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)] .

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 and another serotoneric drug is warranted, reassess the patient, particularly during treatment initiation and dosage increases. Discontinue metaxalone if serotonin syndrome is suspected or it occurs.

5.2 Central Nervous System Depression

Because of its 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)] .

Follow metaxalone-treated patients 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 increases.

7.1 Serotonergic Drugs

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

Serotonin syndrome has resulted from concomitant use of metaxalone (within the recommended dosage range) with other serotonergic drugs [see Warnings and Precautions ( 5.1) and Adverse Reactions ( 6)] .

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).

7.2 CNS Depressants

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 increases.

Due to the additive pharmacologic effect, concomitant use of metaxalone 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 metaxalone-treated patients. A glucose-specific test will differentiate findings.

8.1 Pregnancy

Risk Summary
There are no available data on metaxalone use in pregnant patients 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 effects on the 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 available to evaluate 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 is 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 in pediatric patients 12 years of age or younger have not been established.

8.5 Geriatric Use

Clinical studies of metaxalone did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger adult patients.

Geriatric patients may be especially susceptible to CNS depression associated with metaxalone use [see Warnings and Precautions ( 5.2)] .

The recommended metaxalone dosage in patients 65 years of age and older is the same as in younger adult patients. Metaxalone peak plasma concentrations (C max) and area under the curve (AUC) were higher in patients 65 years of age and older in the fasted state; however, a clinically significant difference was not observed when metaxalone was administered in the fed state [see Clinical Pharmacology ( 12.3)] .

8.6 Hepatic Impairment

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

8.7 Renal Impairment

Metaxalone is contraindicated in patients with severe renal impairment. Metaxalone should be used with caution and additional follow-up 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

Metaxalone’s mechanism of action has not been fully characterized, but may be related to its sedative properties. 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

Metaxalone pharmacokinetics were evaluated in two groups of healthy volunteers that received a single oral dose of 800 mg of metaxalone or 400 mg of metaxalone (0.5 times the approved recommended dose) [the 400 mg strength of metaxalone is not currently marketed by Lannett Company, Inc.]. Metaxalone pharmacokinetic parameters are presented below as mean (% CV) unless otherwise specified. Observed metaxalone peak plasma concentrations (C max) and area under the curve (AUC) are shown in Table 1. Doubling the dose of metaxalone from 400 mg (0.5 times the approved recommended dose) to 800 mg resulted in a proportional increase in metaxalone C maxand AUC.

Table 1: Metaxalone Exposure after a Single-Dose of Metaxalone Under Fasting Conditions

10.5 times the approved recommended dose
2Mean (% CV)

Absorption
The absolute bioavailability of metaxalone is not known. Peak plasma metaxalone concentrations occurred at a mean T maxof 3.3 hours (1.5 – 5 hours) of metaxalone under fasted conditions.

The single-dose pharmacokinetic parameters of metaxalone in two groups of healthy volunteers who received 400 mg or 800 mg of metaxalone are shown in Table 1.

Effect of Food:Peak plasma metaxalone concentrations were noted at a mean T maxof 4.3 hours (1.5 – 12 hours) under fed conditions. The mean T maxunder fasting and fed conditions was 3.3 and 4.3 hours, respectively. Metaxalone exposure was increased and the half-life (t 1/2) was decreased following metaxalone administration with a high fat meal as shown in Table 2. The increase in metaxalone exposure coinciding with a reduction in half-life may be attributed to more complete absorption of metaxalone in the presence of a high fat meal.

Table 2: Relative Changes in Metaxalone Exposure, T max, and t 1/2Following Metaxalone Administration with a High Fat Meal Compared to Fasting

* 0.5 times the approved recommended dose.

Distribution
Metaxalone apparent volume of distribution is approximately 800 Liters; however, plasma protein binding is unknown.

Elimination
Metaxalone mean ± SD terminal t 1/2is 9 ± 4.8 hours and apparent clearance is approximately 67 ± 34 L/h under fasted conditions.

Metabolism:Metaxalone is primarily metabolized by CYP1A2, CYP2D6, CYP2E1, and CYP3A4 and, to a lesser extent, CYP2C8, CYP2C9, and CYP2C19.

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

Specific Populations
The effect of renal impairment and hepatic impairment on metaxalone pharmacokinetics is unknown [see Use in Specific Populations ( 8.6, 8.7)] .

Geriatric Patients:The effects of age on the pharmacokinetics of metaxalone were determined following administration of 800 mg of metaxalone under fasted and fed conditions. Age had a significantly greater effect on metaxalone pharmacokinetics under fasted conditions than under fed conditions. Bioavailability under fasted conditions increased with age. Metaxalone bioavailability under fasted and fed conditions in the three groups of healthy volunteers of varying age is shown in Table 3.

Table 3: Metaxalone Pharmacokinetic Parameters under Fasted and Fed Conditions in Three Age Groups Following Oral Administration of 800 mg of Metaxalone

1Mean values (% CV)

Male and Female Patients:The exposure of metaxalone was significantly higher in females compared to males as evidenced by C max. (2115 ng/mL versus 1335 ng/mL) and AUC  ∞(17884 ng∙h/mL versus 10328 ng∙h/mL) following administration of 800 mg of metaxalone under fasted conditions. The mean half-life was 11.1 hours in females and 7.6 hours in males. The apparent volume of distribution of metaxalone was approximately 22% higher in males than in females.

Drug Interaction Studies
In Vitro Studies:Metaxalone does not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4. Metaxalone does not induce CYP1A2, CYP2B6, and CYP3A4.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies to evaluate the carcinogenic potential of metaxalone have not been conducted. Studies to evaluate the mutagenic potential of metaxalone have not been conducted. No effects on fertility were observed in rats administered metaxalone.