CYCLOBENZAPRINE HYDROCHLORIDE- cyclobenzaprine hydrochloride capsule, extended release
Global Pharmaceuticals, Division of Impax Laboratories Inc.
Cyclobenzaprine hydrochloride extended-release capsules is a skeletal muscle relaxant which relieves muscle spasm of local origin without interfering with muscle function. The active ingredient in cyclobenzaprine hydrochloride extended-release capsules is cyclobenzaprine hydrochloride, USP. Cyclobenzaprine hydrochloride (HCl) is a white, crystalline tricyclic amine salt with the empirical formula C20 H21 N•HCl and a molecular weight of 311.9. It has a melting point of 217°C, and a pKa of 8.47 at 25°C. It is freely soluble in water and alcohol, sparingly soluble in isopropanol, and insoluble in hydrocarbon solvents. If aqueous solutions are made alkaline, the free base separates. Cyclobenzaprine HCl is designated chemically as 3-(5H -dibenzo[a,d ] cyclohepten-5-ylidene)-N,N -dimethyl-1-propanamine hydrochloride, and has the following structural formula:
Cyclobenzaprine hydrochloride extended-release capsules for oral administration are supplied in 15 and 30 mg strengths. Cyclobenzaprine hydrochloride extended-release capsules contain the following inactive ingredients: diethyl phthalate NF, ethylcellulose NF (Ethocel Standard 10 Premium), gelatin, Opadry® Clear YS-1-7006, sugar spheres NF (20-25 mesh), and titanium dioxide. Cyclobenzaprine hydrochloride extended-release capsules 15 mg also contain D&C yellow #10, FD&C green #3, and FD&C red #40. Cyclobenzaprine hydrochloride extended-release capsules 30 mg also contain FD&C blue #1, FD&C blue #2, FD&C red #40, and FD&C yellow #6.
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.
In a single-dose study comprised of healthy adult males (n=15), the dose adjusted ratios of the arithmetic means of AUC0-168 and AUC0-∞ indicated that exposure of the cyclobenzaprine hydrochloride extended-release capsules 30 mg was about 16% and 10% higher than that of cyclobenzaprine hydrochloride extended-release capsules 15 mg, respectively. The dose-adjusted ratios of the arithmetic means of Cmax indicated that the peak plasma concentration of cyclobenzaprine hydrochloride extended-release capsules 30 mg was about 20% higher than that of cyclobenzaprine hydrochloride extended-release capsules 15 mg. The half-lives and time to peak plasma cyclobenzaprine concentration were similar for both cyclobenzaprine hydrochloride extended-release capsules 15 mg and 30 mg. These data are summarized below.
|Parameter||Cyclobenzaprine hydrochloride extended-release capsules15 mg||Cyclobenzaprine hydrochloride extended-release capsules30 mg|
|Mean ± SD||(N=15)||(N=14)|
|SD = standard deviation|
|AUC0-168 (ng∙hr/mL)||318.3 ± 114.7||736.6 ± 259.4|
|AUC0-∞ (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|
|t1/2 (hrs)||33.4 ± 10.3||32.0 ± 10.1|
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 (Cmax ) and a 20% increase in exposure (AUC0-168 and AUC0-∞ ) in the presence of food. No effect, however, was noted in Tlag , 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 cyclobenzaprine hydrochloride 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.
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 cyclobenzaprine hydrochloride extended-release capsules.
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 cyclobenzaprine hydrochloride extended-release capsules compared to younger subjects (32 hours). Pharmacokinetic characteristics of cyclobenzaprine following multiple-dose administration of cyclobenzaprine hydrochloride extended-release capsules in the elderly were not evaluated.
|Parameter||18 to 45 years Cyclobenzaprine hydrochloride extended-release capsules30 mg||65 to 75 years Cyclobenzaprine hydrochloride extended-release capsules30 mg|
|Mean + SD||(N=18)||(N=17)|
|SD = standard deviation|
|AUC0-168 (ng⋅hr/mL)||715.1 ± 264.2||945.9 ± 255.2|
|AUC0-∞ (ng⋅hr/mL)||751.2 ± 271.5||1055.2 ± 301.9|
|Cmax (ng/mL)*||19.2 ± 5.6||19.2 ± 5.1|
|Tmax (hrs)*||6.8 ± 1.9||8.5 ± 2.3|
|t1/2 (hrs)||32.4 ± 8.1||49.0 ± 8.3|
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