Amrix (Cyclobenzaprine HCl Extended-Release Capsules) Drug Information: Clinical Pharmacology

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May 24, 2012

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CLINICAL PHARMACOLOGY

Cyclobenzaprine relieves skeletal muscle spasm of local origin without interfering with muscle function. Cyclobenzaprine has not been shown to be effective in muscle spasm due to central nervous system disease. In animal models, cyclobenzaprine reduced or abolished skeletal muscle hyperactivity. Animal studies indicate that cyclobenzaprine does not act at the neuromuscular junction or directly on skeletal muscle. Such studies show that cyclobenzaprine acts primarily within the central nervous system at the brain stem as opposed to the spinal cord level, although an overlapping action on the latter may contribute to its overall skeletal muscle relaxant activity. Evidence suggests that the net effect of cyclobenzaprine is a reduction of tonic somatic motor activity, influencing both gamma (γ) and alpha (α) motor systems. Pharmacological studies in animals demonstrated a similarity between the effects of cyclobenzaprine and the structurally related tricyclic antidepressants, including reserpine antagonism, norepinephrine potentiation, potent peripheral and central anticholinergic effects, and sedation. Cyclobenzaprine caused slight to moderate increase in heart rate in animals.

Pharmacokinetics

Absorption

In a single-dose study comprised of healthy adult males (n=15), the dose adjusted ratios of the arithmetic means of AUC_0-168 and AUC_0-∞ indicated that exposure of the AMRIX (cyclobenzaprine hcl extended-release capsules) 30 mg was about 16% and 10% higher than that of AMRIX (cyclobenzaprine hcl extended-release capsules) 15 mg, respectively. The dose-adjusted ratios of the arithmetic means of Cmax indicated that the peak plasma concentration of AMRIX (cyclobenzaprine hcl extended-release capsules) 30 mg was about 20% higher than that of AMRIX (cyclobenzaprine hcl extended-release capsules) 15 mg. The half-lives and time to peak plasma cyclobenzaprine concentration were similar for both AMRIX (cyclobenzaprine hcl extended-release capsules) 15 mg and 30 mg. These data are summarized below.

Table1: Summary of pharmacokinetic Parameters in Healthy Adult Subjects

Parameter Mean±SD	AMRIX 15	AMRIX 30
Parameter Mean±SD	(N=15)	(N=14)
AUC_0-168 (ng•hr/mL)	318.3 ± 114.7	736.6 ± 259.4
AUC_0-∞(ng•hr/mL)	354.1 ± 119.8	779.9 ± 277.6
Cmax(ng/mL)	8.3 ± 2.2	19.9 ± 5.9
Tmax (hrs)	8.1 ± 2.9	7.1 ± 1.6
t_½ (hrs)	33.4 ± 10.3	32.0 ± 10.1
SD= Standarard deviation

A food effect study conducted in healthy adult subjects (n=15) utilizing a single dose of AMRIX (cyclobenzaprine hcl extended-release capsules) 30 mg demonstrated a statistically significant increase in bioavailability when AMRIX (cyclobenzaprine hcl extended-release capsules) 30 mg was given with food relative to the fasted state. There was a 35% increase in peak plasma cyclobenzaprine concentration (Cmax) and a 20% increase in exposure (AUC_0-168 and AUC_0-∞) in the presence of food. No effect, however, was noted in T_lag, Tmax, or the shape of the mean plasma cyclobenzaprine concentration versus time profile. Cyclobenzaprine in plasma was first detectable in both the fed and fasted states at 1.5 hours.

In a multiple-dose study utilizing AMRIX (cyclobenzaprine hcl extended-release capsules) 30 mg administered once daily for 7 days in a group of healthy adult volunteers (n=35) a 2.5-fold accumulation of plasma cyclobenzaprine levels was noted at steady-state.

Metabolism and Elimination

Cyclobenzaprine is extensively metabolized and is excreted primarily as glucuronides via the kidney. Cytochromes P-450 3A4, 1A2, and, to a lesser extent, 2D6, mediate N-demethylation, one of the oxidative pathways for cyclobenzaprine. Cyclobenzaprine has an elimination half-life of 32 hours (range 8-37 hours; n=18); plasma clearance is 0.7 L/min following single dose administration of AMRIX (cyclobenzaprine hcl extended-release capsules) .

Special Populations

Elderly

Although there were no notable differences in Cmax or Tmax, cyclobenzaprine plasma AUC is increased by 40% and the plasma half-life of cyclobenzaprine is prolonged in elderly subjects greater than 65 years of age (50 hours) after dosing with AMRIX (cyclobenzaprine hcl extended-release capsules) compared to younger subjects (32 hours). Pharmacokinetic characteristics of cyclobenzaprine following multiple-dose administration of AMRIX (cyclobenzaprine hcl extended-release capsules) in the elderly were not evaluated.

