Cyclobenzaprine Hcl 15 mg (ER) · Hard-gelatin capsules

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.

Absorption — Following single-dose administration of cyclobenzaprine hydrochloride extended-release capsules, 15 mg and 30 mg in healthy adult subjects (n=15) ,C max,AUC 0-168hand AUC 0-∞increased in an approximately dose-proportional manner from 15 mg to 30 mg. The time to peak plasma cyclobenzaprine concentration (T max) was 7 to 8 hours for both doses of cyclobenzaprine hydrochloride extended-release capsules.

A food effect study conducted in healthy adult subjects (n=15) utilizing a single dose of cyclobenzaprine hydrochloride extended-release capsules, 30 mg demonstrated a statistically significant increase in bioavailability when cyclobenzaprine hydrochloride extended-release capsules, 30 mg was given with food relative to the fasted state. There was a 35% increase in peak plasma cyclobenzaprine concentration (C max) and a 20% increase in exposure (AUC 0-168hand AUC 0-∞) in the presence of food. No effect, however, was noted in T maxor 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.

When the contents of cyclobenzaprine hydrochloride extended-release capsules were administered by sprinkling on applesauce, it was found to be bioequivalent to the same dose when administered as an intact capsule.

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

Metabolism and Excretion — 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 to 37 hours; n=18); plasma clearance is 0.7 L/min following single-dose administration of cyclobenzaprine hydrochloride extended-release capsules.

Elderly — Although there were no notable differences in C maxor T max, 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 cyclobenzaprine hydrochloride extended-release capsules compared to younger subjects 18 to 45 years of age (32 hours). Pharmacokinetic characteristics of cyclobenzaprine following multiple-dose administration of cyclobenzaprine hydrochloride extended-release capsules in the elderly were not evaluated.

Hepatic Impairment — In a pharmacokinetic study of immediate-release cyclobenzaprine in 16 subjects with hepatic impairment (15 mild, 1 moderate per Child-Pugh score), both AUC and C maxwere approximately double the values seen in the healthy control group. The pharmacokinetics of cyclobenzaprine in subjects with severe hepatic impairment is not known.