2000 to 2006, headache occurred in 2 (1.4%) patients (Forrester, 2010).
    D) PSYCHOMOTOR AGITATION
    1) WITH THERAPEUTIC USE
    a) Nervousness or irritability has been frequently reported following metaxalone use (Prod Info SKELAXIN(R) oral tablets, 2008).
    2) WITH POISONING/EXPOSURE
    a) ADULTS: In a retrospective review of 142 adult metaxalone ingestions collected by the Texas Poison Center Network during 2000 to 2006, agitation occurred in 5 (3.5%) patients; of the 61 (43%) cases where the dose ingested was known, agitation occurred in 4 (6.6%) patients after ingesting metaxalone (mean dose: 8100 mg; range: 1600 to 20,000 mg) (Forrester, 2010).
    b) CHILDREN: In a retrospective review of 148 children (5 years or younger) metaxalone ingestions collected by the Texas Poison Center Network during 2000 to 2007, agitation developed in 2 (1.4%) patients; of the 80 (54.1%) cases where the dose ingested was known, agitation occurred in 1 patient after ingesting 1200 mg of metaxalone (Forrester, 2010a).
    E) ATAXIA
    1) WITH POISONING/EXPOSURE
    a) ADULTS: In a retrospective review of 142 adult metaxalone ingestions collected by the Texas Poison Center Network during 2000 to 2006, 1 patient developed ataxia after ingesting 4800 mg of metaxalone (Forrester, 2010).
    b) CHILDREN: In a retrospective review of 148 children (5 years or younger) metaxalone ingestions collected by the Texas Poison Center Network during 2000 to 2007, ataxia occurred in 1 patient after ingesting 200 mg of metaxalone (Forrester, 2010a).
    F) TREMOR
    1) WITH POISONING/EXPOSURE
    a) ADULTS: In a retrospective review of 142 adult metaxalone ingestions collected by the Texas Poison Center Network during 2000 to 2006, tremor occurred in 3 (4.9%) patients after ingesting metaxalone (mean dose, 25,600 mg; range, 12,800 to 44,000 mg) (Forrester, 2010).
    G) SEIZURE
    1) WITH POISONING/EXPOSURE
    a) ADULTS: In a retrospective review of 142 adult metaxalone ingestions collected by the Texas Poison Center Network during 2000 to 2006, seizures occurred in 1 patient (Forrester, 2010).
    H) SLURRED SPEECH
    1) WITH POISONING/EXPOSURE
    a) ADULTS: In a retrospective review of 142 adult metaxalone ingestions collected by the Texas Poison Center Network during 2000 to 2006, slurred speech occurred in 4 (2.8%) patients; of the 61 (43%) cases where the dose ingested was known, slurred speech occurred in 3 (4.9%) patients after ingesting metaxalone (mean dose: 12,000 mg; range: 2400 to 28,000 mg) (Forrester, 2010).
    I) COMA
    1) WITH POISONING/EXPOSURE
    a) ADULTS: In a retrospective review of 142 adult metaxalone ingestions collected by the Texas Poison Center Network during 2000 to 2006, coma occurred in 2 (1.4%) patients (Forrester, 2010).
    J) CLOUDED CONSCIOUSNESS
    1) WITH POISONING/EXPOSURE
    a) ADULTS: In a retrospective review of 142 adult metaxalone ingestions collected by the Texas Poison Center Network during 2000 to 2006, confusion occurred in 2 (1.4%) patients (Forrester, 2010).
    K) CENTRAL NERVOUS SYSTEM DEPRESSION
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 44-year-old woman with a history of multiple sclerosis ingested 90 grams of metaxalone. The patient developed severe muscular rigidity and central nervous system depression (pupils fixed and dilated for 48 hours). The patient returned to her neurological baseline following intensive supportive care, which included intubation, sedation with a propofol infusion, and intermittent paralysis to control muscular rigidity. Due to physical weakness, the patient was placed in an extended care facility for physical therapy and rehabilitation (Snyder et al, 2001).
    b) ANIMAL STUDY: In animal studies, progressive sedation, hypnosis, and respiratory failure were observed in rats and mice when obtaining metaxalone LD50 (1200 +/- 173 mg/kg) (Gruszecki et al, 2003; Prod Info SKELAXIN(R) oral tablets, 2008).
    3.7.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) In animal studies, progressive sedation, hypnosis, and respiratory failure were observed in rats and mice when obtaining metaxalone LD50 (1200 +/- 173 mg/kg) (Gruszecki et al, 2003; Prod Info SKELAXIN(R) oral tablets, 2008).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) Nausea, vomiting, and gastrointestinal upset have been frequently reported with metaxalone use (Prod Info SKELAXIN(R) oral tablets, 2008; Dent & Ervin, 1975).
    2) WITH POISONING/EXPOSURE
    a) ADULTS: In a retrospective review of 142 adult metaxalone ingestions collected by the Texas Poison Center Network during 2000 to 2006, nausea occurred in 4 (2.8%) patients; of the 61 (43%) cases where the dose ingested was known, nausea occurred in 3 (4.9%) patients after ingesting metaxalone (mean dose: 533.3 mg; range: 400 to 800 mg). One patient developed vomiting after ingesting 400 mg of metaxalone (Forrester, 2010).
