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.
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. (See PRECAUTIONS, Use in the
Elderly and PRECAUTIONS, Impaired Hepatic Function.)
Elderly
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 FLEXERIL in the elderly should be
initiated with a 5 mg dose and titrated slowly upward.
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,
FLEXERIL 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 FLEXERIL
in subjects with moderate to severe impairment is not recommended.
No significant effect on plasma levels or bioavailability of FLEXERIL or aspirin
was noted when single or multiple doses of the two drugs were administered concomitantly.
Concomitant administration of FLEXERIL and naproxen or diflunisal was well tolerated
with no reported unexpected adverse effects. However combination therapy of
FLEXERIL 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 FLEXERIL enhances the clinical effect of
aspirin or other analgesics, or whether analgesics enhance the clinical effect
of FLEXERIL in acute musculoskeletal conditions.
Clinical Studies
Eight double-blind controlled clinical studies were performed in 642 patients
comparing FLEXERIL 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 FLEXERIL 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 FLEXERIL were comparable to those observed in patients treated
with diazepam, dry mouth was observed more frequently in patients treated with
FLEXERIL 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 FLEXERIL 5 mg was demonstrated in two seven-day, double-blind,
controlled clinical trials enrolling 1405 patients. One study compared FLEXERIL
5 and 10 mg t.i.d. to placebo; and a second study compared FLEXERIL 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 spasm.
Comparisons of FLEXERIL 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 FLEXERIL 10 mg (all endpoints). Physician-assessed
secondary endpoints also showed that FLEXERIL 5 mg was associated with a greater
reduction in palpable muscle spasm than placebo.
Analysis of the data from controlled studies shows that FLEXERIL produces clinical
improvement whether or not sedation occurs.
Surveillance Program
A post-marketing surveillance program was carried out in 7607 patients with
acute musculoskeletal disorders, and included 297 patients treated with FLEXERIL
10 mg for 30 days or longer. The overall effectiveness of FLEXERIL was similar
to that observed in the double-blind controlled studies; the overall incidence
of adverse effects was less (see ADVERSE REACTIONS).
**VALIUM® (diazepam, Roche)
Last updated on RxList: 4/5/2007
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