Fexmid

DESCRIPTION

Fexmid^®(cyclobenzaprine hydrochloride) is a white, crystalline tricyclicaminesalt. It has a melting point of 217°C, and a pK_aof 8.47 at 25°C. It is freely soluble in water and alcohol, sparingly soluble in isopropanol, and insoluble inhydrocarbonsolvents. 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,N-dimethyl-1-propanamine hydrochloride, and has the following structural formula:

Fexmid is available for oral administration as 7.5 mg tablets. Fexmid contains the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, dibasic calcium phosphate, hydroxypropyl cellulose, hypromellose, polyethylene glycol, magnesium stearate, microcrystalline cellulose, and titanium dioxide.

INDICATIONS

Fexmid 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.

Fexmid 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.

Fexmid has not been found effective in the treatment of spasticity associated with cerebral or spinal cord disease, or in children with cerebral palsy.

DOSAGE AND ADMINISTRATION

For most patients, the recommended dose of cyclobenzaprine HCl is 5 mg three times a day. Based on individual patient response, the dose may be increased to either 7.5 mg or 10 mg three times a day. Use of Fexmid for periods longer than two or three weeks is not recommended. (SeeINDICATIONS.)

Less frequent dosing should be considered for hepatically impaired or elderly patients (seePRECAUTIONS,Impaired Hepatic Function, andUse In The Elderly）.

HOW SUPPLIED

Fexmid (cyclobenzaprine hydrochloride tablets USP, 7.5 mg) are round, white, film-coated tablets imprintedWATSONand3330supplied in bottles of 100 (NDC70199-014-01).

Pharmacist

分发与child-res置于阴凉istant closure.

Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].

Manufactured for: Cas per Pharma LLC East Brunswick, NJ 08816. Revised: Mar 2019

SIDE EFFECTS

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

	Cyclobenzaprine HCl Tablets 5 mg	Cyclobenzaprine HCl Tablets 10 mg	Placebo
	N=464	N=249	N=469
Drowsiness	29%	38%	10%
Dry Mouth	21%	32%	7%
Fatigue	6%	6%	3%
Headache	5%	5%	8%
‡Note: Cyclobenzaprine HCl Tablets 10 mg data are from one clinical trial. Cyclobenzaprine HCl Tablets 5 mg and placebo data are from two studies.

Adverse reactions which were reported in 1% to 3% of the patients were: abdominal pain, acidregurgitation, constipation, diarrhea, dizziness, nausea, irritability, mental acuity decreased, nervousness,upper respiratory infection, andpharyngitis.

The following list of adverse reactions is based on the experience in 473 patients treated with cyclobenzaprine HCl 10 mg in additional controlled clinical studies, 7607 patients in the postmarketing 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 cyclobenzaprine HCl were drowsiness,dry mouthand dizziness. The incidence of these common adverse reactions was lower in the surveillance program than in the controlled clinical studies:

	Clinical Studies with	Surveillance Program with
	Cyclobenzaprine HCl Tablets 10 mg	Cyclobenzaprine HCl Tablets 10 mg
Drowsiness	39%	16%
Dry mouth	27%	7%
Dizziness	11%	3%

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.

The following adverse reactions have been reported in postmarketing experience or with an incidence of less than 1% of patients in clinical trials with the 10 mg tablet:

Body as a Whole:Syncope;malaise.

Cardiovascular:Tachycardia;arrhythmia; vasodilatation; palpitation;hypotension.

Digestive:Vomiting;anorexia; diarrhea;gastrointestinalpain;gastritis; thirst;flatulence; edema of the tongue; abnormal liver function and rare reports ofhepatitis,jaundiceandcholestasis.

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

Musculoskeletal:Local weakness.

Nervous System and Psychiatric:Seizures,ataxia;vertigo;dysarthria; tremors;hypertonia; convulsions; muscletwitching; disorientation; insomnia; depressed mood; abnormal sensations; anxiety; agitation;psychosis, abnormal thinking and dreaming; hallucinations; excitement;paresthesia;diplopia,serotoninsyndrome.

Skin:Sweating.

Special Senses:Ageusia;tinnitus.

Urogenital:Urinary frequency and/or retention.

Causal Relations Hip Unknown

其他反应,cyclobenzapri报道很少ne HCl 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:InappropriateADHsyndrome.

Hematic and Lymphatic:Purpura;bone marrowdepression;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 increasedlibido; abnormalgait; delusions; aggressive behavior; paranoia;peripheral neuropathy;Bell’spalsy; alteration inEEGpatterns; extrapyramidal symptoms.