    b) CHILDREN: In a retrospective review of 148 children (5 years or younger) metaxalone ingestions collected by the Texas Poison Center Network during 2000 to 2007, vomiting occurred in 3 patients; of the 80 (54.1%) cases where the dose ingested was known, vomiting occurred in 2 patients after ingesting metaxalone (mean dose: 2400 mg; range: 800 to 4000 mg) (Forrester, 2010a).
    B) ABDOMINAL PAIN
    1) WITH POISONING/EXPOSURE
    a) ADULTS: In a retrospective review of 142 adult metaxalone ingestions collected by the Texas Poison Center Network during 2000 to 2006, abdominal pain occurred in 1 patient (Forrester, 2010).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) JAUNDICE
    1) WITH THERAPEUTIC USE
    a) Jaundice has been reported with metaxalone use (Prod Info SKELAXIN(R) oral tablets, 2008).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) RETENTION OF URINE
    1) WITH POISONING/EXPOSURE
    a) ADULTS: In a retrospective review of 142 adult metaxalone ingestions collected by the Texas Poison Center Network during 2000 to 2006, urinary retention occurred in 1 patient (Forrester, 2010).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) LEUKOPENIA
    1) WITH THERAPEUTIC USE
    a) Leukopenia has been reported with metaxalone use (Prod Info SKELAXIN(R) oral tablets, 2008).
    B) HEMOLYTIC ANEMIA
    1) WITH THERAPEUTIC USE
    a) Hemolytic anemia has been reported with metaxalone use (Prod Info SKELAXIN(R) oral tablets, 2008).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ERUPTION
    1) WITH THERAPEUTIC USE
    a) Rash, with or without pruritus, has been reported with metaxalone use (Prod Info SKELAXIN(R) oral tablets, 2008).
    2) WITH POISONING/EXPOSURE
    a) ADULTS: In a retrospective review of 142 adult metaxalone ingestions collected by the Texas Poison Center Network during 2000 to 2006, rash occurred in 4 (2.8%) patients; of the 61 (43%) cases where the dose ingested was known, rash developed in 1 patient after ingesting 800 mg of metaxalone (Forrester, 2010).
    b) CHILDREN: In a retrospective review of 148 children (5 years or younger) metaxalone ingestions collected by the Texas Poison Center Network during 2000 to 2007, rash developed in 1 patient after ingesting 1600 mg of metaxalone (Forrester, 2010a).
    B) SKIN IRRITATION
    1) WITH POISONING/EXPOSURE
    a) ADULTS: In a retrospective review of 142 adult metaxalone ingestions collected by the Texas Poison Center Network during 2000 to 2006, skin irritation/pain occurred in 1 patient (Forrester, 2010).
    C) EXCESSIVE SWEATING
    1) WITH POISONING/EXPOSURE
    a) ADULTS: In a retrospective review of 142 adult metaxalone ingestions collected by the Texas Poison Center Network during 2000 to 2006, diaphoresis occurred in 1 patient (Forrester, 2010).
    D) PALE - SYMPTOM
    1) WITH POISONING/EXPOSURE
    a) ADULTS: In a retrospective review of 142 adult metaxalone ingestions collected by the Texas Poison Center Network during 2000 to 2006, pallor occurred in 1 patient (Forrester, 2010).
    E) ITCHING OF SKIN
    1) WITH POISONING/EXPOSURE
    a) ADULTS: In a retrospective review of 142 adult metaxalone ingestions collected by the Texas Poison Center Network during 2000 to 2006, pruritus occurred in 2 (1.4%) patients (Forrester, 2010).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) MUSCLE RIGIDITY
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 44-year-old woman with a history of multiple sclerosis ingested 90 grams of metaxalone. The patient developed severe muscular rigidity and central nervous system depression (pupils fixed and dilated for 48 hours). The patient returned to her neurological baseline following intensive supportive care, which included intubation, sedation with a propofol infusion, and intermittent paralysis to control muscular rigidity. Due to physical weakness, the patient was placed in an extended care facility for physical therapy and rehabilitation (Snyder et al, 2001).
    b) ADULTS: In a retrospective review of 142 adult metaxalone ingestions collected by the Texas Poison Center Network during 2000 to 2006, muscle rigidity developed in 1 patient (Forrester, 2010).
    B) INCREASED CREATINE KINASE LEVEL
    1) WITH POISONING/EXPOSURE
    a) ADULTS: In a retrospective review of 142 adult metaxalone ingestions collected by the Texas Poison Center Network during 2000 to 2006, elevated creatine phosphokinase levels occurred in 1 patient (Forrester, 2010).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) HYPERSENSITIVITY REACTION
    1) WITH THERAPEUTIC USE
    a) Hypersensitivity reactions, including rash with or without pruritus, have been reported with metaxalone use (Prod Info SKELAXIN(R) oral tablets, 2008).
    B) ANAPHYLACTOID REACTION
    1) WITH THERAPEUTIC USE
    a) Anaphylactoid reactions have been reported with metaxalone use (Prod Info SKELAXIN(R) oral tablets, 2008).

