Source: Health Products and Food Branch (CA) Revision Year: 2020
Controlled clinical studies show that cyclobenzaprine hydrochloride improves the signs and symptoms of skeletal muscle spasm.
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.
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.
Cyclobenzaprine hydrochloride is well absorbed in man after oral administration, but there is a large intersubject variation in plasma levels. After oral or intravenous doses (10 mg) of 14C-labelled cyclobenzaprine hydrochloride to human subjects, plasma levels of radioactivity were comparable. In addition, the excretion of radioactivity was similar after both routes (38-51% in the urine; 14-15% in the feces), suggesting that oral absorption is almost complete. The half-life varies from one to three days. In 14 human subjects, the co-administration of cyclobenzaprine hydrochloride and multiple doses of acetylsalicylic acid had no effect on cyclobenzaprine plasma levels or bioavailability.
Cyclobenzaprine hydrochloride is extensively metabolized in man. In the study with 14C-labelled drug, about 1% of the dose was excreted in the urine as unchanged cyclobenzaprine hydrochloride. The metabolites (probably glucuronides) were excreted as water-soluble conjugates. After oral or intravenous administration of 40 mg of unlabelled cyclobenzaprine hydrochloride to two subjects, only 0.2 to 1.5% of the dose was excreted as unchanged drug in the urine within 24 hours.
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.
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 41.1142.5 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, cyclobenzaprine therapy in the elderly should be initiated with lower (e.g. less frequent) dosing 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 should be used with caution in subjects with mild hepatic impairment; reduced (e.g. less frequent) daily doses should be considered. Due to the lack of data in subjects with more severe hepatic insufficiency, the use of cyclobenzaprine in subjects with moderate to severe impairment is not recommended.
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 hydrochloride has skeletal muscle spasmolytic activity in a number of experimental situations, including tetanus toxin hyperactivity in rabbits, supraspinal rigidity and ischemic cord (spinal) rigidity in cats, and muscle spasm in mice.
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 (μ) and alpha (α) motor systems.
Studies in several species of laboratory test animals showed that cyclobenzaprine hydrochloride also possesses psychotropic activity (evidenced by tetrabenazine and reserpine antagonism in mice and rats, potentiation of norepinephrine pressor response in anesthetized dogs, typical ataraxic drug taming action in monkeys), significant anticholinergic and antihistaminic activity, weak adrenergic blocking and antiserotonin activity, and minor local anesthetic action. In dogs with Heidenhain gastric pouches, cyclobenzaprine did not stimulate gastric secretion.
Following either oral or intravenous doses of 14C-labelled drug, peak plasma levels of radioactivity appeared in half an hour in rats, in two hours in dogs, and in two to four hours in monkeys. Radioactivity was excreted mainly in the feces in rats (59% of the dose vs 13%t in the urine), mainly in the urine in dogs (55% vs 29% in the feces), and mostly in the urine in monkeys (75% vs 9% in the feces). Rats excreted 25% of an intravenous dose in the bile in six hours. Urinary radioactivity was present almost entirely as water-soluble conjugates, but some species differences were observed in preliminary extraction experiments. The excretion pattern was similar after oral and intravenous doses, suggesting that the drug is extensively absorbed. In rats, all tissues except red blood cells contained higher levels of radioactivity than did plasma two hours after an intravenous dose of labelled drug. Levels were particularly high in small intestine, lung, kidney, and liver. After 48 hours all levels had declined, but activity persisted in liver, kidney and red blood cells.
Oral LD50 values were approximately 338 mg/kg in mice and 425 mg/kg in rats (27 and 69 times the MRHD on mg/m² basis respectively). Signs of drug effects were similar in both species and included ataxia, decreased respiratory rate, sedation, flaccid hind legs, loss of the ear flick reflex, loss of righting reflex with swimming movements, and intermittent clonic convulsions. Death occurred 30 minutes to seven days following administration and was preceded by weight loss and lethargy. Dogs given single oral doses of 180 mg/kg (97 times the MRHD on mg/m² basis) or more by gavage developed ptyalism, emesis, tremors, convulsions, and increased respiratory rate, and died within an hour. When the same dose was given in a capsule, dogs developed similar physical signs, followed by sedation, but recovered after three days, suggesting that the oral dosage form may influence the toxicity. The drug was more toxic to infant and weanling rats than to young adults.
