FLEXERIL* (Cyclobenzaprine HCl) is supplied as 10 mg tablets for oral administration.
Tablets FLEXERIL contain the following inactive ingredients: hydroxypropyl cellulose, hydroxypropyl methylcellulose, iron oxide, lactose, magnesium stearate, starch, and titanium dioxide.
*Registered trademark of MERCK & CO., INC.
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 ((gamma)) and alpha ((alpha)) 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.
Cyclobenzaprine is well absorbed after oral administration, but there is a large intersubject variation in plasma levels. Cyclobenzaprine is eliminated quite slowly with a half-life as long as one to three days. It is highly bound to plasma proteins, is extensively metabolized primarily to glucuronide-like conjugates, and is excreted primarily via the kidneys.
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 aspirin is usually well tolerated and no unexpected or serious clinical or laboratory adverse effects have been observed. No studies have been performed to indicate whether FLEXERIL enhances the clinical effect of aspirin or other analgesics, or whether analgesics enhance the clinical effect of FLEXERIL in acute musculoskeletal conditions.
Controlled clinical studies show that FLEXERIL significantly improves the signs and symptoms of skeletal muscle spasm as compared with placebo. The clinical responses include improvement in muscle spasm as determined by palpation, reduction in local pain and tenderness, increased range of motion, and less restriction in activities of daily living. When daily observations were made, clinical improvement was observed as early as the first day of therapy.
Eight double-blind controlled clinical studies were performed in 642 patients comparing FLEXERIL, 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.
Analysis of the data from controlled studies shows that FLEXERIL produces clinical improvement whether or not sedation occurs.
**VALIUM® (diazepam, Roche)
A post-marketing surveillance program was carried out in 7607 patients with acute musculoskeletal disorders, and included 297 patients treated 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 ).
FLEXERIL is indicated as an adjunct to rest and physical therapy for relief of muscle spasm associated with acute, painful musculoskeletal conditions.
Improvement is manifested by relief of muscle spasm and its associated signs and symptoms, namely, pain, tenderness, limitation of motion, and restriction in activities of daily living.
FLEXERIL (Cyclobenzaprine HCl) should be used only for short periods (up to two or three weeks) because adequate evidence of effectiveness for more prolonged use is not available and because muscle spasm associated with acute, painful musculoskeletal conditions is generally of short duration and specific therapy for longer periods is seldom warranted.
FLEXERIL has not been found effective in the treatment of spasticity associated with cerebral or spinal cord disease, or in children with cerebral palsy.
Hypersensitivity to the drug.
Concomitant use of monoamine oxidase inhibitors or within 14 days after their discontinuation.
Acute recovery phase of myocardial infarction, and patients with arrhythmias, heart block or conduction disturbances, or congestive heart failure.
Hyperthyroidism.
Cyclobenzaprine is closely related to the tricyclic antidepressants, e.g., amitriptyline and imipramine. In short term studies for indications other than muscle spasm associated with acute musculoskeletal conditions, and usually at doses somewhat greater than those recommended for skeletal muscle spasm, some of the more serious central nervous system reactions noted with the tricyclic antidepressants have occurred (see , below, and ADVERSE REACTIONS ).
FLEXERIL may interact with monoamine oxidase (MAO) inhibitors. Hyperpyretic crisis, severe convulsions, and deaths have occurred in patients receiving tricyclic antidepressants and MAO inhibitor drugs.
Tricyclic antidepressants have been reported to produce arrhythmias, sinus tachycardia, prolongation of the conduction time leading to myocardial infarction and stroke.
FLEXERIL may enhance the effects of alcohol, barbiturates, and other CNS depressants.
Because of its atropine-like action, FLEXERIL should be used with caution in patients with a history of urinary retention, angle-closure glaucoma, increased intraocular pressure, and in patients taking anticholinergic medication.
The elderly may be more at risk for CNS adverse effects such as hallucinations and confusion.
