Metaxalone

1 INDICATIONS AND USAGE 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 adults and pediatric patients 13 years of age and older. Metaxalone Tablets, 640 mg, is a muscle relaxant, indicated as an adjunct to rest, physical therapy, and other measures for the relief of discomforts associated with acute, painful musculoskeletal conditions in adult and pediatric patients 13 years of age and older. ( 1 )

2 DOSAGE AND ADMINISTRATION The recommended dosage of Metaxalone Tablets, 640 mg in adults and pediatric patients 13 years of age and older is 640 mg taken orally with or without food, three to four times a day. The maximum recommended daily dosage is 2,560 mg (one tablet four times a day). Metaxalone Tablets, 640 mg and SKELAXIN 800 mg are not mutually substitutable on a mg-to-mg basis due to differences in pharmacokinetic profiles [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.3) ]. When it is appropriate to switch a patient taking SKELAXIN 800 mg on an empty stomach to Metaxalone Tablets, 640 mg: Stop SKELAXIN 800 mg three times a day and start Metaxalone Tablets 640 mg three times a day on an empty stomach, OR Stop SKELAXIN 800 mg four times a day and start Metaxalone Tablets 640 mg four times a day on an empty stomach. For patients who have been taking either product with food, do not switch between SKELAXIN 800 mg and Metaxalone Tablets, 640 mg. Recommended dosage in adults and pediatric patients 13 years of age and older is 640 mg taken orally, with or without food, three to four times a day ( 2 ) Maximum recommended daily dosage is 2,560 mg (one tablet four times a day) ( 2 ) Metaxalone Tablets 640 mg and SKELAXIN 800 mg tablets are not mutually substitutable on a mg-to-mg basis due to differences in pharmacokinetic profiles ( 5.3 , 12.3 ). When it is appropriate to switch a patient taking SKELAXIN 800 mg on an empty stomach to Metaxalone Tablets, 640 mg ( 2 ): Stop SKELAXIN 800 mg three times a day and start Metaxalone Tablets 640 mg three times a day on an empty stomach OR Stop SKELAXIN 800 mg four times a day and start Metaxalone Tablets 640 mg four times a day on an empty stomach. For patients who have been taking either product with food, do not switch between SKELAXIN 800 mg and Metaxalone Tablets, 640 mg ( 2 ).

5 WARNINGS AND PRECAUTIONS 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 and with the use of metaxalone as the only serotonergic drug taken at a dosage higher than the recommended dosage. If concomitant use with another serotonergic drug is warranted, carefully observe the patient, particularly during treatment initiation and dosage increases. Discontinue Metaxalone Tablets, 640 mg if serotonin syndrome is suspected or it occurs. ( 5.1 , 7.1 ) Central Nervous System (CNS) Depression : Metaxalone Tablets, 640 mg may impair mental and/or physical abilities required for the performance of hazardous tasks, such as operating machinery or driving a motor vehicle, and may enhance the effects of other CNS depressants including alcohol. Follow patients closely for signs and symptoms of respiratory depression and sedation. If concomitant use with another CNS depressant is warranted, closely monitor for signs of respiratory depression and sedation, particularly during treatment initiation and dosage increases. ( 5.2 , 7.2 ) Risk with Inappropriate Switching to Metaxalone Tablets, 640 mg Inappropriate switching on a mg-to-mg basis from SKELAXIN (metaxalone) tablets, 800 mg to Metaxalone Tablets, 640 mg to achieve the same total daily metaxalone dosage may result in a clinically significant increase in metaxalone exposure which may increase the risk of metaxalone-associated adverse reactions including CNS depression. Metaxalone Tablets, 640 mg and SKELAXIN (metaxalone) tablets, 800 mg are not mutually substitutable on a mg-to-mg basis ( 5.3 , 12.3 ). 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 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, benzodiazep…

4 CONTRAINDICATIONS The use of Metaxalone Tablets, 640 mg is contraindicated in patients with: Known hypersensitivity to any components of this product. Known tendency for drug-induced, hemolytic, or other anemias. Severe renal or hepatic impairment. • Known hypersensitivity to any components of this product. ( 4 ) • Known tendency to drug induced, hemolytic, or other anemias. ( 4 ) • Severe renal or hepatic impairment. ( 4 )

7 DRUG INTERACTIONS 7.1 Serotonergic Drugs If concomitant use of Metaxalone Tablets, 640 mg 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 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 metaxalone-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.

6 ADVERSE REACTIONS The following adverse reactions associated with the use of metaxalone were identified in clinical studies or postmarketing reports. Because some of these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The most frequent reactions to metaxalone were: CNS : drowsiness, dizziness, headache, and nervousness or “irritability” Digestive : nausea, vomiting, gastrointestinal upset. Other adverse reactions were: Allergic : anaphylaxis have been reported with metaxalone. CNS : 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 and with the use of metaxalone as the only serotonergic drug taken at a dosage higher than the recommended dosage [see Warnings and Precautions (5.1) , Drug Interactions (7.2) , and Overdosage (10) ]. Hematologic : leucopenia; hemolytic anemia. Hepatobiliary : jaundice. Immune System : hypersensitivity reaction, rash with or without pruritus. The most common adverse reactions to Metaxalone Tablets, 640 mg include drowsiness, dizziness, headache, and nervousness or “irritability”, nausea, vomiting, gastrointestinal upset. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact INA Pharmaceutics, Inc. at 1-866-835-0469 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.