Flexeril (Cyclobenzaprine Hcl): Side Effects, Uses, Dosage, Interactions, Warnings (2024)

Description for Flexeril

Cyclobenzaprine hydrochloride is a white, crystalline tricyclic amine salt with the empirical formula C₂₀H₂₁N•HCl and a molecular weight of 311.9. It has a melting point of 217°C, and a pKa of 8.47 at 25°C. It is freely soluble in water and alcohol, sparingly soluble in isopropanol, and insoluble in hydrocarbon solvents. If aqueous solutions are made alkaline, the free base separates. Cyclobenzaprine HCl is designated chemically as 3-(5H-dibenzo[a,d] cyclohepten-5-ylidene)-N, Ndimethyl- 1-propanamine hydrochloride, and has the following structural formula:

FLEXERIL 5 mg (Cyclobenzaprine HCl) is supplied as a 5 mg tablet for oral administration. FLEXERIL 10 mg (Cyclobenzaprine HCl) is supplied as a 10 mg tablet for oral administration.

FLEXERIL tablets contain the following inactive ingredients: hydroxypropyl cellulose, hydroxypropyl methylcellulose, iron oxide, lactose, magnesium stearate, starch, and titanium dioxide. FLEXERIL 5 mg tablets also contain Yellow D&C #10 Aluminum Lake HT, and Yellow FD&C #6 Aluminum Lake.

Uses for Flexeril

FLEXERIL is indicated as an adjunct to rest and physicaltherapy for relief of muscle spasm associated with acute, painfulmusculoskeletal conditions.

Improvement is manifested by relief of muscle spasm andits associated signs and symptoms, namely, pain, tenderness, limitation ofmotion, and restriction in activities of daily living.

FLEXERIL should be used only for short periods (up totwo or three weeks) because adequate evidence of effectiveness for moreprolonged use is not available and because muscle spasm associated with acute,painful musculoskeletal conditions is generally of short duration and specifictherapy 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.

Dosage for Flexeril

For most patients, the recommended dose of FLEXERIL is 5mg three times a day. Based on individual patient response, the dose may beincreased to 10 mg three times a day. Use of FLEXERIL for periods longer than twoor three weeks is not recommended. (see INDICATIONS AND USAGE).

Less frequent dosing should be considered for hepaticallyimpaired or elderly patients (see PRECAUTIONS, Impaired HepaticFunction, and Use in the Elderly).

HOW SUPPLIED

FLEXERIL tablets are available in 5 mg and 10 mg dosagestrengths. The 5 mg tablets are yellow-orange, 5-sided, film coated tablets,coded FLEX over 5 on one side and without coding on the other. The 10 mgtablets are butterscotch yellow, 5-sided D-shaped bi-convex, film coatedtablets, coded FLEXERIL on one side and without coding on the other. The twodosage strengths are supplied as follows:

5 mg 100 count bottle NDC 50458-280-10
10 mg 100 count bottle NDC 50458-874-11

Storage

Store at 25°C (77°F); excursions permitted to 15-30°C(59-86°F). [see USP Controlled Room Temperature].

Manufactured by: McNeil Consumer Healthcare. Division ofMcNeil-PPC, Inc. Fort Washington, PA 19034. Manufactured for: McNeil Pediatrics Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc. Titusville, NJ 08560.Edition: April 2013

Side Effects for Flexeril

Incidence of most common adverse reactions in the 2double-blind‡, placebo-controlled 5 mg studies (incidence of > 3% onFLEXERIL 5 mg):

Adverse reactions which were reported in 1% to 3% of thepatients were: abdominal pain, acid regurgitation, constipation, diarrhea,dizziness, nausea, irritability, mental acuity decreased, nervousness, upperrespiratory infection, and pharyngitis.

The following list of adverse reactions is based on theexperience in 473 patients treated with FLEXERIL 10 mg in additional controlledclinical studies, 7607 patients in the post-marketing surveillance program, andreports received since the drug was marketed. The overall incidence of adversereactions among patients in the surveillance program was less than theincidence in the controlled clinical studies.

