Cyclobenzaprine 10 mg

In Canada, cyclobenzaprine is available only as a 10 mg tablet; however, recent clinical studies have shown that a dose of 5 mg three times daily is as effective as 10 mg three times daily, and that the lower dose produces less sedation. Splitting tablets may result in increased variation in the administered dose, although the potential lower risk of adverse events may be preferred, especially in elderly patients.

In patients with mild hepatic impairment the AUC and C_max of cyclobenzaprine were approximately double those in healthy volunteers. For this reason, cyclobenzaprine should be used with caution in patients with mild hepatic impairment, and patients should be monitored for signs of cyclobenzaprine excess (e.g., sedation) and use of the drug should be avoided in patients with moderate to severe hepatic impairment.

Dosage and safety in children less than 15 years of age have not been established.

abdominal pain, acid reflux, anorexia, constipation, diarrhea, flatulence, gastritis, gastrointestinal pain, nausea, paralytic ileus.

Cyclobenzaprine is associated with anticholinergic adverse effects.

blurred vision.

ageusia, stomatitis, tinnitus, vertigo, unpleasant taste.

urinary frequency, urinary retention.

bone marrow suppression, eosinophilia, leukopenia, thrombocytopenia, purpura.

anaphylaxis, angioedema, pruritus, facial edema, urticaria.

local weakness, myalgia.

abnormal gait, ataxia, tremors, Bell's palsy, extrapyramidal symptoms.

elevated blood sugar, lowering of blood sugar, SIADH, weight gain, weight loss.

agitation, anxiety, confusion, convulsions, decreased mental acuity, depressed mood, diplopia, disorientation, dizziness, dysarthria, hallucinations, headache, hypertonia, insomnia, irritability, malaise, nervousness, paresthesias, psychosis, seizures.

alopecia, rash, sweating, photosensitivity.

decreased libido, increased libido, impotence.

arrhythmia, edema, heart block, hypotension, hypertension, myocardial infarction, stroke, syncope, tachycardia, vasodilation.

hepatitis (jaundice, cholestasis, elevated transaminases).

Cyclobenzaprine has anticholinergic effects. The drug should be used with caution in elderly patients who may be more susceptible to such effects.

The safety and efficacy of cyclobenzaprine has not been established in children aged less than 15 years.

Adults and children in whom overdose is suspected should be evaluated in hospital without delay. A regional poison centre should be consulted to assist in the management of patients with serious toxicity. Asymptomatic cases of overdose without ECG abnormalities should be monitored for a minimum of 6 hours. Protect the patient's airway, and support ventilation and perfusion. Treatment should be designed to ensure maintenance of the vital functions and careful monitoring of ECG, blood gases, serum electrolytes and acid-base balance. Secure intravenous access.

Hypotension should be promptly corrected using crystalloid and direct-acting pressors such as norepinephrine, if necessary. Sodium bicarbonate may be helpful in patients with a widened QRS interval (>100-120 msec), particularly those with myocardial depression.

Typically, 1-2 mEq/kg of sodium bicarbonate (1 to 3 ampoules for an average adult) can be given for QRS widening >100 msec, or ventricular arrhythmias, which may reflect myocardial fast sodium channel antagonism. The blood pH should be maintained in the range of 7.45 to 7.55, and the use of sodium bicarbonate should be reconsidered in patients with hypokalemia, congestive heart failure or volume overload states.

Most patients will require potassium supplementation. Hyperventilation has also been used to alkalinize the blood.

Ventricular arrhythmias refractory to bicarbonate may respond to lidocaine. Quinidine, procainamide and other type 1A or 1C antiarrhythmic agents should not be used because they may exacerbate arrhythmias and conduction slowing due to the overdose. Overdrive pacing should be considered in patients whose arrhythmias are not responding to drug therapy.

Forced diuresis, peritoneal dialysis and hemodialysis are ineffective in the removal of cyclobenzaprine. Hyperpyrexia, if severe, should be controlled by evaporative cooling.

If seizures occur, anticonvulsants (preferably i.v. lorazepam or diazepam) should be administered. Although most seizures are short-lived, barbiturates and other measures should be employed for refractory cases. Phenytoin is less likely to interrupt seizures resulting from overdose. Start artificial ventilation if the patient fails to respond rapidly to anticonvulsants. Seizures aggravate hypoxia and acidosis and may precipitate cardiac arrhythmias and arrest, so they must be promptly controlled.

Flumazenil is contraindicated in any patient with an altered level of consciousness who has or may have taken a cyclic antidepressant, as it may precipitate seizures, even in cases of mixed overdoses in which the patient is known to have taken benzodiazepines. Patients with significant central anticholinergic features and no ECG evidence of sodium channel toxicity may benefit from the judicious use of physostigmine, a short-acting cholinesterase inhibitor (available through the Special Access Programme, see Appendix 2). This should generally be done only after consultation with a regional poison centre.