Table2: Summary of pharmacokinetic Parameters of AMRIX (cyclobenzaprine hcl extended-release capsules) 30 mg Extended-Release Capsules, By Age Group

Parameter Mean±SD	AMRIX 30 QD	AMRIX 30 QD
Parameter Mean±SD	18 to 45 Years (N=18)	65 to 75 Years (N=17)
AUC_0-168 (ng•hr/mL)	715.1 ± 264.2	945.9 ± 255.2
AUC_0-∞(ng•hr/mL)	751.2 ± 271.5	779.9 ± 277.6
Cmax(ng/mL)*	19.2 ± 5.6	19.2 ± 5.1
Tmax (hrs)*	6.8 ± 1.9	8.5 ± 2.3
t_½ (hrs)	32.4 ± 8.1	49.0 ± 8.3
* measured over the entire 24 hour period SD= Standarard deviation

Hepatic Impairment

In a pharmacokinetic study of immediate-release cyclobenzaprine in sixteen subjects with hepatic impairment (15 mild, 1 moderate per Child-Pugh score), both AUC and Cmax were approximately double the values seen in the healthy control group. The pharmacokinetics of cyclobenzaprine in subjects with severe hepatic impairment is not known.

Clinical Studies

Efficacy was assessed in two double-blind, parallel-group, placebocontrolled studies of identical design of AMRIX (Cyclobenzaprine Hydrochloride Extended-Release Capsules) 15 mg and 30 mg taken once daily in patients with muscle spasms associated with acute painful musculoskeletal conditions.

There were significant differences in the primary efficacy analysis, the patient's rating of medication helpfulness, between the AMRIX (cyclobenzaprine hcl extended-release capsules) 15 mg group and the placebo group at Days 4 and 14 in one study and between the AMRIX (cyclobenzaprine hcl extended-release capsules) 30 mg group and the placebo group at Day 4 in the second study.

Table 3: Subject's Rating of Medication Helpfulness - Study 1105

	Day 4		Day 14
	Number of Subjects (%)		Number of Subjects (%)
	Placebo (N=64)	AMRIX 30 mg (N=64)	Placebo (N=64)	AMRIX 30 mg (N=64)
Excellent	1 (1.6%)	3 (4.7%)	12 (18.8%)	15 (23.4%)
Very Good	5 (7.8%)	13 (20.3%)	9 (14.1%)	19 (29.7%)
Good	15 (23.4%)	22 (34.4%)	10 (15.6%)	15 (23.4%)
Fair	24 (37.5%)	20 (31.3%)	16 (25.0%)	10 (15.6%)
Poor	10 (15.6%)	5 (7.8%)	9 (14.1%)	4 (6.3%)
Missing	9 (14.1%)	1 (1.6%)	8 (12.5%)	1 (1.6%)

Table 4: Subject's Rating of Medication Helpfulness - Study 1108

	Day 4		Day 14
	Number of Subjects (%)		Number of Subjects (%)
	Placebo (N=64)	AMRIX 15 mg (N=63)	Placebo (N=64)	AMRIX 15 mg (N=63)
Excellent	1 (1.6%)	2 (3.2%)	10 (15.6%)	13 (20.6%)
Very Good	10 (15.6%)	12 (19.0%)	12 (18.8%)	21 (33.3%)
Good	14 (21.9%)	21 (33.3%)	13 (20.3%)	9(14.3%)
Fair	16 (25.0%)	17 (27.0%)	14 (21.9%)	10 (15.9%)
Poor	19 (29.7%)	6 (9.5%)	12 (18.8%)	5 (7.9%)
Missing	4 (6.3%)	5 (17.9%)	3(4.7%)	5 (7.9%)

In addition, one of the two studies demonstrated significant differences between the AMRIX (cyclobenzaprine hcl extended-release capsules) 30 mg group and the placebo group in terms of patient-rated relief from local pain due to muscle spasm at Day 4 and Day 8, in subject-rated restriction of movement at Day 4 and Day 8, and in patient-rated global impression of change at Day 4, Day 8, and Day 14.

There were no significant treatment differences between the AMRIX (cyclobenzaprine hcl extended-release capsules) treatment groups and the placebo group in physician's global assessment, in subject-rated restriction in activities of daily living, or quality of night-time sleep.

Last reviewed on RxList: 6/3/2008
This monograph has been modified to include the generic and brand name in many instances.