5.1 Serotonin Syndrome

Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of metaxalone (within the recommended dosage range) and other serotonergic drugs [see Drug Interactions (7)] and with the use of metaxalone as the only serotonergic drug taken at a dosage higher than the recommended dosage [See Overdosage (10)]. Serotonergic drugs include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, opioids (particularly fentanyl, meperidine, and methadone), drugs that affect the serotonergic neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), and drugs that impair metabolism of serotonin (including monoamine oxidase (MAO) inhibitors, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue) [See Drug Interactions (7.2)].

Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination, rigidity), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The onset of symptoms generally occurs within several hours to a few days after initiation of a serotonergic drug, but may occur later than that.

If concomitant use of Metaxalone Tablets, 640 mg and another serotonergic drug is warranted, reassess the patient, particularly during treatment initiation and dosage modification. Discontinue Metaxalone Tablets, 640 mg if serotonin syndrome is suspected or occurs.

5.2 Central Nervous System (CNS) Depression

Because of central nervous system (CNS) depressant effects, metaxalone may impair mental and/or physical abilities required for performance of hazardous tasks, such as operating machinery or driving a motor vehicle, especially when used with other CNS depressants including alcohol. Geriatric patients may be especially susceptible to CNS depression associated with metaxalone use. When used concomitantly, the sedative effects of metaxalone and other CNS depressants (e.g., alcohol, benzodiazepines, opioids, tricyclic antidepressants) may be additive [see Drug Interactions (7)].

Skeletal muscle relaxants as a class have been associated with drowsiness and sedation to varying degrees.

In a crossover trial, participants taking SKELAXIN 800 mg tablets reported a 10.7% incidence of adverse events characterized as “nervous system disorders” (dizziness; lethargy; headache), compared to 0% among participants taking Metaxalone Tablets, 640 mg.

Follow patients treated with Metaxalone Tablets, 640 mg closely for signs and symptoms of respiratory depression and sedation. If concomitant use of metaxalone and another CNS depressant is warranted, closely monitor for signs of respiratory depression and sedation, particularly during treatment initiation and dosage modification. 

5.3 Risk Associated with Inappropriate Switching from Metaxalone Tablets, 640 mg

Inappropriate switching on a mg-to-mg basis from Metaxalone Tablets, 640 mg to SKELAXIN (metaxalone) tablets, 800 mg to achieve the same total daily metaxalone dosage may result in a clinically significant decrease in metaxalone exposure and effect.  [see Dosage and Administration (2)].  Metaxalone Tablets 640 mg and SKELAXIN (metaxalone) tablets, 800 mg are not mutually substitutable on a mg-to-mg basis [see Clinical Pharmacology (12.3)].  

It is generally inappropriate to switch between Metaxalone Tablets, 640 mg and SKELAXIN 800 mg tablets to mediate metaxalone-associated allergic or hypersensitive adverse reactions.

For recommendations on how to switch from SKELAXIN (metaxalone) tablets, 800 mg, to Metaxalone Tablets, 640 mg, see Dosage and Administration (2).

7.1 Serotonergic Drugs

If concomitant use of metaxalone and another serotonergic drug is warranted, carefully observe the patient, particularly during treatment initiation and dosage modification. Discontinue Metaxalone Tablets, 640 mg if serotonin syndrome is suspected or if it occurs.

Serotonin syndrome has resulted from concomitant use of metaxalone (within the recommended dosage range) and other serotonergic drugs [see Warnings and Precautions (5.1)].

Serotonergic drugs include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, opioids (particularly fentanyl, meperidine, and methadone), drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).

7.2 CNS Depressants

If concomitant use of Metaxalone Tablets, 640 mg and another CNS depressant is warranted, closely monitor for signs of respiratory depression and sedation, particularly during treatment initiation and dosage modification. 

Due to the additive pharmacologic effect, concomitant use of Metaxalone Tablets, 640 mg with other CNS depressants may increase the risk of sedation and respiratory depression [see Warnings and Precautions (5.2)].

7.3 Interaction of Metaxalone with Benedict’s Tests

False-positive Benedict's tests, due to an unknown reducing substance, have been noted in SKELAXIN (metaxalone) 800mg tablets treated patients. A glucose-specific test will differentiate findings.

8.1 Pregnancy

Risk Summary

There are no available data on metaxalone use in pregnancy to evaluate for a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes despite decades of metaxalone use. Reproduction studies in rats have not revealed evidence of impaired fertility or harm to fetus due to metaxalone.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

8.2 Lactation

Risk Summary

There are no data on the presence of metaxalone or its metabolite in either human or animal milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for metaxalone and any potential adverse effects on the breastfed infant from metaxalone or from the underlying maternal condition.

