Metaxalone

221.25

221.25

216-777-6

758703|170959

DTXSID3023269

White to almost white crystalline powder|Crystals from ethyl acetate

2934990002

47.6

2.2

white to tan

1.1514 (rough estimate)

121.5-123 °C

225°C/1.5mmHg(lit.)

9 °C

1.5200 (estimate)

DMSO: ≥2mg/mL (warmed to 60 °C)

-20°C Freezer

4.41X10-6 mm Hg at 25 deg C (est)

Odorless

Henry's Law constant = 2.68X01-10 atm-cu m/mol at 25 °C (est)

Hydroxyl radical reaction rate constant = 1.71X10-10 cu cm/molec-sec at 25 °C (est)

UN1230 - class 3 - PG 2 - Methanol, solution

3

11-23/24/25-39/23/24/25

7-16-36/37-45

RQ3850000

F,T

P301 + P312 + P330

H302

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.|SRP: At the time of review, regulatory criteria for small quantity disposal are subject to significant revision, however, household quantities of waste pharmaceuticals may be managed as follows: Mix with wet cat litter or coffee grounds, double bag in plastic, discard in trash.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, including metaxalone, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

|Warning|H302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]|P264, P270, P301+P312, P330, and P501|Aggregated GHS information provided by 44 companies from 2 notifications to the ECHA C&L Inventory.

Metaxalone was detected in one of three wastewater treatment plant effluents associated with facilities involved in the manufacture of pharmaceuticals in New York; 35-38 samples were collected from each plant between 2004 and 2009. The concentration of metaxalone was 3,800 ug/L in the one New York sample, which receives 20% of its discharge from a pharmaceutical formulation facility. The median concentration ranged from 0.5 to >400 ug/L. It was not detected in twenty-three plants across the US were analyzed once between 2004 and 2009 as part of a National Survey; more than half of these plants receive hospital discharge. Detection limit = 0.011 ug/L. These findings suggest that current manufacturing practices at pharmaceutical formulation facilities can result in pharmaceuticals concentrations from 10 to 1000 times higher than those typically found in wastewater treatment plant effluents(1).

LD50=775mg/kg (Rat, oral); LD50=1690 mg/kg (Mouse, oral). When determining the LD50 in rats and mice, progressive sedation, hypnosis and finally respiratoryfailure were noted as the dosage increased. In dogs, no LD50 could be determined as the higher doses produced an emetic action in 15 to 30 minutes. Some adverse events associated with the drug include nausea, vomiting, drowsiness and CNS side effects such as dizziness, headache, and irritability.

According to the product brochure, metaxalone may cause jaundice, although there are no specific case reports of hepatotoxicity from metaxalone in the literature and no prospective trials with routine monitoring of aminotransferase levels. Given its long history, metaxalone appears to be without significant hepatotoxicity.

Additive CNS depression may occur when metaxalone is administered concomitantly with other CNS depressants, including alcohol. If metaxalone is used concomitantly with other depressant drugs, caution should be used to avoid overdosage.

Patients should be warned that metaxalone may impair ability to perform hazardous activities requiring mental alertness or physical coordination, such as operating machinery or driving a motor vehicle. In addition, patients should be warned that additive CNS depression may occur when the drug is administered concomitantly with other CNS depressants, including alcohol. Metaxalone should be used with caution in geriatric patients and in patients with hepatic or renal impairment. Liver function studies should be performed periodically during metaxalone therapy in patients with preexisting liver damage. The drug is contraindicated in patients with substantially impaired hepatic or renal function, known hypersensitivity to the drug or any ingredient in the formulation, or a history of drug-induced, hemolytic, or other anemias.

Metaxalone's production and use as a medication(1) may result in its release to the environment through various waste streams(SRC).