Reproductive

    3.20.1) SUMMARY
    A) At the time of this review, no data were available to assess the teratogenic potential of this agent in humans. Studies conducted in rats did not find evidence of fetal harm when metaxalone was administered (dose not given).
    3.20.2) TERATOGENICITY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the teratogenic potential of this agent in humans.
    B) ANIMAL STUDIES
    1) RATS: Studies conducted in rats did not find evidence of fetal harm when metaxalone was administered (dose not given) (Prod Info SKELAXIN(R) oral tablets, 2008).
    3.20.3) EFFECTS IN PREGNANCY
    A) LACK OF INFORMATION
    1) There are no adequate and well-controlled studies of metaxalone use in pregnant women. Until further data are available, it is recommended that metaxalone tablets should not be used in women who are or may become pregnant and particularly during early pregnancy, unless the potential benefit to the mother justifies the risk to the fetus (Prod Info SKELAXIN(R) oral tablets, 2008).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the potential effects of exposure to metaxalone during lactation in humans (Prod Info SKELAXIN(R) oral tablets, 2008).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) RATS: Studies conducted in rats did not find evidence of impaired fertility when metaxalone was administered (dose not given) (Prod Info SKELAXIN(R) oral tablets, 2008).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) At the time of this review, no human data were available to assess the potential carcinogenic activity of metaxalone.
    3.21.3) HUMAN STUDIES
    A) LACK OF INFORMATION
    1) At the time of this review, no human data were available to assess the potential carcinogenic activity of metaxalone (Prod Info SKELAXIN(R) oral tablets, 2008).
    3.21.4) ANIMAL STUDIES
    A) LACK OF INFORMATION
    1) At the time of this review, no animal data were available to assess the potential carcinogenic activity of metaxalone (Prod Info SKELAXIN(R) oral tablets, 2008).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs and mental status.
    B) Monitor patients with significant CNS depression for respiratory insufficiency.
    C) Monitor serum electrolytes in patients with prolonged vomiting.
    D) Qualitative or quantitative levels of metaxalone in the blood or urine may be obtained by certain labs, but are not useful or generally available for clinical management.

