y 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).

in 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. risks from concomitant use with alcohol or other cns depressants the sedative effects of metaxalone tablets and other cns depressants (e.g., alcohol, benzodiazepines, opioids, tricyclic antidepressants (tcas)) may be additive. exercise caution with patients who take more than one of these cns depressants simultaneously. follow patients closely for signs and symptoms of respiratory depression and sedation (see precautions: drug interactions).

y 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).

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) c max (ng/ml) t max (h) auc ∞ (ng.h/ml) t 1/2 (h) cl/f (l/h) 400 * 983 (53) 3.3 (35) 7479 (51) 9.0 (53) 68 (50) 800 † 1816 (43) 3.0 (39) 15044 (46) 8.0 (58) 66 (51) * subjects received 1x400 mg tablet under fasted conditions (n=42) † subjects received 2x400 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 metaxalone in 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 c max (ng/ml) 1816 (43) 3510 (41) 2719 (46) 2915 (55) 3168 (43) 3680 (59) t max (h) 3.0 (39) 4.9 (48) 3.0 (40) 8.7 (91) 2.6 (30) 6.5 (67) auc 0-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 tablets should be used with caution in patients with hepatic and/or renal impairment. figure 1