Cyclobenzaprine HCl relieves skeletal muscle spasm of local origin without interfering with muscle function. It is ineffective in muscle spasm due to central nervous system disease.
Cyclobenzaprine reduced or abolished skeletal muscle hyperactivity in several animal models. 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 brain stem as opposed to spinal cord levels, although its 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 showed 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.
Cyclobenzaprine Pharmacokinetics
Estimates of mean oral bioavailability of Cyclobenzaprine range from 33% to 55%. Cyclobenzaprine exhibits linear pharmacokinetics over the dose range 2.5 mg to 10 mg, and is subject to enterohepatic circulation. It is highly bound to plasma proteins. Drug accumulates when dosed three times a day, reaching steady-state within 3-4 days at plasma concentrations about four-fold higher than after a single dose. At steady state in healthy subjects receiving 10 mg t.i.d. (n=18), peak plasma concentration was 25.9 ng/mL (range, 12.8-46.1 ng/mL), and area under the concentration-time (AUC) curve over an 8-hour dosing interval was 177 ng.hr/mL (range, 80-319 ng.hr/mL).
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 is eliminated quite slowly, with an effective half-life of 18 hours (range 8-37 hours; n=18); plasma clearance is 0.7 L/min.
The plasma concentration of Cyclobenzaprine is generally higher in the elderly and in patients with hepatic impairment.
Cyclobenzaprine Elderly use
In a pharmacokinetic study in elderly individuals (≥65yrs old), mean (n=10) steady-state Cyclobenzaprine AUC values were approximately 1.7 fold (171.0 ng.hr/mL, range 96.1-255.3) higher than those seen in a group of eighteen younger adults (101.4 ng.hr/mL, range 36.1-182.9) from another study. Elderly male subjects had the highest observed mean increase, approximately 2.4 fold (198.3 ng.hr/mL, range 155.6-255.3 versus 83.2 ng.hr/mL, range 41.1-142.5 for younger males) while levels in elderly females were increased to a much lesser extent, approximately 1.2 fold (143.8 ng.hr/mL, range 96.1-196.3 versus 115.9 ng.hr/mL, range 36.1-182.9 for younger females).
In light of these findings, therapy with Cyclobenzaprine hydrochloride in the elderly should be initiated with a 5 mg dose and titrated slowly upward.
Cyclobenzaprine and Hepatic Impairment
In a pharmacokinetic study of 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. Based on the findings, Cyclobenzaprine hydrochloride should be used with caution in subjects with mild hepatic impairment starting with the 5 mg dose and titrating slowly upward. Due to the lack of data in subjects with more severe hepatic insufficiency, the use of Cyclobenzaprine hydrochloride in subjects with moderate to severe impairment is not recommended.
No significant effect on plasma levels or bioavailability of Cyclobenzaprine hydrochloride or aspirin was noted when single or multiple doses of the two drugs were administered concomitantly. Concomitant administration of Cyclobenzaprine hydrochloride and naproxen or diflunisal was well tolerated with no reported unexpected adverse effects. However combination therapy of Cyclobenzaprine hydrochloride with naproxen was associated with more side effects than therapy with naproxen alone, primarily in the form of drowsiness. No well controlled studies have been performed to indicate that Cyclobenzaprine hydrochloride enhances the clinical effect of aspirin or other analgesics, or whether analgesics enhance the clinical effect of Cyclobenzaprine hydrochloride in acute musculoskeletal conditions.
Cyclobenzaprine Clinical Studies
Eight double-blind controlled clinical studies were performed in 642 patients comparing Cyclobenzaprine hydrochloride 10 mg, diazepam**, and placebo. Muscle spasm, local pain and tenderness, limitation of motion, and restriction in activities of daily living were evaluated. In three of these studies there was a significantly greater improvement with Cyclobenzaprine hydrochloride than with diazepam, while in the other studies the improvement following both treatments was comparable.
Although the frequency and severity of adverse reactions observed in patients treated with Cyclobenzaprine hydrochloride were comparable to those observed in patients treated with diazepam, dry mouth was observed more frequently in patients treated with Cyclobenzaprine hydrochloride and dizziness more frequently in those treated with diazepam. The incidence of drowsiness, the most frequent adverse reaction, was similar with both drugs.
The efficacy of Cyclobenzaprine hydrochloride 5 mg was demonstrated in two seven-day, double-blind, controlled clinical trials enrolling 1405 patients. One study compared Cyclobenzaprine hydrochloride 5 mg and 10 mg t.i.d. to placebo; and a second study compared Cyclobenzaprine hydrochloride 5 mg and 2.5 mg t.i.d. to placebo. Primary endpoints for both trials were determined by patient-generated data and included global impression of change, medication helpfulness, and relief from starting backache. Each endpoint consisted of a score on a 5-point rating scale (from 0 or worst outcome to 4 or best outcome). Secondary endpoints included a physician’s evaluation of the presence and extent of palpable muscle spasm.
Comparisons of Cyclobenzaprine hydrochloride 5 mg and placebo groups in both trials established the statistically significant superiority of the 5 mg dose for all three primary endpoints at day 8 and, in the study comparing 5 and 10 mg, at day 3 or 4 as well. A similar effect was observed with Cyclobenzaprine hydrochloride 10 mg (all endpoints). Physician-assessed secondary endpoints also showed that Cyclobenzaprine hydrochloride 5 mg was associated with a greater reduction in palpable muscle spasm than placebo.
Analysis of the data from controlled studies shows that Cyclobenzaprine hydrochloride produces clinical improvement whether or not sedation occurs.
**VALIUM® (diazepam, Roche)
Cyclobenzaprine Surveillance Program
A post-marketing surveillance program was carried out in 7607 patients with acute musculoskeletal disorders, and included 297 patients treated with Cyclobenzaprine hydrochloride 10 mg for 30 days or longer. The overall effectiveness of Cyclobenzaprine hydrochloride was similar to that observed in the double-blind controlled studies; the overall incidence of adverse effects was less.
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