Cyclobenzaprine

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.

Special Populations and Conditions

Geriatrics

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.

Hepatic Insufficiency

In a pharmacokinetic study of sixteen subjects with hepatic impairment (15 mild, 1 moderate per Child-Pugh score), both AUC and C_max 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.

Acute Toxicity

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.

Subacute and Chronic Toxicity

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.

^* Based on a Maximum Recommended Human Dose of 60 mg/day (1.0 mg/kg/day), on a mg/m² basis:

• 10 mg/kg/day in mice is 0.8 times, and 20 mg/kg/day is 1.6 times the MRHD;
• 10 mg/kg/day in rats is 1.6 times, and 40 mg/kg/day is 6.4 times the MRHD;
• 10 mg/kg/day in dogs is 5.4 times, and 120 mg/kg/day is 65 times the MRHD;
• 10 mg/kg/day in monkeys and rabbits is 3.2 times, and 20 mg/kg/d is 6.4 times the MRHD.