FLEXERIL may impair mental and/or physical abilities required for performance of hazardous tasks, such as operating machinery or driving a motor vehicle.
Tricyclic antidepressants may block the antihypertensive action of guanethidine and similarly acting compounds.
Tricyclic antidepressants may enhance the seizure risk in patients taking tramadol.
*** ULTRAM® (tramadol HCl tablets, Ortho-McNeil Pharmaceutical)
In rats treated with FLEXERIL for up to 67 weeks at doses of approximately 5 to 40 times the maximum recommended human dose, pale, sometimes enlarged, livers were noted and there was a dose-related hepatocyte vacuolation with lipidosis. In the higher dose groups this microscopic change was seen after 26 weeks and even earlier in rats which died prior to 26 weeks; at lower doses, the change was not seen until after 26 weeks.
Cyclobenzaprine did not affect the onset, incidence or distribution of neoplasia in an 81-week study in the mouse or in a 105-week study in the rat.
At oral doses of up to 10 times the human dose, cyclobenzaprine did not adversely affect the reproductive performance or fertility of male or female rats. Cyclobenzaprine did not demonstrate mutagenic activity in the male mouse at dose levels of up to 20 times the human dose.
Pregnancy Category B: Reproduction studies have been performed in rats, mice and rabbits at doses up to 20 times the human dose, and have revealed no evidence of impaired fertility or harm to the fetus due to FLEXERIL. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
It is not known whether this drug is excreted in human milk. Because cyclobenzaprine is closely related to the tricyclic antidepressants, some of which are known to be excreted in human milk, caution should be exercised when FLEXERIL is administered to a nursing woman.
Safety and effectiveness of FLEXERIL in pediatric patients below 15 years of age have not been established.
The following list of adverse reactions is based on the experience in 473 patients treated with FLEXERIL in controlled clinical studies, 7607 patients in the post-marketing surveillance program, and reports received since the drug was marketed. The overall incidence of adverse reactions among patients in the surveillance program was less than the incidence in the controlled clinical studies.
The adverse reactions reported most frequently with FLEXERIL were drowsiness, dry mouth and dizziness. The incidence of these common adverse reactions was lower in the surveillance program than in the controlled clinical studies:
Studies Surveillance
Among the less frequent adverse reactions, there was no appreciable difference in incidence in controlled clinical studies or in the surveillance program. Adverse reactions which were reported in 1% to 3% of the patients were: fatigue/tiredness, asthenia, nausea, constipation, dyspepsia, unpleasant taste, blurred vision, headache, nervousness, and confusion.
Incidence Less Than 1 in 100
The following adverse reactions have been reported at an incidence of less than 1 in 100:
Body as a Whole: Syncope; malaise.
Cardiovascular: Tachycardia; arrhythmia; vasodilatation; palpitation; hypotension.
Digestive: Vomiting; anorexia; diarrhea; gastrointestinal pain; gastritis; thirst; flatulence; edema of the tongue; abnormal liver function and rare reports of hepatitis, jaundice and cholestasis.
Hypersensitivity: Anaphylaxis; angioedema; pruritus; facial edema; urticaria; rash.
Musculoskeletal: Local weakness.
Nervous System and Psychiatric: Ataxia; vertigo; dysarthria; tremors; hypertonia; convulsions; muscle twitching; disorientation; insomnia; depressed mood; abnormal sensations; anxiety; agitation; abnormal thinking and dreaming; hallucinations; excitement; paresthesia; diplopia.
Skin: Sweating
Special Senses: Ageusia; tinnitus.
Urogenital: Urinary frequency and/or retention.
Causal Relationship Unknown
Other reactions, reported rarely for FLEXERIL under circumstances where a causal relationship could not be established or reported for other tricyclic drugs, are listed to serve as alerting information to physicians:
Body as a Whole: Chest pain; edema.
Cardiovascular: Hypertension; myocardial infarction; heart block; stroke.
Digestive: Paralytic ileus; tongue discoloration; stomatitis; parotid swelling.