8.4 Pediatric Use

Metaxalone Tablets, 640 mg are indicated as an adjunct to rest, physical therapy, and other measures for the relief of discomforts associated with acute, painful musculoskeletal conditions in pediatric patients 13 years of age and older.

The safety and effectiveness of Metaxalone Tablets, 640 mg in pediatric patients less than 13 years of age have not been established.

8.5 Geriatric Use

Clinical studies of Metaxalone Tablets, 640 mg did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger adult patients.  The effects of age on the pharmacokinetics of Metaxalone Tablets, 640 mg have not been evaluated. Geriatric patients may be especially susceptible to CNS depression associated with metaxalone use [see Warnings and Precautions (5.2)].

8.6 Hepatic Impairment

Metaxalone Tablets. 640 mg are contraindicated in patients with severe hepatic impairment. Metaxalone Tablets, 640 mg should be used with caution and additional monitoring should be considered in patients with mild to moderate hepatic impairment. The effect of hepatic impairment on metaxalone pharmacokinetics is unknown; however, metaxalone undergoes extensive hepatic metabolism [see Clinical Pharmacology (12.3)].

8.7 Renal Impairment

Metaxalone Tablets, 640 mg are contraindicated in patients with severe renal impairment. Metaxalone Tablets, 640 mg should be used with caution and additional monitoring should be considered in patients with mild to moderate renal impairment. The effect of renal impairment on metaxalone pharmacokinetics is unknown; however, metaxalone undergoes renal excretion as unidentified metabolites [see Clinical Pharmacology (12.3)]. 

12.1 Mechanism of Action

The mechanism of action of metaxalone as an adjunct to rest, physical therapy, and other measures for the relief of discomfort associated with acute, painful musculoskeletal conditions has not been established, but may be due to general CNS depression. Metaxalone has no direct action on the contractile mechanism of striated muscle, the motor end plate, or the nerve fiber.

12.2 Pharmacodynamics

The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of metaxalone not been fully characterized.

12.3 Pharmacokinetics

Absorption

In a relative bioavailability study in healthy adult volunteers, the Cmax (peak plasma concentration) and AUC (extent of absorption) values of metaxalone from Metaxalone Tablets, 640 mg were found to be similar to those from SKELAXIN 800 mg tablets. After a single dose of Metaxalone Tablets, 640 mg, under fasted conditions, mean Cmax and AUC values were 2 mcg/mL and 14 mcg*h/mL, respectively. The time-to-peak plasma concentration (Tmax) occurred at 3h (range 1.5-12h). The plasma half-life in adult healthy subjects was approximately 5 hours after administration of Metaxalone Tablets, 640 mg.

Effect of Food:  Compared to the fasted condition, intake of Metaxalone Tablets, 640 mg in the presence of a high fat meal resulted in a 23% increase in Cmax, an increase in AUC (AUC0-t and AUCꝏ) by 7% and 6%, and Tmax of 8 hours (range 3.5-24 hours).  In comparison, SKELAXIN 800 mg tablets taken in the presence of a high fat meal yielded a 76% increase in Cmax, an increase in AUC (AUC0-t and AUCꝏ) by 39% and 32% and a Tmax of 5h (range 2.5-24h). See Figure 1.

Figure 1. Mean Metaxalone Plasma Concentrations (following Metaxalone Tablets 640 mg and SKELAXIN 800 mg in the Fasting and Fed States) versus Time (0 – 36 hours) for All Subjects (N = 47)

Distribution

For Metaxalone Tablets, 640 mg, the metaxalone apparent volume of distribution (V/F) was approximately 800 Liters. Metaxalone plasma protein binding is unknown.

Elimination

For Metaxalone Tablets, 640 mg, the metaxalone plasma half-life was approximately 5 hours.

Metabolism: 

Metaxalone is metabolized by the liver. CYP1A2, CYP2D6, CYP2E1, and CYP3A4 and, to a lesser extent, CYP2C8, CYP2C9, and CYP2C19 are involved in metaxalone metabolism.

Excretion: 

Metaxalone is excreted in the urine as unidentified metabolites.

Specific Populations

For Metaxalone Tablets, 640 mg, the effect of age, renal impairment, and hepatic impairment on the pharmacokinetics of metaxalone is unknown.

Drug Interaction Studies

In Vitro Studies: 

Metaxalone does not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 or induce CYP1A2, CYP2B6, and CYP3A4.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Long-term studies to evaluate the carcinogenic potential of metaxalone have not been conducted.

Mutagenesis

Studies to evaluate the mutagenic potential of metaxalone have not been conducted.

Impairment of Fertility

Reproduction studies in rats have not revealed evidence of impaired fertility or harm to the fetus due to metaxalone.