Signs of drug effect in subacute and chronic toxicity studies in rats, dogs, and monkeys were primarily related to the pharmacologic activity of the compound.
In a 67-week study with rats that received cyclobenzaprine at oral doses of 10 to 40 mg/kg/day (1.6 to 6.5 times the MRHD on mg/m² basis), there were findings in the liver consisting of midzonal vacuolation with lipidosis for males and midzonal and centrilobular hepatocytic enlargement for females. In addition, there were findings of centrilobular coagulative necrosis. In the higher dose groups, these microscopic changes were seen after 26 weeks and even earlier in rats that died prior to 26 weeks; at lower doses, these changes were not seen until after 26 weeks.
In a 26-week study with Cynomolgus monkeys that received cyclobenzaprine at oral of doses of 2.5, 5, 10, or 20 mg/kg/day, one monkey at 20 mg/kg/day (6.4 times the MRHD on mg/m² basis) was euthanized in week 17. Morbidity for this animal was attributed to findings of chronic pancreatitis, cholecystitis, cholangitis, and focal liver necrosis.
| Dose mg/kg/day* | Duration | Physical Signs | Post-mortem Findings |
|---|---|---|---|
| Rats | |||
| 5 mg | 56 wks. | ptyalism | low incidence of midzonal hepatocytic vacuolation with lipidosis. |
| 10 mg | 67 wks. | ptyalism, decreased activity, chromorhinorrhea, rales, frequent micturition, flaccidity, resistance to dosing, irritability | midzonal hepatocytic vacuolation with lipidosis, enlarged hepatocytes, centrilobular necrosis |
| 20 or 40 mg | 67 wks. | depressed body weight gain, increased mortality | same as above. More frequent in males |
| 60 mg | 2 wks. | decreased physical activity, decreased growth rate | no post-mortem examinations |
| 120 mg or 240 mg | 2 to 8 doses | severe weight loss, collapse, convulsions, death | no post-mortem examinations |
| Dogs | |||
| 2 mg | 53 wks. | minimal ptyalism, vomiting, dry nose, dry gums | no treatment related changes |
| 4 or 8 mg | 53 wks. | same as above but more pronounced | small foci of gastric mucosal necrosis, hemorrhage, or inflammation in three of 16 dogs |
| 10 mg | 28 wks. | slight weight loss, slightly prominent P and T waves in ECC recordings | small focus of unilateral renal papillary edema in 1 of 4 dogs |
| 60 or 120 mg | 6 to 8 doses | tachycardia, sedation, ataxia, convulsions, death | no post-mortem examinations |
| Monkeys | |||
| 2.5 mg | 26 wks. | non-observed | no treatment related changes |
| 5 or 10 mg | 26 wks. | sleepiness (rare) | no treatment related changes |
| 20 mg | 26 wks. | general debilitation (1/6 monkeys), sleepiness | chronic pancreatitis, cholecystitis, cholangitis, focal peritonitis (1/6 monkeys) |
* Based on a Maximum Recommended Human Dose of 60 mg/day (1.0 mg/kg/day), on a mg/m² basis:
Cyclobenzaprine hydrochloride did not have any effect on the onset, incidence or distribution of neoplasms when given in oral doses of up to 10 mg/kg/day to mice for 81 weeks or to rats for 105 weeks (1 and 1.6 times the MRHD on a mg/m² basis, respectively).
Studies in mice and rabbits did not reveal any evidence of embryo lethality or teratogenicity at oral doses up to 20 mg/kg/day (respectively, 1.6 and 6.4 times the MRHD on a mg/m² basis)
In rats, doses of 5 mg or 10 mg/kg/day did not adversely affect the reproduction performance or fertility of males or females, or the growth and survival of their offspring. At doses of 20 mg/kg/day (3.2 times the MRHD on a mg/m² basis) there was decrease in litter size, decrease in size and survival of the pups, and reduced weight gain of mothers.
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