Cyclobenzaprine is extremely toxic in overdose.

Symptoms of overdose may vary in severity depending on factors such as the amount of drug absorbed, the interval between drug ingestion and the start of treatment and the age of the patient.

Although it is not an antidepressant, cyclobenzaprine overdose shares many similarities with overdose of tricyclic antidepressants (TCAs), and deaths, while rare, may occur. Toxicity most commonly occurs within two hours of ingestion. The onset of symptoms is frequently precipitous, with the rapid development of neurologic and cardiac manifestations in patients who appear otherwise well. Central nervous system involvement stems from the sedative and anticholinergic properties of the drug with manifestations ranging from somnolence to confusion, agitated delirium and coma. Peripheral anticholinergic signs (e.g., constipation, dry mucous membranes, mydriasis, urinary retention and, occasionally, adynamic ileus) may also be present. Patients may have elevated body temperatures, in part related to impaired dissipation of heat. Myoclonus, twitching, hyperreflexia, hypertonicity, nystagmus and parkinsonism can occur rarely. Seizures have been reported in some patients.

Serious cardiovascular abnormalities can occur with large overdoses and mimic those of TCA overdose. Sinus tachycardia is common, but is not a reliable predictor of serious toxicity. Other possible cardiac disturbances include QT interval prolongation and ECG manifestations of sodium channel blockade (widening of the QRS complex and a dominant terminal 40-msec of the QRS complex in a lead VR). Hypotension and bradycardia, when present, suggest either a co-ingestant or severe (and possibly preterminal) cyclobenzaprine toxicity. Accidental ingestion in children should be regarded as serious.

Plasma levels of cyclobenzaprine are elevated in elderly people. Moreover, older individuals may be more susceptible to anticholinergic adverse events than younger individuals. For these reasons elderly patients should be closely supervised during treatment with cyclobenzaprine.

Cyclobenzaprine may impair mental or physical abilities required to operate machinery or drive a motor vehicle, particularly if taken with alcohol or drugs with CNS depressant properties.

Cyclobenzaprine may enhance the effects of central nervous system depressants such as alcohol, barbiturates and other drugs.

Cyclobenzaprine has anticholinergic (atropine-like) effects that may precipitate or exacerbate the following conditions: urinary retention, angle-closure glaucoma, increased intra-ocular pressure.

The anticholinergic effects of cyclobenzaprine may be additive to those of other agents.

Plasma concentrations are increased in the elderly and in those with mild hepatic impairment.

There is no evidence of harm to the fetus in animal studies. The drug should be used in pregnancy only if clearly needed.

It is not known whether cyclobenzaprine is excreted in human breast milk. Some closely related tricyclic antidepressants are excreted in breast milk; therefore, caution is advised when considering use of this agent in women who are nursing infants.

Steady state plasma concentrations in elderly subjects were approximately two-fold greater than those in healthy young volunteers.

Plasma concentrations increased in proportion to dose in healthy volunteers receiving 2.5 to 10 mg three times daily. Upon multiple dose administration the plasma levels increased approximately four-fold relative to single-dose studies. At steady state, the mean peak plasma concentrations in 18 volunteers receiving 10 mg three times daily was 25.9 ng/mL (range 12.8 to 46.1 ng/mL). The AUC during the 8 hour dosing interval in these same individuals was 177 ng·h/mL (range 80 to 319 ng·h/mL).

Cyclobenzaprine is highly bound to plasma proteins in circulation and undergoes enterohepatic recirculation.

The mean oral bioavailability of cyclobenzaprine is estimated to range from 33% to 55%.

Cyclobenzaprine is structurally related to the tricyclic antidepressants and, in common with this class of agents, cyclobenzaprine potentiates the effect of norepinephrine, has central and peripheral anticholinergic effects, including increasing heart rate, and also causes sedation.

With respect to the muscle relaxant properties of the drug, these appear to result from effects at the level of the brain stem that result in a net reduction in tonic somatic motor activity in both the alpha and gamma systems. Cyclobenzaprine does not act directly on skeletal muscle cells or at the level of the neuromuscular junction. Cyclobenzaprine relieves muscle spasm of local origin and is ineffective in muscle spasm due to central nervous system disease.

Plasma clearance of cyclobenzaprine in healthy volunteers was approximately 689 mL/min. The terminal elimination half-life of the drug was estimated to be approximately 18 hours in healthy volunteers (range 8 to 37 hours). Only a small proportion of an administered dose is excreted unchanged in urine.

There is little difference in steady state plasma concentrations between males and females.

Cyclobenzaprine undergoes extensive hepatic metabolism in humans. The results of in vitro studies with human microsomes suggest that CYP3A4, CYP1A2 and to a lesser extent CYP2D6, are involved in the production of cyclobenzaprine N-demethylation. The drug also undergoes N+ glucuronidation, and more than 10% of an administered dose is excreted as the quaternary ammonium-linked glucuronide metabolite.