Respiratory:Dyspnea.

Skin:Photosensitization;alopecia.

Urogenital:Impaired urination;dilatationofurinary tract;impotence; testicular swelling;gynecomastia; breast enlargement;galactorrhea.

To report SUSPECTED ADVERSE REACTIONS, contact Cas per Pharma LLC. at 1-844-5- CASPER (1-844-522-7737) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS

Fexmid may have life-threatening interactions with MAO inhibitors (seeCONTRAINDICATIONS）.Postmarketing cases of serotonin syndrome have been reported during combined use of Cyclobenzaprine Hydrochloride and other drugs, such as SSRIs, SNRIs, TCAs, tramadol, bupropion, meperidine, verapamil, or MAO inhibitors. If concomitant treatment with Fexmid and other serotonergic drugs is clinically warranted, careful observation is advised, particularly during treatment initiation or dose increases (see警告）.

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

Tricyclic antidepressantsmay block theantihypertensiveaction of guanethidine and similarly acting compounds.

Drug Abuse And Dependence

Pharmacologic similarities among the tricyclic drugs require that certainwithdrawal symptomsbe considered when Fexmid is administered, even though they have not been reported to occur with this drug. Abrupt cessation of treatment after prolonged administration rarely may produce nausea, headache, and malaise. These are not indicative of addiction.

警告

Serotonin Syndrome

The development of a potentially life-threatening serotonin syndrome has been reported with Cyclobenzaprine Hydrochloride when used in combination with other drugs, such as selective serotoninreuptakeinhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclicantidepressants(TCAs), tramadol, bupropion, meperidine, verapamil, or MAO inhibitors. The concomitant use of Fexmid with MAO inhibitors is contraindicated (seeCONTRAINDICATIONS）.5 -羟色胺综合征症状可能包括e mental status changes (e.g., confusion, agitation, hallucinations), autonomic instability (e.g., diaphoresis, tachycardia,labileblood pressure,hyperthermia),neuromuscularabnormalities (e.g.,tremor, ataxia, hyperreflexia, clonus, muscle rigidity), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Treatment with Fexmid and any concomitant serotonergic agents should be discontinued immediately if the above reactions occur and supportivesymptomatic treatmentshould be initiated. If concomitant treatment with Fexmid and other serotonergic drugs is clinically warranted, careful observation is advised, particularly during treatment initiation or dose increases (seeDRUG INTERACTIONS）.

Fexmid is closely related to the tricyclic antidepressants, e.g.,amitriptylineand imipramine. In short term studies for indications other thanmuscle spasmassociated with acute musculoskeletal conditions, and usually at doses somewhat greater than those recommended forskeletal musclespasm, some of the more seriouscentral nervous systemreactions noted with the tricyclic antidepressants have occurred (see警告, below, andADVERSE REACTIONS）.

Tricyclic antidepressants have been reported to produce arrhythmias,sinus tachycardia,传导时间的延长导致myocardialinfarctionand stroke.

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

PRECAUTIONS

General

Because of itsatropine-like action, Fexmid should be used with caution in patients with a history of urinary retention,angle-closure glaucoma, increasedintraocular pressure, and in patients takinganticholinergicmedication.

Impaired Hepatic Function

The plasma concentration of cyclobenzaprine is increased in patients with hepatic impairment (seeCLINICAL PHARMACOLOGY,Pharmacokinetics,Hepatic Impairment）.

These patients are generally more susceptible to drugs with potentially sedating effects, including cyclobenzaprine. Cyclobenzaprine HCl should be used with caution in subjects with mild hepatic impairment starting with a 5 mg dose and titrating slowly upward. Due to the lack of data in subjects with more severe hepatic insufficiency, the use of Fexmid in subjects with moderate to severe impairment is not recommended.

Carcinogenesis, Mutagenesis, Impairment Of Fertility

In rats treated with cyclobenzaprine HCl 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 doserelated hepatocyte vacuolation with lipidosis. In the higher dose groups thismicroscopicchange 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 ofneoplasiain 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

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 cyclobenzaprine HCl. 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.

Nursing Mothers

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 cyclobenzaprine HCl is administered to a nursing woman.

Pediatric Use

Safety and effectiveness of Fexmid in pediatric patients below 15 years of age have not been established.

Use In The Elderly

The plasma concentration of cyclobenzaprine is increased in the elderly (seeCLINICAL PHARMACOLOGY,Pharmacokinetics,Elderly）.The elderly may also be more at risk for CNS adverse events such as hallucinations and confusion, cardiac events resulting in falls or othersequelae, drug-drug and drug-disease interactions. For these reasons, in the elderly, Fexmid should be used only if clearly needed. In such patients cyclobenzaprine HCl should be initiated with a 5 mg dose and titrated slowly upward.