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 who are symptomatic after a 6 to 12 hour period of observation should be admitted to the hospital. Criteria for discharge should be clear improvement of symptoms (eg, patient is alert and able to ambulate safely).
    6.3.1.2) HOME CRITERIA/ORAL
    A) Adults with only mild symptoms who have unintentional ingestions of 2400 mg or less can be observed at home. Children with mild symptoms and unintentional ingestions of 4000 mg or less can be observed at home.
    B) ADULTS: In a retrospective review of 142 adult metaxalone ingestions collected by the Texas Poison Center Network during 2000 to 2006, inadvertent ingestion of doses of less than 2400 mg in adults was generally not associated with significant toxicity and could usually be managed at home with telephone follow up (Forrester, 2010).
    C) CHILDREN: Pediatric ingestions of up to 4000 mg or 285.71 mg/kg of metaxalone usually result in minor effects (Forrester, 2010a).
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) A medical toxicologist or poison center should be consulted for patients with severe toxicity or unclear diagnosis.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Any patient with a deliberate ingestion or more than mild symptoms should be referred to a healthcare facility for evaluation and treatment. Adults with inadvertent ingestions of more than 2400 mg and children with inadvertent ingestions of more than 4000 mg or more than 285 mg/kg should be referred to a healthcare facility.
    B) ADULTS: In a retrospective review of 142 adult metaxalone ingestions collected by the Texas Poison Center Network during 2000 to 2006, metaxalone ingestions of greater than 2400 mg in adults were more likely to be associated with intentional exposure and more serious adverse events. These patients should generally be referred to a health care facility (Forrester, 2010).

Monitoring

    A) Monitor vital signs and mental status.
    B) Monitor patients with significant CNS depression for respiratory insufficiency.
    C) Monitor serum electrolytes in patients with prolonged vomiting.
    D) Qualitative or quantitative levels of metaxalone in the blood or urine may be obtained by certain labs, but are not useful or generally available for clinical management.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Prehospital decontamination is not recommended because of the risk of CNS and respiratory depression and subsequent aspiration.
    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) MONITORING OF PATIENT
    1) Monitor vital signs and mental status.
    2) Monitor patients with significant CNS depression for respiratory insufficiency.
    3) Monitor serum electrolytes in patients with prolonged vomiting.
    4) Qualitative or quantitative levels of metaxalone in the blood or urine may be obtained by certain labs, but are not useful or generally available for clinical management.
    B) HYPOTENSIVE EPISODE
    1) SUMMARY
    a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.
    2) DOPAMINE
    a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    3) NOREPINEPHRINE
    a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
    b) DOSE
    1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
    2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
    3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).
    C) SEIZURE
    1) SUMMARY
    a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
    b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
    c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).
    2) DIAZEPAM
    a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
    3) NO INTRAVENOUS ACCESS
    a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
    b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
    4) LORAZEPAM
    a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
    b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
    c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2010; Chin et al, 2008).
    5) PHENOBARBITAL
    a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
    b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
    c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
    d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
    e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
    f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).
    6) OTHER AGENTS
    a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):
    1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
    2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
    3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
    4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).
    7) RECURRING SEIZURES
    a) If seizures are not controlled by the above measures, patients will require endotracheal intubation, mechanical ventilation, continuous EEG monitoring, a continuous infusion of an anticonvulsant, and may require neuromuscular paralysis and vasopressor support. Consider continuous infusions of the following agents:
    1) MIDAZOLAM: ADULT DOSE: An initial dose of 0.2 mg/kg slow bolus, at an infusion rate of 2 mg/minute; maintenance doses of 0.05 to 2 mg/kg/hour continuous infusion dosing, titrated to EEG (Brophy et al, 2012). PEDIATRIC DOSE: 0.1 to 0.3 mg/kg followed by a continuous infusion starting at 1 mcg/kg/minute, titrated upwards every 5 minutes as needed (Loddenkemper & Goodkin, 2011).
    2) PROPOFOL: ADULT DOSE: Start at 20 mcg/kg/min with 1 to 2 mg/kg loading dose; maintenance doses of 30 to 200 mcg/kg/minute continuous infusion dosing, titrated to EEG; caution with high doses greater than 80 mcg/kg/minute in adults for extended periods of time (ie, longer than 48 hours) (Brophy et al, 2012); PEDIATRIC DOSE: IV loading dose of up to 2 mg/kg; maintenance doses of 2 to 5 mg/kg/hour may be used in older adolescents; avoid doses of 5 mg/kg/hour over prolonged periods because of propofol infusion syndrome (Loddenkemper & Goodkin, 2011); caution with high doses greater than 65 mcg/kg/min in children for extended periods of time; contraindicated in small children (Brophy et al, 2012).
    3) PENTOBARBITAL: ADULT DOSE: A loading dose of 5 to 15 mg/kg at an infusion rate of 50 mg/minute or lower; may administer additional 5 to 10 mg/kg. Maintenance dose of 0.5 to 5 mg/kg/hour continuous infusion dosing, titrated to EEG (Brophy et al, 2012). PEDIATRIC DOSE: A loading dose of 3 to 15 mg/kg followed by a maintenance dose of 1 to 5 mg/kg/hour (Loddenkemper & Goodkin, 2011).
    4) THIOPENTAL: ADULT DOSE: 2 to 7 mg/kg, at an infusion rate of 50 mg/minute or lower. Maintenance dose of 0.5 to 5 mg/kg/hour continuous infusing dosing, titrated to EEG (Brophy et al, 2012)
    b) Endotracheal intubation, mechanical ventilation, and vasopressors will be required (Brophy et al, 2012) and consultation with a neurologist is strongly advised.
    c) Neuromuscular paralysis (eg, rocuronium bromide, a short-acting nondepolarizing agent) may be required to avoid hyperthermia, severe acidosis, and rhabdomyolysis. If rhabdomyolysis is possible, avoid succinylcholine chloride, because of the risk of hyperkalemic-induced cardiac dysrhythmias. Continuous EEG monitoring is mandatory if neuromuscular paralysis is used (Manno, 2003).