The adverse reactions reported most frequently withFLEXERIL were drowsiness, dry mouth and dizziness. The incidence of thesecommon adverse reactions was lower in the surveillance program than in thecontrolled clinical studies:

‡ Note: FLEXERIL 10 mg data are from one clinicaltrial. FLEXERIL 5 mg and placebo data are from two studies.

Among the less frequent adverse reactions, there was noappreciable difference in incidence in controlled clinical studies or in thesurveillance program. Adverse reactions which were reported in 1% to 3% of thepatients were: fatigue/tiredness, asthenia, nausea, constipation, dyspepsia, unpleasanttaste, blurred vision, headache, nervousness, and confusion.

The following adverse reactions have been reported inpost-marketing experience or with an incidence of less than 1% of patients inclinical trials with the 10 mg tablet:

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 andcholestasis.

Hypersensitivity: Anaphylaxis; angioedema; pruritus; facial edema; urticaria; rash.

Musculoskeletal: Local weakness.

Nervous System and Psychiatric: Seizures, ataxia; vertigo; dysarthria; tremors; hypertonia; convulsions; muscle twitching;disorientation; insomnia; depressed mood; abnormal sensations; anxiety;agitation; psychosis, 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 undercirc*mstances where a causal relationship could not be established or reportedfor other tricyclic drugs, are listed to serve as alerting information tophysicians:

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 andlowering of blood sugar levels; weight gain or loss.

Musculoskeletal: Myalgia.

Nervous System and Psychiatric: Decreased orincreased libido; abnormal gait; delusions; aggressive behavior; paranoia; peripheral neuropathy; Bell's palsy; alteration in EEG patterns; extrapyramidalsymptoms.

Respiratory: Dyspnea.

Skin: Photosensitization; alopecia.

Urogenital: Impaired urination; dilatation of urinary tract; impotence; testicular swelling; gynecomastia; breastenlargement; galactorrhea.

Drug Abuse And Dependence

Pharmacologic similarities among the tricyclic drugsrequire that certain withdrawal symptoms be considered when FLEXERIL isadministered, even though they have not been reported to occur with this drug.Abrupt cessation of treatment after prolonged administration rarely may producenausea, headache, and malaise. These are not indicative of addiction.

Drug Interactions for Flexeril

FLEXERIL may have life-threatening interactions with MAOinhibitors. (See CONTRAINDICATIONS.)

FLEXERIL may enhance the effects of alcohol,barbiturates, and other CNS depressants.

Tricyclic antidepressants may block the antihypertensive action of guanethidine and similarly acting compounds.

Tricyclic antidepressants may enhance the seizure risk inpatients taking tramadol.†

†ULTRAM® (tramadol HCl tablets, Ortho-McNeilPharmaceutical)
ULTRACET® (tramadol HCl and acetaminophen tablets,Ortho-McNeil Pharmaceutical)

Warnings for Flexeril

Cyclobenzaprine is closely related to the tricyclic antidepressants, e.g., amitriptyline and imipramine. In short term studies forindications other than muscle spasm associated with acute musculoskeletal conditions,and usually at doses somewhat greater than those recommended for skeletalmuscle spasm, some of the more serious central nervous system reactions notedwith the tricyclic antidepressants have occurred (see WARNINGS, below, andADVERSE REACTIONS).

Tricyclic antidepressants have been reported to producearrhythmias, 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.

Precautions for Flexeril

General

Because of its atropine-like action, FLEXERIL should beused with caution in patients with a history of urinary retention, angle-closure glaucoma, increased intraocular pressure, and in patients taking anticholinergic medication.

Impaired Hepatic Function

The plasma concentration of cyclobenzaprine is increasedin patients with hepatic impairment (see CLINICAL PHARMACOLOGY,Pharmaco*kinetics, Hepatic Impairment).

These patients are generally more susceptible to drugswith potentially sedating effects, including cyclobenzaprine. FLEXERIL shouldbe used with caution in subjects with mild hepatic impairment starting with a 5mg dose and titrating slowly upward. Due to the lack of data in subjects withmore severe hepatic insufficiency, the use of FLEXERIL in subjects withmoderate to severe impairment is not recommended.

