Metaxalone

Adverse Reactions The most frequent reactions to metaxalone include: CNS: drowsiness, dizziness, headache, and nervousness or “irritability”; Digestive: nausea, vomiting, gastrointestinal upset. Other adverse reactions are: Immune System: anaphylaxis, hypersensitivity reaction, rash with or without pruritus; Hematologic: leukopenia; hemolytic anemia; Hepatobiliary: jaundice; CNS: 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 and with metaxalone as a single agent taken at doses higher than the recommended dose (see WARNINGS, PRECAUTIONS: DRUG INTERACTIONS, and OVERDOSAGE).

Contraindications Known hypersensitivity to any components of this product. Known tendency to drug induced, hemolytic, or other anemias. Significantly impaired renal or hepatic function.

Description Metaxalone is available as an 800 mg pink, capsule shaped, scored tablet. Chemically, metaxalone 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: Metaxalone is a white to almost white, odorless crystalline powder freely soluble in chloroform, soluble in methanol and in 96% ethanol, but practically insoluble in ether or water. Each tablet contains 800 mg metaxalone and the following inactive ingredients: carboxymethylcellulose sodium, alginic acid, stearic acid, hydrogenated castor oil, magnesium stearate, colloidal silicon dioxide, sodium lauryl sulfate, and FD&C Red #40 Aluminum Lake. Structure

Dosage and Administration Section DOSAGE AND ADMINISTRATION The recommended dose for adults and children over 12 years of age is one 800 mg tablet three to four times a day.

Indications and Usage Section INDICATIONS AND USAGE Metaxalone is indicated as an adjunct to rest, physical therapy, and other measures for the relief of discomforts associated with acute, painful musculoskeletal conditions. The mode of action of this drug has not been clearly identified, but may be related to its sedative properties. Metaxalone does not directly relax tense skeletal muscles in man.

Overdosage Deaths by deliberate or accidental overdose have occurred with metaxalone, particularly in combination with antidepressants, and have been reported with this class of drug in combination with alcohol. Serotonin syndrome has been reported when metaxalone was used at doses higher than the recommended dose (see WARNINGS and ADVERSE REACTIONS). When determining the LD50 in rats and mice, progressive sedation, hypnosis, and finally respiratory failure were noted as the dosage increased. In dogs, no LD50 could be determined as the higher doses produced an emetic action in 15 to 30 minutes. Treatment - Gastric lavage and supportive therapy. Consultation with a regional poison control center is recommended.