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 530(SRC), determined from a structure estimation method(2), indicates that metaxalone is expected to have low mobility in soil(SRC). Volatilization of metaxalone from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 2.7X10-10 atm-cu m/mole(SRC), using a fragment constant estimation method(3). Metaxalone is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 4.4X10-6 mm Hg at 25 °C(SRC), determined from a fragment constant method(4). Biodegradation data were not available(SRC, 2010).|AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 530(SRC), determined from a structure estimation method(2), indicates that metaxalone is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 2.7X10-10 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(5), an estimated BCF of 24(SRC), from an estimated log Kow of 2.6(6) and a regression-derived equation(7), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Biodegradation data were not available(SRC, 2010).|ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), metaxalone, which has an estimated vapor pressure of 4.4X10-6 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), will exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase metaxalone is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 2.2 hours(SRC), calculated from its rate constant of 1.7X10-10 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(3). Particulate-phase metaxalone may be removed from the air by wet or dry deposition(SRC). Metaxalone does not contain chromophores that absorb at wavelengths >290 nm(4), and therefore is not expected to be susceptible to direct photolysis by sunlight(SRC).

The rate constant for the vapor-phase reaction of metaxalone with photochemically-produced hydroxyl radicals has been estimated as 1.7X10-10 cu cm/molecule-sec at 25 °C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 2.2 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). A base-catalyzed second-order hydrolysis rate constant of 1.7X10-5 L/mole-sec(SRC) was estimated using a structure estimation method(2); this corresponds to half-lives of 1.2X10+4 and 1,200 years at pH values of 7 and 8, respectively(2), indicating that hydrolysis is not an important environmental fate process(SRC). Metaxalone does not contain chromophores that absorb at wavelengths >290 nm(3), and therefore is not expected to be susceptible to direct photolysis by sunlight(SRC).

An estimated BCF of 24 was calculated in fish for metaxalone(SRC), using an estimated log Kow of 2.60(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC).

Using a structure estimation method based on molecular connectivity indices(1), the Koc of metaxalone can be estimated to be 530(SRC). According to a classification scheme(2), this estimated Koc value suggests that metaxalone is expected to have low mobility in soil.

The Henry's Law constant for metaxalone is estimated as 2.7X10-10 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that metaxalone is expected to be essentially nonvolatile from water surfaces(2). Metaxalone's Henry's Law constant indicates that volatilization from moist soil surfaces may not occur(SRC). Metaxalone is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 4.4X10-6 mm Hg(SRC), determined from a fragment constant method(3).

EXPERIMENTAL: It is not known whether metaxalone is distributed into milk.

Occupational exposure to metaxalone may occur through inhalation and dermal contact with this compound at workplaces where metaxalone is produced or used. Limited monitoring data indicate that the general population may be exposed to metaxalone via contact with contaminated water. Exposure to metaxalone among the general population may be limited to those administered the drug, a muscoskeletal analgesic. (SRC)

For the treatment of painful peripheral musculoskeletal conditions and spasticity from upper motor neuron syndromes.|FDA Label

Metaxalone is a centrally acting skeletal muscle relaxant that has been in use for more than 40 years. Metaxalone has not been associated with serum aminotransferase elevations during therapy or with clinically apparent hepatic injury.

Muscle Relaxants

Metaxalone is used as an adjunct to rest, physical therapy, analgesics, and other measures for the relief of discomfort associated with acute, painful musculoskeletal conditions. /Included in US product label/

The most frequent adverse effects of metaxalone are drowsiness, dizziness, headache, nervousness or irritability, nausea, vomiting, and GI upset. Other adverse effects include confusion, anorexia, dry mouth, and urinary retention. Exacerbation of tonic-clonic (grand mal) seizures has also been reported.|Hypersensitivity reactions and rash (with or without pruritus) have occurred in patients receiving metaxalone. Anaphylactoid reactions, leukopenia, hemolytic anemia, and jaundice have occurred rarely. Abnormalities in liver function tests, such as increased serum concentrations of AST (SGOT), ALT (SGPT), alkaline phosphatase, and bilirubin, and increased sulfobromophthalein (BSP) retention and thymol turbidity, have occurred in patients receiving metaxalone. Although a causal relationship to metaxalone has not been established, nephrotoxicity and proteinuria have occurred rarely during treatment with the drug; pyuria and nephrolithiasis have also been reported.|Safety and efficacy of metaxalone in children 12 years of age or younger have not been established; therefore, the drug should not be administered to children in this age group.|Patients should be warned that metaxalone may impair ability to perform hazardous activities requiring mental alertness or physical coordination, such as operating machinery or driving a motor vehicle. In addition, patients should be warned that additive CNS depression may occur when the drug is administered concomitantly with other CNS depressants, including alcohol. Metaxalone should be used with caution in geriatric patients and in patients with hepatic or renal impairment. Liver function studies should be performed periodically during metaxalone therapy in patients with preexisting liver damage. The drug is contraindicated in patients with substantially impaired hepatic or renal function, known hypersensitivity to the drug or any ingredient in the formulation, or a history of drug-induced, hemolytic, or other anemias.|For more Drug Warnings (Complete) data for METAXALONE (8 total), please visit the HSDB record page.