OVERDOSE

Although rare, deaths may occur from overdosage with Fexmid. Multiple drug ingestion (including alcohol) is common in deliberate cyclobenzaprine overdose.As management of overdose is complex and changing, it is recommended that the physician contact a poison control center for current information on treatment.Signs and symptoms of toxicity may develop rapidly after Fexmid overdose; therefore, hospital monitoring is required as soon as possible. The acute oral LD₅₀of cyclobenzaprine HCl is approximately 338 and 425 mg/kg in mice and rats, respectively.

Manifestations

The most common effects associated with cyclobenzaprine overdose 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 manifestations of overdose are cardiac arrest, chest pain, cardiac dysrhythmias, severe hypotension, seizures, andneurolepticmalignantsyndrome. Changes in theelectrocardiogram, particularly in QRSaxisor width, are clinically significant indicators of cyclobenzaprine toxicity.

Other potential effects of overdosage include any of the symptoms listed underADVERSE REACTIONS.

Management

General

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

In order to protect against the rare but potentially critical manifestations described above, obtain anECGand immediately initiate cardiac monitoring. Protect the patient’s airway, establish an intravenous line and initiategastricdecontamination. Observation with cardiac monitoring and observation for signs of CNS orrespiratory depression, hypotension, cardiac dysrhythmias and/or conduction blocks, and seizures is necessary. If signs of toxicity occur at any time during this period, extended monitoring is required. Monitoring of plasma drug levels should not guide management of the patient.Dialysisis probably of no value because of low plasma concentrations of the drug.

Gastrointestinal Decontamination

所有患者涉嫌与Fexmid过量should receive gastrointestinal decontamination. This should include large volume gastric lavage followed byactivated charcoal. If consciousness is impaired, the airway should be secured prior to lavage andemesisis contraindicated.

Cardiovascular

A maximal limb-lead QRS duration of ≥0.10 seconds may be the best indication of the severity of the overdose. Serum alkalinization, to a pH of 7.45 to 7.55, using intravenoussodium bicarbonateandhyperventilation(as needed), should be instituted for patients with dysrhythmias and/or QRS widening. A pH>7.60 or a pCO₂<20 mmHg is undesirable. Dysrhythmias unresponsive to sodiumbicarbonate治疗/换气过度可能对利多卡因,bretylium or phenytoin. Type 1A and 1C antiarrhythmics are generally contraindicated (e.g., quinidine, disopyramide, and procainamide).

CNS

In patients with CNS depression, earlyintubationis advised because of the potential for abrupt deterioration. Seizures should be controlled withbenzodiazepinesor, if these are ineffective, other anticonvulsants (e.g. phenobarbital, phenytoin). Physostigmine is not recommended except to treat lifethreatening 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 may attempt suicide by other means during the recovery phase. Psychiatricreferralmay be appropriate.

Pediatric Management

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

CONTRAINDICATIONS

Hypersensitivity to any component of this product.

Concomitant use of monoamine oxidase (MAO) inhibitors or within 14 days after their discontinuation. Hyperpyretic crisis seizures, and deaths have occurred in patients receiving cyclobenzaprine (or structurally similar tricyclic antidepressants) concomitantly withMAO inhibitordrugs.

Acute recovery phase of myocardial infarction, and patients with arrhythmias, heart block or conduction disturbances, orcongestive heart failure.

Hyperthyroidism

CLINICAL PHARMACOLOGY

Fexmid 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 musclehyperactivityin 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 tospinal cordlevels, although its action on the latter may contribute to its overall skeletalmuscle relaxantactivity. Evidence suggests that the net effect of cyclobenzaprine is a reduction of tonicsomaticmotor activity, influencing both gamma (γ) and alpha (α) 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.

Pharmacokinetics

Estimates of mean oral bioavailability of cyclobenzaprine range from 33% to 55%. Cyclobenzaprine exhibits linear pharmacokinetics over the dose range 2.5 mg to 10 mg, and is subject to enterohepaticcirculation. It is highly bound to plasma proteins. Drug accumulates when dosed three times a day, reaching steady-state within 3-4 days at plasma concentrations about four-fold higher than after a single dose. At steady state in healthy subjects receiving 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 an 8-hour dosing interval was 177 ng.hr/mL (range, 80-319 ng.hr/mL).