Clinical Pharmacology Mechanism of Action The mechanism of action of metaxalone in humans has not been established, but may be due to general central nervous system (CNS) depression. Metaxalone has no direct action on the contractile mechanism of striated muscle, the motor end plate, or the nerve fiber. Pharmacokinetics The pharmacokinetics of metaxalone have been evaluated in healthy adult volunteers after single dose administration of metaxalone under fasted and fed conditions at doses ranging from 400 mg to 800 mg. Absorption Peak plasma concentrations of metaxalone occur approximately 3 hours after a 400 mg oral dose under fasted conditions. Thereafter, metaxalone concentrations decline log-linearly with a terminal half-life of 9.0 ± 4.8 hours. Doubling the dose of metaxalone from 400 mg to 800 mg results in a roughly proportional increase in metaxalone exposure as indicated by peak plasma concentrations (Cmax) and area under the curve (AUC). Dose proportionality at doses above 800 mg has not been studied. The absolute bioavailability of metaxalone is not known. The single-dose pharmacokinetic parameters of metaxalone in two groups of healthy volunteers are shown in Table 1. Table 1: Mean (%CV) Metaxalone Pharmacokinetic Parameters Dose (mg) Cmax (ng/mL) Tmax (h) AUC∞ (ng•h/mL) t½ (h) CL/F (L/h) 4001 983 (53) 3.3 (35) 7479 (51) 9.0 (53) 68 (50) 8002 1816 (43) 3.0 (39) 15044 (46) 8.0 (58) 66 (51) 1 Subjects received 1×400 mg tablet under fasted conditions (N=42) 2 Subjects received 2×400 mg tablets under fasted conditions (N=59) Food Effects A randomized, two-way, crossover study was conducted in 42 healthy volunteers (31 males, 11 females) administered one 400 mg metaxalone tablet under fasted conditions and following a standard high-fat breakfast. Subjects ranged in age from 18 to 48 years (mean age = 23.5 ± 5.7 years). Compared to fasted conditions, the presence of a high fat meal at the time of drug administration increased Cmax by 177.5% and increased AUC (AUC0-t, AUC∞) by 123.5% and 115.4%, respectively. Time-to-peak concentration (Tmax) was also delayed (4.3 h versus 3.3 h) and terminal half-life was decreased (2.4 h versus 9.0 h) under fed conditions compared to fasted. In a second food effect study of similar design, two 400 mg metaxalone tablets (800 mg) were administered to healthy volunteers (N=59, 37 males, 22 females), ranging in age from 18-50 years (mean age = 25.6 ± 8.7 years). Compared to fasted conditions, the presence of a high fat meal at the time of drug administration increased Cmax by 193.6% and increased AUC (AUC0-t, AUC∞) by 146.4% and 142.2%, respectively. Time-to-peak concentration (Tmax) was also delayed (4.9 h versus 3.0 h) and terminal half-life was decreased (4.2 h versus 8.0 h) under fed conditions compared to fasted conditions. Similar food effect results were observed in the above study when one metaxalone 800 mg tablet was administered in place of two metaxalone 400 mg tablets. The increase in metaxalone exposure coinciding with a reduction in half-life may be attributed to more complete absorption of metaxalonein the presence of a high fat meal (Figure 1) .​ Distribution, Metabolism, and Excretion 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. Metaxalone is metabolized by the liver and excreted in the urine as unidentified metabolites. 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. Pharmacokinetics in Special Populations Age: The effects of age on the pharmacokinetics of metaxalone were determined following single administration of two 400 mg tablets (800 mg) under fasted and fed conditions. The results were analyzed separately, as well as in combination with the results from three other studies. Using the combined data, the results indicate that the pharmacokinetics of metaxalone are significantly more affected by age under fasted conditions than under fed conditions, with bioavailability under fasted conditions increasing with age. The bioavailability of metaxalone under fasted and fed conditions in three groups of healthy volunteers of varying age is shown in Table 2. Table 2: Mean (%CV) Pharmacokinetic Parameters Following Single Administration of Two 400 mg Metaxalone Tablets (800 mg) under Fasted and Fed Conditions Younger Volunteers Older Volunteers Age (years) 25.6 ± 8.7 39.3 ± 10.8 71.5 ± 5.0 N 59 21 23 Food Fasted Fed Fasted Fed Fasted Fed Cmax (ng/mL) 1816 (43) 3510 (41) 2719 (46) 2915 (55) 3168 (43) 3680 (59) Tmax (h) 3.0 (39) 4.9 (48) 3.0 (40) 8.7 (91) 2.6 (30) 6.5 (67) AUC0-t (ng•h/mL) 14531 (47) 20683 (41) 19836 (40) 20482 (37) 23797 (45) 24340 (48) AUC∞ (ng•h/mL) 15045 (46) 20833 (41) 20490 (39) 20815 (37) 24194 (44) 24704 (47) Gender: The effect of gender on the pharmacokinetics of metaxalone was assessed in an open label study, in which 48 healthy adult volunteers (24 males, 24 females) were administered two metaxalone 400 mg tablets (800 mg) under fasted conditions. The bioavailability of metaxalone was significantly higher in females compared to males as evidenced by Cmax (2115 ng/mL versus 1335 ng/mL) and AUC∞ (17884 ng•h/mL versus 10328 ng•h/mL). 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, but not significantly different when adjusted for body weight. Similar findings were also seen when the previously described combined dataset was used in the analysis. Hepatic/Renal Insufficiency: The impact of hepatic and renal disease on the pharmacokinetics of metaxalone has not been determined. In the absence of such information, metaxalone should be used with caution in patients with hepatic and/or renal impairment. FIG 1

20230208

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Metaxalone Metaxalone METAXALONE METAXALONE LCI;1435

ANDA204770

Metaxalone

Metaxalone

80425-0122

HUMAN PRESCRIPTION DRUG

ORAL

Principal Display Panel label 1 label 2 label 3

How Supplied/Storage and Handling Metaxalone Tablets, USP are available as 800 mg pink, capsule shaped, scored tablets, debossed “LCI” on one side and “14” bisect “35” on the other side. Available in: Bottles of 30 Tablets NDC: 80425-0122-01 Bottles of 60 Tablets NDC: 80425-0122-02 Bottles of 90 Tablets NDC: 80425-0122-03 Store at 20º C to 25º C (68º to 77ºF) [See USP Controlled Room Temperature]. Distributed by: Lannett Company, Inc. Philadelphia, PA 19136 CIB71144E Rev. 12/19