Carcinogenesis, Mutagenesis, Impairment Of Fertility

In rats treated with FLEXERIL for up to 67 weeks at dosesof approximately 5 to 40 times the maximum recommended human dose, pale,sometimes enlarged, livers were noted and there was a dose-related hepatocytevacuolation with lipidosis. In the higher dose groups this microscopic change wasseen after 26 weeks and even earlier in rats which died prior to 26 weeks; atlower doses, the change was not seen until after 26 weeks.

Cyclobenzaprine did not affect the onset, incidence ordistribution of neoplasia in an 81-week study in the mouse or in a 105-weekstudy in the rat.

At oral doses of up to 10 times the human dose,cyclobenzaprine did not adversely affect the reproductive performance orfertility of male or female rats. Cyclobenzaprine did not demonstrate mutagenicactivity in the male mouse at dose levels of up to 20 times the human dose.

Pregnancy

Pregnancy Category B: Reproduction studies havebeen performed in rats, mice and rabbits at doses up to 20 times the humandose, and have revealed no evidence of impaired fertility or harm to the fetus dueto FLEXERIL. There are, however, no adequate and well-controlled studies inpregnant women. Because animal reproduction studies are not always predictiveof human response, this drug should be used during pregnancy only if clearlyneeded.

Nursing Mothers

It is not known whether this drug is excreted in humanmilk. Because cyclobenzaprine is closely related to the tricyclicantidepressants, some of which are known to be excreted in human milk, caution shouldbe exercised when FLEXERIL is administered to a nursing woman.

Pediatric Use

Safety and effectiveness of FLEXERIL in pediatricpatients below 15 years of age have not been established.

Use Iin The Elderly

The plasma concentration of cyclobenzaprine is increasedin the elderly (see CLINICAL PHARMACOLOGY, Pharmaco*kinetics, Elderly). Theelderly may also be more at risk for CNS adverse events such as hallucinationsand confusion, cardiac events resulting in falls or other sequelae, drug-drugand drug-disease interactions. For these reasons, in the elderly,cyclobenzaprine should be used only if clearly needed. In such patientsFLEXERIL should be initiated with a 5 mg dose and titrated slowly upward.

Overdose Information for Flexeril

Although rare, deaths may occur from overdosage withFLEXERIL. Multiple drug ingestion (including alcohol) is common in deliberatecyclobenzaprine overdose. As management of overdose is complex and changing,it is recommended that the physician contact a poison control center forcurrent information on treatment. Signs and symptoms of toxicity maydevelop rapidly after cyclobenzaprine overdose; therefore, hospital monitoringis required as soon as possible. The acute oral LD50 of FLEXERIL isapproximately 338 and 425 mg/kg in mice and rats, respectively.

Manifestations

The most common effects associated with cyclobenzaprineoverdose are drowsiness and tachycardia. Less frequent manifestations include tremor, agitation, coma, ataxia, hypertension, slurred speech, confusion,dizziness, nausea, vomiting, and hallucinations. Rare but potentially critical manifestationsof overdose are cardiac arrest, chest pain, cardiac dysrhythmias, severe hypotension, seizures, and neuroleptic malignant syndrome. Changes in the electrocardiogram, particularly in QRS axis or width, are clinicallysignificant indicators of cyclobenzaprine toxicity.

Other potential effects of overdosage include any of thesymptoms listed under ADVERSE REACTIONS.

Management

General

As management of overdose is complex and changing, itis recommended that the physician contact a poison control center for currentinformation on treatment.

In order to protect against the rare but potentiallycritical manifestations described above, obtain an ECG and immediately initiatecardiac monitoring. Protect the patient's airway, establish an intravenous lineand initiate gastric decontamination. Observation with cardiac monitoring and observationfor signs of CNS or respiratory depression, hypotension, cardiac dysrhythmiasand/or conduction blocks, and seizures is necessary. If signs of toxicity occurat any time during this period, extended monitoring is required. Monitoring ofplasma drug levels should not guide management of the patient. Dialysis isprobably of no value because of low plasma concentrations of the drug.

Gastrointestinal Decontamination

All patients suspected of an overdose with FLEXERILshould receive gastrointestinal decontamination. This should include largevolume gastric lavage followed by activated charcoal. If consciousness isimpaired, the airway should be secured prior to lavage and emesis iscontraindicated.