Enhanced Elimination

    A) SUMMARY
    1) There is no role for dialysis, hemoperfusion, urinary alkalinization, or multiple dose activated charcoal.

Range Of Toxicity

Summary

    A) TOXICITY: ADULTS: An adult with multiple sclerosis developed CNS depression and muscle rigidity after ingesting 90 g of metaxalone, but recovered with supportive care. In a retrospective review of adults metaxalone ingestions (61 patients with known doses; mean dose, 7732.8 mg; range: 400 to 44,000 mg), ingestion of 2400 mg or less was associated with relatively minor adverse effects. CHILDREN: In a retrospective review of children metaxalone ingestions (80 patients with known doses; mean dose was 655 mg; range: 40 to 4000 mg), ingestion of 4,000 mg (285.71 mg/kg) or less resulted in minor adverse effects. Deaths have been reported in patients ingesting large doses of metaxalone in combination with other drugs that cause respiratory or CNS depression (eg, antidepressants, acetaminophen/hydrocodone). However, the causal relationship was not established. THERAPEUTIC DOSE: ADULTS AND CHILDREN OVER 12 YEARS OF AGE: 800 mg orally 3 or 4 times daily. 12 YEARS AND YOUNGER: Safety and efficacy of metaxalone have not been established.

Therapeutic Dose

    7.2.1) ADULT
    A) The recommended dose is 800 mg orally 3 or 4 times daily (Prod Info metaxalone oral tablets, 2013).
    7.2.2) PEDIATRIC
    A) OVER 12 YEARS: The recommended dose is 800 mg orally 3 or 4 times daily (Prod Info metaxalone oral tablets, 2013).
    B) 12 YEARS AND YOUNGER: Safety and efficacy of metaxalone have not been established (Prod Info metaxalone oral tablets, 2013).

Minimum Lethal Exposure

    A) Deaths have been reported in patients ingesting large doses of metaxalone in combination with other drugs (eg, antidepressants, acetaminophen/hydrocodone) (Prod Info SKELAXIN(R) oral tablets, 2008; Poklis et al, 2004). However, the causal relationship was not established.

