Geriatric Use

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

Central Nervous System (CNS) Depression

PATIENT COUNSELING INFORMATION

Driving or Operating Heavy Machinery

Advise patients that FLEXURA Tablets 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 and other CNS depressants. Elderly patients may be especially susceptible to CNS effects.

Serotonin Syndrome

Inform patients that FLEXURA Tablets could cause a rare but potentially life-threatening condition resulting from administration of doses higher than the recommended dose or from concomitant administration of serotonergic drugs with FLEXURA Tablets used within the recommended dosage range. Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop. Instruct patients to inform their healthcare providers if they are taking, or plan to take, serotonergic medications.

INDICATIONS AND USAGE

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

DOSAGE AND ADMINISTRATION

The recommended dose for adults and pediatric patients 13 years of age and older is one 640 mg tablet three to four times a day.

DOSAGE FORMS AND STRENGTHS

FLEXURA Tablet is available as a 640 mg oval, peach-colored tablet, debossed on one side with M640 and plain on the other side.

CONTRAINDICATIONS

The use of FLEXURA Tablets is contraindicated in the following conditions:

·         Known hypersensitivity to any components of this product.

·         Known tendency to drug-induced, hemolytic, or other anemias.

·         Patients with severely impaired renal or hepatic function.

WARNINGS AND PRECAUTIONS

Serotonin Syndrome

Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of serotonergic drugs with FLEXURA used within the recommended dosage range [See Drug Interactions (7)] and with FLEXURA 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 FLEXURA Tablets if serotonin syndrome is suspected.

Hepatic and Renal Impairment Patients

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

ADVERSE REACTIONS

The most frequent reactions to FLEXURA Tablets include:

CNS: drowsiness, dizziness, headache, and nervousness or “irritability”, Digestive: nausea, vomiting, gastrointestinal upset.

Other adverse reactions are:

Immune System: hypersensitivity reaction, rash with or without pruritus, Hematologic: leucopenia; hemolytic anemia,

Hepatobiliary: jaundice.

CNS: cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of serotonergic drugs with FLEXURA used within the recommended dosage range and with FLEXURA as a single agent taken at doses higher than the recommended dose [See Warnings and Precautions (5.1), Drug Interactions (7), and Overdosage (10)].

Anaphylactoid reactions have been reported with FLEXURA.

DRUG INTERACTIONS

CNS Depressants

The sedative effects of FLEXURA Tablets and other CNS depressants (e.g., alcohol, benzodiazepines, opioids, tricyclic antidepressants) may be additive. Therefore, caution should be exercised with patients who take more than one of these CNS depressants simultaneously.

Serotonergic Drugs

Serotonin syndrome has resulted from concomitant use of serotonergic drugs with FLEXURA used within the recommended dosage range [See Warnings and Precautions (5.3)]. If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue FLEXURA Tablets if serotonin syndrome is suspected.

Examples of 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

USE IN SPECIFIC POPULATIONS

Pregnancy

Risk Summary

There are no available data on FLEXURA 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 FLEXURA use. Reproduction studies in rats have not revealed evidence of impaired fertility or harm to fetus due to FLEXURA.

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.

Lactation

Risk Summary
There are no data on the presence of FLEXURA 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 FLEXURA and any potential adverse effects on the breastfed infant from FLEXURA or from the underlying maternal condition.

Pediatric Use

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

Hepatic Impairment

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

Renal Impairment

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

OVERDOSAGE

Deaths by deliberate or accidental overdose have occurred with FLEXURA, particularly in combination with antidepressants, and have been reported with this class of drug in combination with alcohol.

 Serotonin syndrome has been reported when FLEXURA was used at doses higher than the recommended dose [See Warnings and Precautions (5.1) and Adverse Reactions (6)].

Treatment – Gastric lavage and supportive therapy. Consultation with a regional poison control center is recommended.

DESCRIPTION

FLEXURA Tablet is a muscle relaxant available as a 640 mg oval, peach-colored tablet, debossed on one side with M640 and plain on the other side. The tablets are for oral administration. Each tablet contains 640 mg FLEXURA and the following inactive ingredients: alginic acid, FD&C yellow #6, lactose monohydrate, magnesium stearate, propylene glycol alginate and povidone.

Chemically, FLEXURA is 5-[(3, 5- dimethylphenoxy) methyl]-2-oxazolidinone. The empirical formula is C12H15NO3, which corresponds to a molecular weight of 221.25. The structural formula is

CLINICAL PHARMACOLOGY

Mechanism of Action

The mechanism of action of FLEXURA in humans has not been established, but may be due to general central nervous system depression. FLEXURA has no direct action on the contractile mechanism of striated muscle, the motor end plate, or the nerve fiber.

pharmacokinetics

Although plasma protein binding and absolute bioavailability of FLEXURA are not known, the apparent volume of distribution (V/F ~ 800 L) and lipophilicity (log P = 2.42) of FLEXURA suggest that the drug is extensively distributed in the tissues.

Elimination

Metabolism

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

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

Excretion

FLEXURA is metabolized by the liver and excreted in the urine as unidentified metabolites. Specific Populations

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

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

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

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

Mutagenesis

Studies to evaluate the mutagenic potential of FLEXURA 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 FLEXURA

CLINICAL STUDIES

Efficacy studies were not conducted with FLEXURA Tablets. The efficacy of FLEXURA Tablets, 640 mg is based on demonstration of similar systemic exposures to the reference drug, Skelaxin® 800 mg tablets [see Clinical Pharmacology (12.3)].

HOW SUPPLIED/STORAGE AND HANDLING

Bottle of 100 tablets, NDC 68040-712-38

Store at 20°C to 25°C (68°F to 77°F), excursions permitted to 15°C-30°C (59°F-86°F). [see USP Controlled Room Temperature].