Cardiovascular

A maximal limb-lead QRS duration of ≥ 0.10 secondsmay be the best indication of the severity of the overdose. Serumalkalinization, to a pH of 7.45 to 7.55, using intravenous sodium bicarbonate and hyperventilation (as needed), should be instituted for patients withdysrhythmias and/or QRS widening. A pH > 7.60 or a pCO2 < 20 mmHg isundesirable. Dysrhythmias unresponsive to sodium bicarbonate therapy/hyperventilationmay respond to lidocaine, bretylium or phenytoin. Type 1A and 1C antiarrhythmicsare generally contraindicated (e.g., quinidine, disopyramide, andprocainamide).

CNS

In patients with CNS depression, early intubation isadvised because of the potential for abrupt deterioration. Seizures should becontrolled with benzodiazepines or, if these are ineffective, other anticonvulsants(e.g. phenobarbital, phenytoin). Physostigmine is not recommended except totreat life-threatening symptoms that have been unresponsive to other therapies,and then only in close consultation with a poison control center.

Psychiatric Follow-Up

Since overdosage is often deliberate, patients mayattempt suicide by other means during the recovery phase. Psychiatric referral may be appropriate.

Pediatric Management

The principles of management of child and adultoverdosages are similar. It is strongly recommended that the physician contactthe local poison control center for specific pediatric treatment.

Contraindications for Flexeril

Hypersensitivity to any component of this product.

Concomitant use of monoamine oxidase (MAO) inhibitors orwithin 14 days after their discontinuation. Hyperpyretic crisis seizures, anddeaths have occurred in patients receiving cyclobenzaprine (or structurallysimilar tricyclic antidepressants) concomitantly with MAO inhibitor drugs.

Acute recovery phase of myocardial infarction, andpatients with arrhythmias, heart block or conduction disturbances, or congestive heart failure.

Hyperthyroidism.

Clinical Pharmacology for Flexeril

Cyclobenzaprine HCl relieves skeletal muscle spasm oflocal origin without interfering with muscle function. It is ineffective inmuscle spasm due to central nervous system disease.

Cyclobenzaprine reduced or abolished skeletal muscle hyperactivity in several animal models. Animal studies indicate thatcyclobenzaprine does not act at the neuromuscular junction or directly onskeletal muscle. Such studies show that cyclobenzaprine acts primarily withinthe 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 isa reduction of tonic somatic motor activity, influencing both gamma (γ)and alpha (α) motor systems.

Pharmacological studies in animals showed a similaritybetween 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.

Pharmaco*kinetics

Estimates of mean oral bioavailability of cyclobenzaprinerange from 33% to 55%. Cyclobenzaprine exhibits linear pharmaco*kinetics overthe dose range 2.5 mg to 10 mg, and is subject to enterohepatic circulation. Itis highly bound to plasma proteins. Drug accumulates when dosed three times aday, reaching steady-state within 3-4 days at plasma concentrations aboutfour-fold higher than after a single dose. At steady state in healthy subjectsreceiving 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 an8-hour dosing interval was 177 ng.hr/mL (range, 80-319 ng.hr/mL).

Cyclobenzaprine is extensively metabolized, and isexcreted primarily as glucuronides via the kidney. Cytochromes P-450 3A4, 1A2,and, to a lesser extent, 2D6, mediate N-demethylation, one of the oxidativepathways for cyclobenzaprine. Cyclobenzaprine is eliminated quite slowly, withan effective half-life of 18 hours (range 8-37 hours; n=18); plasma clearanceis 0.7 L/min.

The plasma concentration of cyclobenzaprine is generallyhigher in the elderly and in patients with hepatic impairment. (See PRECAUTIONS,Use in the Elderly and PRECAUTIONS, Impaired Hepatic Function.)

Elderly

In a pharmaco*kinetic study in elderly individuals( ≥ 65yrs old), mean (n=10) steady-state cyclobenzaprine AUC values wereapproximately 1.7 fold (171.0 ng.hr/mL, range 96.1-255.3) higher than thoseseen 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 meanincrease, approximately 2.4 fold (198.3 ng.hr/mL, range 155.6-255.3 versus 83.2ng.hr/mL, range 41.1-142.5 for younger males) while levels in elderly femaleswere 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 theelderly should be initiated with a 5 mg dose and titrated slowly upward.