Metaxalone is a skeletal muscle relaxant indicated as an adjunct to rest, physical therapy, and other measures for the relief of discomforts associated with acute, painful musculoskeletal conditions. The mode of action of this drug has not been clearly identified, but may be related to its sedative properties. Metaxalone does not directly relax tense skeletal muscles in man.

Drugs used for their actions on skeletal muscle. Included are agents that act directly on skeletal muscle, those that alter neuromuscular transmission (NEUROMUSCULAR BLOCKING AGENTS), and drugs that act centrally as skeletal muscle relaxants (MUSCLE RELAXANTS, CENTRAL). Drugs used in the treatment of movement disorders are ANTI-DYSKINESIA AGENTS. (See all compounds classified as Neuromuscular Agents.)

The absolute bioavailability of metaxalone from Skelaxin tablets is not known.|Metaxalone is metabolized by the liver and excreted in the urine as unidentified metabolites.|800 L|68 +/- 50 L/h [Subjects received 1×400mg tablet under fasted conditions]|Although plasma protein binding and absolute bioavailability of metaxalone are not known, the apparent volume of distribution (V/F ~ 800 L) and lipophilicity (log P = 2.42) of metaxalone suggest that the drug is extensively distributed in the tissues. Metaxalone is metabolized by the liver and excreted in the urine as unidentified metabolites.|Peak plasma concentrations of metaxalone occur approximately 3 hours after a 400 mg oral dose under fasted conditions. Thereafter, metaxalone concentrations decline log-linearly with a terminal half-life of 9.0 + or - 4.8 hours. Doubling the dose of skelaxin from 400 mg to 800 mg results in a roughly proportional increase in metaxalone exposure as indicated by peak plasma concentrations (Cmax) and area under the curve (AUC). Dose proportionality at doses above 800 mg has not been studied. The absolute bioavailability of metaxalone is not known

Probably hepatic.|Biotransformations...studied in dogs and in man. 5-(3-methyl-5-carboxyphenoxymethyl)-2-oxazolidinone, major metabolite, is excreted in urine and feces; this also occurs in urine as ester glucuronide. Fission of ether linkage...affords...3,5-xylenol and 5-hydroxymethyloxazolidinone. Oxazolidinone ring is stable in mammals.|Yields 5-(5-carboxy-3-methylphenoxymethyl)-2-oxazolidone in man & in dogs, yields 3,5-dimethylphenol in man and in dogs. /From table/|Metaxalone is metabolized by the liver and excreted in the urine as unidentified metabolites.

9.2 (+/- 4.8) hours|Terminal half-life /is/ 9.0 + or - 4.8 hours

The mechanism of action of metaxalone in humans has not been established, but may be due to general central nervous system depression.|Metaxalone is a CNS depressant that has sedative and skeletal muscle relaxant effects. The precise mechanism of action of the drug is not known. The skeletal muscle relaxant effects of orally administered metaxalone are minimal and are probably related to its sedative effect. The drug does not directly relax skeletal muscle and, unlike neuromuscular blocking agents, does not depress neuronal conduction, neuromuscular transmission, or muscle excitability.|The mechanism of action of metaxalone in humans has not been established, but may be due to general central nervous system depression. Metaxalone has no direct action on the contractile mechanism of striated muscle, the motor end plate or the nerve fiber.

Emergency and Supportive Measures. Maintain an open airway and assist ventilation if necessary. Administer supplemental oxygen. Treat coma, hypothermia, hypotension, and pulmonary edema if they occur. Hypotension usually responds promptly to supine position and intravenous fluids. Monitor patients for at least 6 hours after ingestion, because delayed absorption may occur. /Skeletal muscle relaxants/|Decontamination. Adminster activated charcoal orally is conditions are appropriate. Gastric lavage is not necessary after small to moderate ingestins if activated charcoal can be given promptly. /Skeletal muscle relaxants/|Enhanced Elimination. Because of extensive tissue distribution, dialysiss and hemoperfusion are not very effective for most of the drugs in this group. ... /Skeletal muscle relaxants/|/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/|For more Antidote and Emergency Treatment (Complete) data for METAXALONE (6 total), please visit the HSDB record page.