Cyclobenzaprine is extensively metabolized, and is excreted primarily as glucuronides via the kidney. 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. (SeePRECAUTIONS,Use In The ElderlyandPRECAUTIONS,Impaired Hepatic Function.)

Elderly

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 to 255.3) higher than those seen in a group of eighteen younger adults (101.4 ng.hr/mL, range 36.1 to 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 to 255.3 versus 83.2 ng.hr/mL, range 41.1 to 142.5 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 to 196.3 versus 115.9 ng.hr/mL, range 36.1 to 182.9 for younger females).

In light of these findings, therapy with cyclobenzaprine HCl in the elderly should be initiated with a 5 mg dose and titrated slowly upward.

Hepatic Impairment

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 HCl should be used with caution in subjects with mild hepatic impairment starting with the 5 mg dose and titrating slowly upward. Due to the lack of data in subjects with more severe hepatic insufficiency, the use of Fexmid in subjects with moderate to severe impairment is not recommended.

No significant effect on plasma levels or bioavailability of cyclobenzaprine HCl or aspirin was noted when single or multiple doses of the two drugs were administered concomitantly. Concomitant administration of cyclobenzaprine HCl and naproxen or diflunisal was well tolerated with no reported unexpected adverse effects. However combination therapy of cyclobenzaprine HCl with naproxen was associated with more side effects than therapy with naproxen alone, primarily in the form of drowsiness. No well-controlled studies have been performed to indicate that cyclobenzaprine HCl enhances the clinical effect of aspirin or other analgesics, or whether analgesics enhance the clinical effect of cyclobenzaprine HCl in acute musculoskeletal conditions.

Clinical Studies

Eight double-blind controlled clinical studies were performed in 642 patients comparing cyclobenzaprine HCl 10 mg, diazepam**, and placebo. Muscle spasm, local pain and tenderness, limitation of motion, and restriction inactivities of daily livingwere evaluated. In three of these studies there was a significantly greater improvement with cyclobenzaprine HCl 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 cyclobenzaprine HCl were comparable to those observed in patients treated with diazepam, dry mouth was observed more frequently in patients treated with cyclobenzaprine HCl and dizziness more frequently in those treated with diazepam. The incidence of drowsiness, the most frequent adverse reaction, was similar with both drugs.

The efficacy of cyclobenzaprine HCl 5 mg was demonstrated in two seven-day, double-blind, controlled clinical trials enrolling 1405 patients. One study compared cyclobenzaprine HCl 5 and 10 mgt.i.d.to placebo; and a second study compared cyclobenzaprine HCl 5 and 2.5 mg t.i.d. to placebo. Primary endpoints for both trials were determined by patient-generated data and included global impression of change, medication helpfulness, and relief from starting backache. Each endpoint consisted of a score on a 5-point rating scale (from 0 or worst outcome to 4 or best outcome). Secondary endpoints included a physician’s evaluation of the presence and extent ofpalpablemuscle spasm.

Comparisons of cyclobenzaprine HCl 5 mg and placebo groups in both trials established the statistically significant superiority of the 5 mg dose for all three primary endpoints at day 8 and, in the study comparing 5 and 10 mg, at day 3 or 4 as well. A similar effect was observed with cyclobenzaprine HCl 10 mg (all endpoints). Physician-assessed secondary endpoints also showed that cyclobenzaprine HCl 5 mg was associated with a greater reduction in palpable muscle spasm than placebo.

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

Surveillance Program

A postmarketing surveillance program was carried out in 7607 patients with acute musculoskeletal disorders, and included 297 patients treated with cyclobenzaprine HCl 10 mg for 30 days or longer. The overall effectiveness of cyclobenzaprine HCl was similar to that observed in the double-blind controlled studies; the overall incidence of adverse effects was less (seeADVERSE REACTIONS）.

PATIENT INFORMATION

Fexmid, especially when used with alcohol or other CNS depressants, may impair mental and/or physical abilities required for performance of hazardous tasks, such as operating machinery or driving a motor vehicle. In the elderly, the frequency and severity of adverse events associated with the use of cyclobenzaprine, with or without concomitant medications, is increased. In elderly patients, cyclobenzaprine HCl should be initiated with a 5 mg dose and titrated slowly upward.

Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of Cyclobenzaprine Hydrochloride and other drugs, such as SSRIs, SNRIs, TCAs, tramadol, bupropion, meperidine, verapamil, or MAO inhibitors. Patients should be advised of the signs and symptoms of serotonin syndrome, and be instructed to seek medical care immediately if they experience these symptoms (see警告, and seeDRUG INTERACTIONS）.