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Metaxalone tablets are available as an 800 mg oval, convex pink tablet.
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 tablets 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.
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
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.
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.
The impact of hepatic and renal disease on the pharmacokinetics of metaxalone has not been determined. In the absence of such information, metasxalone tablets should be used with caution in patients with hepatic and/or renal impairment.
INDICATIONS AND USAGE
Known hypersensitivity to any components of this product.
Information for Patients
Metaxalone 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 or other CNS depressants.
The sedative effects of metaxalone tablets an dother CNS depressants (e.g., alcohol benzodiazepines, opiods, trycyclic antidepressants) may be additive. Therefore, caution should be exercised with patients who take more than one of these CNS depressants simultaneoulsy.
Carcinogenesis, Mutagenesis, Impairment of Fertility
The carcinogenic potential of metaxalone has not been determined.
Reproduction studies in rats have not revealed evidence of impaired fertility or harm to the fetus due to metaxalone. Post marketing experience has not revealed evidence of fetal injury, but such experience cannot exclude the possibility of infrequent or subtle damage to the human fetus. Safe use of metaxalone has not been established with regard to possible adverse effects upon fetal development. Therefore, metaxalone tablets should not be used in women who are or may become pregnant and particularly during early pregnancy unless in the judgement of the physician, the potential benefits outweigh the possible hazards.
It is not known whether this drug is secreted in human milk. As a general rule, nursing should not be undertaken while a patient is on a drug since many drugs are excreted in human milk.
The most frequent reactions to metaxalone include:
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.
DOSAGE AND ADMINISTRATION
Metaxalone tablets are available as an 800 mg oval, convex, pink tablet with one side debossed "M" and other side debossed "58/59".
MF# 704-01 April 2010
St. Mary's MPP
MANAGED PHARMACY PROGRAMS
TAKE .. TAB .. TIMES A DAY OR EVERY .. HOURS MAY CAUSE DROWSINESS
Rx only STORE AT CONTROLLED ROOM TEMPERATURE 15-30 degree CENTIGRADE (59-86 degree FAHRENHEIT)
Revised: 01/2011 St. Marys Medical Park Pharmacy
Reproduced with permission of U.S. National Library of Medicine
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