Hepatic Impairment

In a pharmaco*kinetic study of sixteen subjects withhepatic impairment (15 mild, 1 moderate per Child-Pugh score), both AUC and Cmaxwere approximately double the values seen in the healthy control group. Basedon the findings, FLEXERIL should be used with caution in subjects with mildhepatic impairment starting with the 5 mg dose and titrating slowly upward. Dueto the lack of data in subjects with more severe hepatic insufficiency, the useof FLEXERIL in subjects with moderate to severe impairment is not recommended.

No significant effect on plasma levels or bioavailabilityof FLEXERIL or aspirin was noted when single or multiple doses of the two drugswere administered concomitantly. Concomitant administration of FLEXERIL andnaproxen or diflunisal was well tolerated with no reported unexpected adverseeffects. However combination therapy of FLEXERIL with naproxen was associatedwith more side effects than therapy with naproxen alone, primarily in the formof drowsiness. No well-controlled studies have been performed to indicate thatFLEXERIL enhances the clinical effect of aspirin or other analgesics, orwhether analgesics enhance the clinical effect of FLEXERIL in acutemusculoskeletal conditions.

Clinical Studies

Eight double-blind controlled clinical studies wereperformed in 642 patients comparing FLEXERIL 10 mg, diazepam, andplacebo. Muscle spasm, local pain and tenderness, limitation of motion, andrestriction in activities of daily living were evaluated. In three of thesestudies there was a significantly greater improvement with FLEXERIL than withdiazepam, while in the other studies the improvement following both treatmentswas comparable.

Although the frequency and severity of adverse reactionsobserved in patients treated with FLEXERIL were comparable to those observed inpatients treated with diazepam, dry mouth was observed more frequently inpatients treated with FLEXERIL and dizziness more frequently in those treatedwith diazepam. The incidence of drowsiness, the most frequent adverse reaction,was similar with both drugs.

The efficacy of FLEXERIL 5 mg was demonstrated in twoseven-day, double-blind, controlled clinical trials enrolling 1405 patients.One study compared FLEXERIL 5 mg and 10 mg t.i.d. to placebo; and a secondstudy compared FLEXERIL 5 mg and 2.5 mg t.i.d. to placebo. Primary endpointsfor both trials were determined by patient-generated data and included globalimpression of change, medication helpfulness, and relief from startingbackache. Each endpoint consisted of a score on a 5-point rating scale (from 0or worst outcome to 4 or best outcome).

Comparisons of FLEXERIL 5 mg and placebo groups in bothtrials established the statistically significant superiority of the 5 mg dosefor all three primary endpoints at day 8 and, in the study comparing 5 and 10mg, at day 3 or 4 as well. A similar effect was observed with FLEXERIL 10 mg(all endpoints). Physician-assessed secondary endpoints also showed thatFLEXERIL 5 mg was associated with a greater reduction in palpable muscle spasmthan placebo.

Analysis of the data from controlled studies shows thatFLEXERIL produces clinical improvement whether or not sedation occurs.

Secondary endpoints included a physician's evaluation ofthe presence and extent of palpable muscle spasm.

Surveillance Program

A post-marketing surveillance program was carried out in7607 patients with acute musculoskeletal disorders, and included 297 patientstreated with FLEXERIL 10 mg for 30 days or longer. The overall effectiveness ofFLEXERIL was similar to that observed in the double-blind controlled studies;the overall incidence of adverse effects was less (see ADVERSE REACTIONS).

Patient Information for Flexeril

FLEXERIL, especially when used with alcohol or other CNSdepressants, may impair mental and/or physical abilities required forperformance of hazardous tasks, such as operating machinery or driving a motorvehicle. In the elderly, the frequency and severity of adverse eventsassociated with the use of cyclobenzaprine, with or without concomitantmedications, is increased. In elderly patients, FLEXERIL should be initiatedwith a 5 mg dose and titrated slowly upward.