Metaxalone’s mechanism of action has not been fully characterized, but may be related to its sedative properties. Metaxalone has no direct action on the contractile mechanism of striated muscle, the motor end plate, or the nerve fiber.
The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of metaxalone not been fully characterized.
Metaxalone pharmacokinetics were evaluated in two groups of healthy volunteers that received a single oral dose of 800 mg of SKELAXIN or 400 mg of SKELAXIN (0.5 times the approved recommended dose) [the 400 mg strength of SKELAXIN is not currently marketed by King Pharmaceuticals]. Metaxalone pharmacokinetic parameters are presented below as mean (% CV) unless otherwise specified. Observed metaxalone peak plasma concentrations (Cmax) and area under the curve (AUC) are shown in Table 1. Doubling the dose of SKELAXIN from 400 mg (0.5 times the approved recommended dose) to 800 mg resulted in a proportional increase in metaxalone Cmax and AUC.
Dose | C max* | AUC ∞ * |
400 mg† | 983 (53) ng/mL | 7,479 (51) ng h/mL |
800 mg | 1,816 (43) ng/mL | 15,044 (46) ng h/mL |
Absorption
The absolute bioavailability of metaxalone is not known. Peak plasma metaxalone concentrations occurred at a mean Tmax of 3.3 hours (1.5 – 5 hours) of SKELAXIN under fasted conditions.
The single-dose pharmacokinetic parameters of metaxalone in two groups of healthy volunteers who received 400 mg or 800 mg of SKELAXIN are shown in Table 1.
Effect of Food: Peak plasma metaxalone concentrations were noted at a mean Tmax of 4.3 hours (1.5-12 hours) under fed conditions. The mean Tmax under fasting and fed conditions was 3.3 and 4.3 hours, respectively. Metaxalone exposure was increased and the half-life (t1/2) was decreased following SKELAXIN administration with a high fat meal as shown in Table 2. 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.
| |||||
Dose (mg) | C max (ng/mL) | AUC 0-t (ng h/mL) | AUC 0-INF (ng h/mL) | T max (hrs) | t 1/2 (hrs) |
400 mg* | ↑ 78% | ↑ 24% | ↑ 15% | ↑ 30% | ↓ 73% |
800 mg | ↑ 94% | ↑ 46% | ↑ 42% | ↑ 63% | ↓ 48% |
Distribution
Metaxalone apparent volume of distribution is approximately 800 Liters; however, plasma protein binding is unknown.
Elimination
Metaxalone mean ± SD terminal t1/2 is 9 ± 4.8 hours and apparent clearance is approximately 67 ± 34 L/h under fasted conditions.
Metabolism: Metaxalone is primarily metabolized by CYP1A2, CYP2D6, CYP2E1, and CYP3A4 and, to a lesser extent, CYP2C8, CYP2C9, and CYP2C19.
Excretion: Metaxalone is metabolized by the liver and excreted in the urine as unidentified metabolites.
Specific Populations
The effect of renal impairment and hepatic impairment on metaxalone pharmacokinetics is unknown [see Use in Specific Populations (8.6, 8.7)].
Geriatric Patients: The effects of age on the pharmacokinetics of metaxalone were determined following administration of 800 mg of SKELAXIN under fasted and fed conditions. Age had a significantly greater effect on metaxalone pharmacokinetics under fasted conditions than under fed conditions. Bioavailability under fasted conditions increased with age. Metaxalone bioavailability under fasted and fed conditions in the three groups of healthy volunteers of varying age is shown in Table 3.
| ||||||
Mean Age in Years (± SD) | 26 ± 9 Years Old | 39 ± 11 Years Old | 72 ± 5 Years Old | |||
Fasted vs. Fed State | Fasted | Fed | Fasted | Fed | Fasted | Fed |
C max (ng/mL)* | 1816 (43) | 3510 (41) | 2719 (46) | 2915 (55) | 3168 (43) | 3680 (59) |
T max (hours)* | 3 (39) | 4.9 (4.8) | 3 (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) |
Male and Female Patients: The exposure 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) following administration of 800 mg of SKELAXIN under fasted conditions. 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.
Drug Interaction Studies
In Vitro Studies: Metaxalone does not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4. Metaxalone does not induce CYP1A2, CYP2B6, and CYP3A4.