/CASE REPORTS/ A 29-year old female with a history of depression was found dead in a hotel room. The death scene investigation found empty pill bottles and an empty liter bottle of wine. Metaxalone, a centrally acting muscle relaxant, along with citalopram, ethanol, and chlorpheniramine were identified in the postmortem samples and quantitated by gas chromatography-mass spectrometry. The concentration of metaxalone in femoral vein blood was 39 mg/L. The heart blood concentration was 54 mg/L. Femoral vein blood concentrations of citalopram and chlorpheniramine were 0.77 mg/L and 0.04 mg/L, respectively. Ethanol levels were 0.13 g/dL in vitreous and 0.08 g/dL in heart blood. Other tissue samples were also analyzed. The authors consider the metaxalone concentrations toxic and potentially fatal. The citalopram concentrations were lower than those reported in fatal cases for this drug alone. Death was ascribed to polydrug abuse/overdose with metaxalone a major contributor. This represents the first reported case to our knowledge in which a metaxalone overdose significantly contributed to death.|/CASE REPORTS/ A case is presented of a 54-year-old white female found dead in a secured apartment. Postmortem toxicologic analysis of the heart blood identified acetaminophen (97 mg/L), citalopram (0.4 mg/L), gabapentin (24 mg/L) and metaxalone (21 mg/L). The metaxalone concentration is within the range of previously reported fatalities involving metaxalone. The medical examiner ruled that the cause of death was metaxalone and gabapentin intoxication and the manner of death was suicide.|/SURVEILLANCE/ The purpose of this study was to describe the pattern of metaxalone ingestions by young children reported to poison control centers. METHODS: Cases were all metaxalone ingestions by patients aged 0 to 5 years reported to Texas poison control centers during 2000 to 2007. Cases with multiple substance ingestions and lack of follow-up were excluded. Cases were analyzed for selected demographic and clinical factors. Of 148 total cases, 56.8% were boys. The distributions by management site were 56.1% on-site, 22.3% already at/en route to a health care facility, and 21.6% referred to a health care facility. Final medical outcomes were no effect for 90.5% cases, minor effect for 8.1%, moderate effect for 0.7%, and major effect for 0.7%. Specific clinical effects reported were drowsiness (11), vomiting (3), agitation (2), rash (1%), tachycardia (1), and ataxia (1). Pediatric metaxalone ingestions reported to Texas poison control centers usually resulted in minor or no effect. Most ingestions did not require hospitalization.|/SURVEILLANCE/ Few data exist on potentially adverse metaxalone ingestions in adults. All metaxalone ingestions involving patients aged > or = 20 years during 2000-2006 were retrieved from Texas poison control centers. Exclusion criteria were lack of follow-up or multiple substance ingestion. Cases were analyzed for selected demographic and clinical factors. Of the 142 patients, 66.2% were female. Dose ingested was reported for 61 patients. Of those cases with a reported dose, distribution by management site was 29.5% on-site, 59.0% already at/en route to health care facility, and 11.5% referred to health care facility. Final medical outcome was 'no effect' for 50.8% cases, 'minor effect' for 31.1%, and 'moderate effect' for 18.0%. The more common adverse clinical effects reported were drowsiness (27.9%), tachycardia (6.6%), agitation (6.6%), nausea (4.9%), dizziness (4.9%), slurred speech (4.9%), and tremor (4.9%). A moderate medical outcome occurred in 13.6% of ingestions of 2400 mg. Management involved a health care facility in 18.2% of ingestions of 2400 mg. This study found that adult ingestions of higher doses of metaxalone, particularly >2400 mg, were associated with more serious medical outcomes and were managed at health care facilities.|For more Human Toxicity Excerpts (Complete) data for METAXALONE (6 total), please visit the HSDB record page.

AHR 438

Oral: Tablets: 800 mg Skelaxin (scored) (King).

Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients|Pharmaceuticals