Maximum Tolerated Exposure

    A) CASE REPORT: A 44-year-old woman with a history of multiple sclerosis survived an ingestion of 90 g of metaxalone. The patient developed severe muscular rigidity and central nervous system depression (pupils fixed and dilated for 48 hours). The patient returned to her neurological baseline following intensive supportive care (Snyder et al, 2001).
    B) ADULTS: In a retrospective review of 142 adult metaxalone ingestions collected by the Texas Poison Center Network during 2000 to 2006, 50.8% of cases reported no effects, 18% reported moderate effects, and 31.1% had minor effects. Of the 61 (43%) cases where the dose ingested was known, the mean dose was 7732.8 mg (range: 400 to 44,000 mg). The most common events reported for these cases included: drowsiness (27.9%), tachycardia (6.6%), agitation (6.6%), nausea (4.9%), dizziness (4.9%), slurred speech (4.9%), and tremor (4.9%). Ingestions of greater than 2400 mg were more likely to be associated with moderate toxicity, more likely to be an intentional ingestion and to require medical care. No deaths were reported (Forrester, 2010).
    C) CHILDREN: In a retrospective review of 148 children (5 years or younger) metaxalone ingestions collected by the Texas Poison Center Network during 2000 to 2007, 90.5% of cases reported no effects, 8.1% reported minor effects, and 0.7% had moderate effects, and 0.7% reported major effects. Of the 80 (54.1%) cases where the dose ingested was known, the mean dose was 655 mg (range: 40 to 4000 mg). The adverse events reported for these cases included: drowsiness (7.4%), vomiting (2%), agitation (1.4%), ataxia (0.7%), rash (0.7%), and tachycardia (0.7%). Pediatric ingestions of up to 4000 mg or 285.71 mg/kg of metaxalone usually result in minor effects (Forrester, 2010a).

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) POLYDRUG FATALITY
    a) Deaths have been reported in patients ingesting large doses of metaxalone in combination with other drugs that cause CNS and respiratory depression (Prod Info SKELAXIN(R) oral tablets, 2008; Moore et al, 2005; Poklis et al, 2004; Gruszecki et al, 2003). The causal relationships to metaxalone were not established.
    1) A 54-year-old woman was found dead after ingesting unknown quantities of acetaminophen, citalopram, gabapentin, and metaxalone; blood concentrations of these agents were 97 mg/L, 0.4 mg/L, 24 mg/L, and 21 mg/L, respectively (Moore et al, 2005).
    2) A 29-year-old woman was found dead after ingesting unknown quantities of metaxalone, citalopram, chlorpheniramine, and caffeine with ethanol. The following postmortem metaxalone concentrations were reported: femoral blood 39 mg/L, heart blood 54 mg/L, brain tissue 163 mg/kg, liver tissue 195 mg/kg, gastric content 75 mg/total volume, duodenum content 164 mg/total volume (Gruszecki et al, 2003).
    3) A 21-year-old woman was found dead after ingesting unknown quantities of metaxalone, acetaminophen/hydrocodone, and other agents. Postmortem results revealed the following aortic blood drug concentrations: metaxalone 19 mg/L; acetaminophen 190 mg/L; hydrocodone 0.28 mg/L; and diazepam, nordiazepam, amitriptyline, and nortriptyline less than 0.1 mg/L. The following postmortem metaxalone concentrations were also reported: femoral blood 17 mg/L; bile 44 mg/L; liver 70 mg/kg; urine 7 mg/L; gastric contents 202 mg/kg; vitreous humor 14 mg/L (Poklis et al, 2004).
    2) CASE REPORT: A 32-year-old woman was found unconscious at home. Despite supportive care, she died about 27 hours after presentation from circulatory shock with hypotension, tachycardia, acidosis, respiratory failure, and disseminated intravascular coagulation (DIC). Laboratory results revealed a blood metaxalone concentration of 37.4 mcg/mL on admission day. Postmortem specimens revealed the following concentrations: 13.5 mcg/mL (heart blood), 4.9 mcg/mL (vitreous humor), 69.4 mcg/g (liver), 74 mcg/g (brain), and an antemortem blood-to-plasma (b/p) ratio of 1.4, suggesting a higher proportion of the drug in whole blood versus plasma/serum samples (Curtis et al, 2015).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Metaxalone has no established mechanism of action, but its clinical effect may be associated with general depression of the nervous system. It has no direct effect on the contractile mechanism of striated muscle, the nerve fiber or the motor end plate (Prod Info SKELAXIN(R) oral tablet, 2003).

Physicochemical

Physical Characteristics

    A) White to almost white, odorless crystalline powder that is practically insoluble in water and in ether, soluble in methanol and in 96% ethanol, and freely soluble in chloroform (Prod Info SKELAXIN(R) oral tablets, 2008).

Molecular Weight

    A) 221.25 (Prod Info SKELAXIN(R) oral tablets, 2008)

References

General Bibliography

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