Metaxalone’s mechanism of action has not been fully characterized, but may be related to its sedative properties. Metaxalone has no direct action on the contractile mechanism of striated muscle, the motor end plate, or the nerve fiber.
The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of metaxalone not been fully characterized.
Metaxalone pharmacokinetics were evaluated in two groups of healthy volunteers that received a single oral dose of 800 mg of SKELAXIN or 400 mg of SKELAXIN (0.5 times the approved recommended dose) [the 400 mg strength of SKELAXIN is not currently marketed by King Pharmaceuticals]. Metaxalone pharmacokinetic parameters are presented below as mean (% CV) unless otherwise specified. Observed metaxalone peak plasma concentrations (Cmax) and area under the curve (AUC) are shown in Table 1. Doubling the dose of SKELAXIN from 400 mg (0.5 times the approved recommended dose) to 800 mg resulted in a proportional increase in metaxalone Cmax and AUC.
Dose | C max* | AUC ∞ * |
400 mg† | 983 (53) ng/mL | 7,479 (51) ng h/mL |
800 mg | 1,816 (43) ng/mL | 15,044 (46) ng h/mL |
Absorption
The absolute bioavailability of metaxalone is not known. Peak plasma metaxalone concentrations occurred at a mean Tmax of 3.3 hours (1.5 – 5 hours) of SKELAXIN under fasted conditions.
The single-dose pharmacokinetic parameters of metaxalone in two groups of healthy volunteers who received 400 mg or 800 mg of SKELAXIN are shown in Table 1.
Effect of Food: Peak plasma metaxalone concentrations were noted at a mean Tmax of 4.3 hours (1.5-12 hours) under fed conditions. The mean Tmax under fasting and fed conditions was 3.3 and 4.3 hours, respectively. Metaxalone exposure was increased and the half-life (t1/2) was decreased following SKELAXIN administration with a high fat meal as shown in Table 2. 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.
| |||||
Dose (mg) | C max (ng/mL) | AUC 0-t (ng h/mL) | AUC 0-INF (ng h/mL) | T max (hrs) | t 1/2 (hrs) |
400 mg* | ↑ 78% | ↑ 24% | ↑ 15% | ↑ 30% | ↓ 73% |
800 mg | ↑ 94% | ↑ 46% | ↑ 42% | ↑ 63% | ↓ 48% |
Distribution
Metaxalone apparent volume of distribution is approximately 800 Liters; however, plasma protein binding is unknown.
Elimination
Metaxalone mean ± SD terminal t1/2 is 9 ± 4.8 hours and apparent clearance is approximately 67 ± 34 L/h under fasted conditions.
Metabolism: Metaxalone is primarily metabolized by CYP1A2, CYP2D6, CYP2E1, and CYP3A4 and, to a lesser extent, CYP2C8, CYP2C9, and CYP2C19.
Excretion: Metaxalone is metabolized by the liver and excreted in the urine as unidentified metabolites.
Specific Populations
The effect of renal impairment and hepatic impairment on metaxalone pharmacokinetics is unknown [see Use in Specific Populations (8.6, 8.7)].
Geriatric Patients: The effects of age on the pharmacokinetics of metaxalone were determined following administration of 800 mg of SKELAXIN under fasted and fed conditions. Age had a significantly greater effect on metaxalone pharmacokinetics under fasted conditions than under fed conditions. Bioavailability under fasted conditions increased with age. Metaxalone bioavailability under fasted and fed conditions in the three groups of healthy volunteers of varying age is shown in Table 3.
| ||||||
Mean Age in Years (± SD) | 26 ± 9 Years Old | 39 ± 11 Years Old | 72 ± 5 Years Old | |||
Fasted vs. Fed State | Fasted | Fed | Fasted | Fed | Fasted | Fed |
C max (ng/mL)* | 1816 (43) | 3510 (41) | 2719 (46) | 2915 (55) | 3168 (43) | 3680 (59) |
T max (hours)* | 3 (39) | 4.9 (4.8) | 3 (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) |
Male and Female Patients: The exposure 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) following administration of 800 mg of SKELAXIN under fasted conditions. 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.
Drug Interaction Studies
In Vitro Studies: Metaxalone does not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4. Metaxalone does not induce CYP1A2, CYP2B6, and CYP3A4.
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