Cyclobenzaprine Hydrochloride 7.5 mg Tablet, Film Coated, 30-count — NDC 69420-1001-3 (Billing 69420-1001-03)

WARNINGS 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 serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), tramadol, bupropion, meperidine, verapamil, or MAO inhibitors. The concomitant use of cyclobenzaprine hydrochloride with MAO inhibitors is contraindicated (see CONTRAINDICATIONS ). Serotonin syndrome symptoms may include mental status changes (e.g., confusion, agitation, hallucinations), autonomic instability (e.g., diaphoresis, tachycardia, labile blood pressure, hyperthermia), neuromuscular abnormalities (e.g., tremor, ataxia, hyperreflexia, clonus, muscle rigidity), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).

Treatment with cyclobenzaprine hydrochloride and any concomitant serotonergic agents should be discontinued immediately if the above reactions occur and supportive symptomatic treatment should be initiated. If concomitant treatment with cyclobenzaprine hydrochloride and other serotonergic drugs is clinically warranted, careful observation is advised, particularly during treatment initiation or dose increases (see PRECAUTIONS : Drug Interactions ). 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 WARNINGS , below, and ADVERSE REACTIONS ). Tricyclic antidepressants have been reported to produce arrhythmias, sinus tachycardia, prolongation of the conduction time leading to myocardial infarction and stroke.

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

ADVERSE REACTIONS Incidence of most common adverse reactions in the two double-blind*, placebo-controlled 5 mg studies (incidence of >3% on cyclobenzaprine hydrochloride 5 mg): Cyclobenzaprine Hydrochloride 5 mg N=464 Cyclobenzaprine Hydrochloride 10 mg N=249 Placebo N=469 Drowsiness 29% 38% 10% Dry Mouth 21% 32% 7% Fatigue 6% 6% 3% Headache 5% 5% 8% *Note: Cyclobenzaprine hydrochloride 10 mg data are from one clinical trial. Cyclobenzaprine hydrochloride 5 mg and placebo data are from two studies. Adverse reactions which were reported in 1% to 3% of the patients were: abdominal pain, acid regurgitation, constipation, diarrhea, dizziness, nausea, irritability, mental acuity decreased, nervousness, upper respiratory infection, and pharyngitis.

The following list of adverse reactions is based on the experience in 473 patients treated with cyclobenzaprine hydrochloride 10 mg in additional controlled clinical studies, 7,607 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 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: Clinical Studies with Cyclobenzaprine Hydrochloride 10 mg Surveillance Program with Cyclobenzaprine Hydrochloride 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; 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: 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, serotonin syndrome.

Skin: Sweating. Special Senses: Ageusia; tinnitus. Urogenital: Urinary frequency and/or retention.

Causal Relationship Unknown Other reactions, reported rarely for cyclobenzaprine 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 W hole: 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’s palsy; alteration in EEG patterns; extrapyramidal symptoms. Respiratory: Dyspnea.

Skin: Photosensitization; alopecia. Urogenital: Impaired urination; dilatation o… [Excerpted — this section continues on DailyMed.]

Drug Interactions Cyclobenzaprine may have life-threatening interactions with MAO inhibitors (see CONTRAINDICATIONS ). 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 cyclobenzaprine hydrochloride and other serotonergic drugs is clinically warranted, careful observation is advised, particularly during treatment initiation or dose increases (see WARNINGS ).

Cyclobenzaprine 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 in patients taking tramadol.

PRECAUTIONS General Because of its atropine-like action, cyclobenzaprine 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. Impaired Hepatic Function The plasma concentration of cyclobenzaprine is increased in patients with hepatic impairment (see CLINICAL PHARMACOLOGY : Pharmacokinetics : Hepatic Impairment ). These patients are generally more susceptible to drugs with potentially sedating effects, including cyclobenzaprine.

Cyclobenzaprine hydrochloride 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 cyclobenzaprine in subjects with moderate to severe impairment is not recommended. Information for P atients Cyclobenzaprine, 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 hydrochloride 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 WARNINGS and PRECAUTIONS : Drug Interactions ). Drug Interactions Cyclobenzaprine may have life-threatening interactions with MAO inhibitors (see CONTRAINDICATIONS ). 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 cyclobenzaprine hydrochloride and other serotonergic drugs is clinically warranted, careful observation is advised, particularly during treatment initiation or dose increases (see WARNINGS ). Cyclobenzaprine 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 in patients taking tramadol. Carcinogenesis, Mutagenesis, Impairment of F ertility In rats treated with cyclobenzaprine 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 Teratogenic Effects. 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. There are, however, no adequate and well-controlled studies in pregnant women.

Because animal reproduction studies are n… [Excerpted — this section continues on DailyMed.]

DRUG ABUSE AND DEPENDENCE Pharmacologic similarities among the tricyclic drugs require that certain withdrawal symptoms be considered when cyclobenzaprine 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.