Endocrine: Inappropriate ADH syndrome.
Hematic and Lymphatic: Purpura; bone marrow depression; leukopenia; eosinophilia; thrombocytopenia.
Metabolic, Nutritional and Immune: Elevation and lowering of blood sugar levels; weight gain or loss.
Musculoskeletal: Myalgia.
Nervous System and Psychiatric: Decreased or increased libido; abnormal gait; delusions; aggressive behavior; paranoia; peripheral neuropathy; Bell' palsy; alteration in EEG patterns; extrapyramidal symptoms.
Respiratory: Dyspnea.
Skin: Photosensitization; alopecia.
Urogenital: Impaired urination; dilatation of urinary tract; impotence; testicular swelling; gynecomastia; breast enlargement; galactorrhea.
DRUG ABUSE AND DEPENDENCE
Pharmacologic similarities among the tricyclic drugs require that certain withdrawal symptoms be considered when FLEXERIL is administered, even though they have not been reported to occur with this drug. Abrupt cessation of treatment after prolonged administration may produce nausea, headache, and malaise. These are not indicative of addiction.
Manifestations: High doses may cause temporary confusion, disturbed concentration, transient visual hallucinations, agitation, hyperactive reflexes, muscle rigidity, vomiting, or hyperpyrexia, in addition to anything listed under ADVERSE REACTIONS. Based on the known pharmacologic actions of the drug, overdosage may cause drowsiness, hypothermia, tachycardia and other cardiac rhythm abnormalities such as bundle branch block, ECG evidence of impaired conduction, and congestive heart failure. Other manifestations may be dilated pupils, convulsions, severe hypotension, stupor, and coma.
The acute oral LD 50 of FLEXERIL is approximately 338 and 425 mg/kg in mice and rats, respectively.
Treatment: Treatment is symptomatic and supportive. Empty the stomach as quickly as possible by emesis, followed by gastric lavage. After gastric lavage, activated charcoal may be administered. Twenty to 30 g of activated charcoal may be given every four to six hours during the first 24 to 48 hours after ingestion. An ECG should be taken and close monitoring of cardiac function must be instituted if there is any evidence of dysrhythmia. Maintenance of an open airway, adequate fluid intake, and regulation of body temperature are necessary.
The intravenous administration of 1-3 mg of physostigmine salicylate is reported to reverse symptoms of poisoning by atropine and other drugs with anticholinergic activity. Physostigmine may be helpful in the treatment of cyclobenzaprine overdose. Because physostigmine is rapidly metabolized, the dosage of physostigmine should be repeated as required, particularly if life-threatening signs such as arrhythmias, convulsions, and deep coma recur or persist after the initial dosage of physostigmine. Because physostigmine itself may be toxic, it is not recommended for routine use.
Standard medical measures should be used to manage circulatory shock and metabolic acidosis. Cardiac arrhythmias may be treated with neostigmine, pyridostigmine, or propranolol. When signs of cardiac failure occur, the use of a short-acting digitalis preparation should be considered. Close monitoring of cardiac function for not less than five days is advisable.
Anticonvulsants may be given to control seizures.
Dialysis is probably of no value because of low plasma concentrations of the drug.
Since overdosage is often deliberate, patients may attempt suicide by other means during the recovery phase. Deaths by deliberate or accidental overdosage have occurred with this class of drugs.
The usual dosage of FLEXERIL is 10 mg three times a day, with a range of 20 to 40 mg a day in divided doses. Dosage should not exceed 60 mg a day. Use of FLEXERIL for periods longer than two or three weeks is not recommended. (See .)
No. 3358--Tablets FLEXERIL, 10 mg, are butterscotch yellow, 5-sided D-shaped, film coated tablets, coded MSD 931 on one side and FLEXERIL on the other. They are supplied as follows:
NDC 0006-0931-68 in bottles of 100
NDC 0006-0931-28 unit dose packages of 100.
7897216 Issued December 1999
COPYRIGHT © MERCK & CO., INC., 1985