Fexmid 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.
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. (See PRECAUTIONS, Use In The Elderly and PRECAUTIONS, Impaired
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 to 255.3) higher than those seen
in a group of eighteen younger adults (101.4 ng.hr/mL, range 36.1 to 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 to 255.3 versus 83.2 ng.hr/mL, range 41.1 to 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 to
196.3 versus 115.9 ng.hr/mL, range 36.1 to 182.9 for younger females).
In light of these findings, therapy with cyclobenzaprine HCl in the elderly should be initiated with a 5
mg dose and titrated slowly upward.
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 HCl 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 Fexmid in subjects with moderate to severe
impairment is not recommended.
No significant effect on plasma levels or bioavailability of cyclobenzaprine HCl or aspirin was noted
when single or multiple doses of the two drugs were administered concomitantly. Concomitant
administration of cyclobenzaprine HCl and naproxen or diflunisal was well tolerated with no reported
unexpected adverse effects. However combination therapy of cyclobenzaprine HCl 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 HCl
enhances the clinical effect of aspirin or other analgesics, or whether analgesics enhance the clinical
effect of cyclobenzaprine HCl in acute musculoskeletal conditions.
Eight double-blind controlled clinical studies were performed in 642 patients comparing
cyclobenzaprine HCl 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 HCl 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 HCl were comparable to those observed in patients treated with diazepam, dry mouth
was observed more frequently in patients treated with cyclobenzaprine HCl 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 HCl 5 mg was demonstrated in two seven-day, double-blind,
controlled clinical trials enrolling 1405 patients. One study compared cyclobenzaprine HCl 5 and 10 mg
t.i.d. to placebo; and a second study compared cyclobenzaprine HCl 5 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
Comparisons of cyclobenzaprine HCl 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 HCl
10 mg (all endpoints). Physician-assessed secondary endpoints also showed that cyclobenzaprine HCl 5
mg was associated with a greater reduction in palpable muscle spasm than placebo.
Analysis of the data from controlled studies shows that cyclobenzaprine HCl produces clinical
improvement whether or not sedation occurs.
A postmarketing surveillance program was carried out in 7607 patients with acute musculoskeletal
disorders, and included 297 patients treated with cyclobenzaprine HCl 10 mg for 30 days or longer.
The overall effectiveness of cyclobenzaprine HCl was similar to that observed in the double-blind
controlled studies; the overall incidence of adverse effects was less (see ADVERSE REACTIONS).