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warnings and cautions
5 WARNINGS AND PRECAUTIONS Serotonin syndrome has been reported with cyclobenzaprine when used in combination with other serotonergic drugs ( ) • 5.1 Cyclobenzaprine is structurally related to tricyclic antidepressants which have been reported to produce adverse cardiovascular effects or CNS depressant effects ( ) • 5.2 Use in the elderly is not recommended ( ) • 5.3 Use in patients with hepatic impairment is not recommended ( ) • 5.4 Use with caution in patients with a history of urinary retention, angle-closure glaucoma, increased intraocular pressure and in patients taking anticholinergic medications ( ) • 5.5 5.2 Tricyclic Antidepressant-like Effects Cyclobenzaprine is structurally related to the tricyclic antidepressants, e.g., amitriptyline and imipramine. Tricyclic antidepressants have been reported to produce arrhythmias, sinus tachycardia, prolongation of the conduction time leading to myocardial infarction and stroke . AMRIX may enhance the effects of alcohol, barbiturates, and other CNS depressants. [see Contraindications (4)] Some of the more serious central nervous system (CNS) reactions noted with the tricyclic antidepressants have occurred in short-term studies of cyclobenzaprine for indications other than muscle spasm associated with acute musculoskeletal conditions, and usually at doses somewhat greater than those recommended for skeletal muscle spasm. If clinically significant CNS symptoms develop, consider discontinuation of AMRIX. 5.3 Use in the Elderly As a result of a 40% increase in cyclobenzaprine plasma levels and a 56% increase in plasma half-life following administration of AMRIX in elderly subjects as compared to young adults, use of AMRIX is not recommended in the elderly. [ ] See Clinical Pharmacology (12.3) 5.4 Use in Patients with Hepatic Impairment As a result of two-fold higher cyclobenzaprine plasma levels in subjects with mild hepatic impairment, as compared to healthy subjects, following administration of immediate-release cyclobenzaprine and because there is limited dosing flexibility with AMRIX, use of AMRIX is not recommended in patients with mild, moderate or severe hepatic impairment. [ ] See Clinical Pharmacology (12.3) 5.5 Atropine-like Action Because of its atropine-like action, AMRIX 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.
warnings and cautions
5.5 Atropine-like Action Because of its atropine-like action, AMRIX 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.
6 ADVERSE REACTIONS Most Common Adverse Reactions in the AMRIX Clinical Trials Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The data described below reflect exposure to AMRIX in 253 patients in 2 clinical trials. AMRIX was studied in two double-blind, parallel-group, placebo-controlled, active-controlled trials of identical design . The study population was composed of patients with muscle spasms associated with acute painful musculoskeletal conditions. Patients received 15 mg or 30 mg of AMRIX taken orally once daily, cyclobenzaprine immediate-release (IR) 10 mg three times a day, or placebo for 14 days. [see Clinical Studies (14)] The most common adverse reactions (incidence ≥3% in any treatment group and greater than placebo) were dry mouth, dizziness, fatigue, constipation, nausea, dyspepsia, and somnolence (see Table 1). Table 1: Incidence of the Most Common Adverse Reactions Occurring in ≥ 3% of Patients in any Treatment Group* and Greater Than Placebo in the Two Phase 3, Double-Blind AMRIX Trials Placebo AMRIX 15 mg AMRIX 30 mg N=128 N=127 N=126 Dry mouth 2% 6% 14% Dizziness 2% 3% 6% Fatigue 2% 3% 3% Constipation 0% 1% 3% Somnolence 0% 1% 2% Nausea 1% 3% 3% Dyspepsia 1% 0% 4% *AMRIX 15 mg QD, AMRIX 30 mg QD, or cyclobenzaprine IR tablets TID Additional Adverse Reactions from Clinical Studies and Postmarketing Experience The following adverse reactions have been reported in clinical studies or postmarketing experience with AMRIX, cyclobenzaprine IR, or tricyclic drugs. Because some of these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. In a postmarketing surveillance program of cyclobenzaprine IR, the adverse reactions reported most frequently were drowsiness, dry mouth, and dizziness and adverse reactions 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 (AMRIX or cyclobenzaprine IR), in clinical studies of cyclobenzaprine IR (incidence <1%), or in postmarketing experience with other tricyclic drugs: Syncope; malaise; chest pain; edema. Body as a Whole: Tachycardia; arrhythmia; vasodilatation; palpitation; hypotension; hypertension; myocardial infarction; heart block; stroke. Cardiovascular: Vomiting; anorexia; diarrhea; gastrointestinal pain; gastritis; thirst; flatulence; edema of the tongue; abnormal liver function and rare reports of hepatitis, jaundice, and cholestasis; paralytic ileus, tongue discoloration; stomatitis; parotid swelling. Digestive: Inappropriate ADH syndrome. Endocrine: Purpura; bone marrow depression; leukopenia; eosinophilia; thrombocytopenia. Hematologic and Lymphatic: Anaphylaxis; angioedema; pruritus; facial edema; urticaria; rash. Hypersensitivity: Elevation and lowering of blood sugar levels; weight gain or loss. Metabolic, Nutritional and Immune: Local weakness; myalgia. Musculoskeletal: 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; neuroleptic malignant syndrome; decreased or increased libido; abnormal gait; delusions; aggressive behavior; paranoia; peripheral neuropathy; Bell’s palsy; alteration in EEG patterns; extrapyramidal symptoms. Nervous System and Psychiatric: Dyspnea. Respiratory: Sweating; photosensitization; alopecia. Skin: Ageusia; tinnitus. Special Senses: Urinary frequency and/or retention; impaired urination; dilatation of urinary tract; impotence; testicular swelling; gynecomastia; breast enlargement; galactorrhea. Urogenital: Most common adverse reactions (incidence ≥3% in any treatment group and greater than placebo): dry mouth, dizziness, fatigue, constipation, nausea, dyspepsia, and somnolence ( ) 6 To report SUSPECTED ADVERSE REACTIONS, contact Teva Pharmaceuticals at 1-800-896-5855 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.