5.1 Serotonin Syndrome

Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of serotonergic drugs with metaxalone used within the recommended dosage range [See Drug Interactions (7)] and with metaxalone as a single agent taken at doses higher than the recommended dose [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)].

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, but may occur later than that. Discontinue Metaxalone Tablets if serotonin syndrome is suspected.

5.2 Central Nervous System (CNS) Depression

Metaxalone Tablets may enhance the effects of alcohol and other CNS depressants (e.g., benzodiazepines, opioids, tricyclic antidepressants) and 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 alcohol or other CNS depressants.  Therefore, Metaxalone Tablets should be used with caution in patients who take one or more of these CNS depressants. [See Drug Interactions (7)] Elderly patients may be especially susceptible to CNS effects.

5.3 Hepatic and Renal Impairment Patients

Metaxalone Tablets are metabolized by the liver and excreted in the urine. Use caution when administering Metaxalone Tablets in patients with mild to moderate hepatic or renal impairment. Consider monitoring of liver and renal function in these patients.  Metaxalone Tablets are contraindicated in patients with severe hepatic or renal impairment [See Contraindications (4) and Use in Specific Populations (8.6, 8.7)].

8.1 Pregnancy

Risk Summary

There are no available data on metaxalone use in pregnant women 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

Safety and effectiveness in children 12 years of age and below have not been established.

8.5 Geriatric Use

The effects of age on the pharmacokinetics of Metaxalone Tablets have not been evaluated.

8.6 Hepatic Impairment

Formal pharmacokinetic studies using Metaxalone Tablets have not been conducted in patients with hepatic impairment.  Since metaxalone undergoes hepatic metabolism, Metaxalone Tablets should be used with caution in patients with mild to moderate hepatic impairment.  Metaxalone Tablets are contraindicated in patients with severe hepatic impairment. [See Contraindications (4) and Warnings and Precautions (5.3)]

8.7 Renal Impairment

Formal pharmacokinetic studies using Metaxalone Tablets have not been conducted in patients with renal impairment.  Since metaxalone is excreted in the urine as unidentified metabolites, Metaxalone Tablets should be used with caution in patients with mild to moderate renal impairment.  Metaxalone Tablets are contraindicated in patients with severe renal impairment. [See Contraindications (4) and Warnings and Precautions (5.3)]

12.1 Mechanism of Action

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.

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 16 mcg.h/mL, respectively. The time-to-peak plasma concentration (Tmax) occurred at 3 h (range 1.5-12h). The plasma half-life in adult healthy subjects was about 5 hours after administration of Metaxalone Tablets.

Effect of Food: Compared to fasted condition, the presence of a high fat meal resulted in 23% increase in Cmax with no change in AUC, and a Tmax of 8h (range 3.5-24h).

Distribution

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.  

Elimination

Metabolism

Hepatic Cytochrome P450 enzymes play a role in the metabolism of metaxalone.  Specifically, CYP1A2, CYP2D6, CYP2E1, and CYP3A4 and, to a lesser extent, CYP2C8, CYP2C9, AND CYP2C19 appear to metabolize metaxalone.

Metaxalone does not significantly inhibit major CYP enzymes such as CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4.  Metaxalone does not significantly induce major CYP enzymes such as CYP1A2, CYP2B6, and CYP3A4 in vitro.

Excretion

Metaxalone is metabolized by the liver and excreted in the urine as unidentified metabolites.

Specific Populations

Age:  The effects of age on the pharmacokinetics of Metaxalone Tablets have not been evaluated. 

Gender:  Females exhibited higher systemic exposure compared to males following administration of Metaxalone Tablets under fasted state in healthy volunteers.  The Cmax and AUC were both found to be about 40% greater in females compared to males. 

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.