Cyclobenzaprine HCL ER

Cyclobenzaprine hydrochloride extended-release capsules are 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, and limitation of motion. Limitations of Use: Cyclobenzaprine hydrochloride extended-release capsules 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. Cyclobenzaprine hydrochloride extended-release capsules have not been found effective in the treatment of spasticity associated with cerebral or spinal cord disease or in children with cerebral palsy.

The recommended adult dose for most patients is one (1) cyclobenzaprine hydrochloride extended-release 15 mg capsule taken once daily. Some patients may require up to 30 mg/day, given as one (1) cyclobenzaprine hydrochloride extended-release 30 mg capsule taken once daily or as two (2) cyclobenzaprine hydrochloride extended-release 15 mg capsules taken once daily. It is recommended that doses be taken at approximately the same time each day. Use of cyclobenzaprine hydrochloride extended-release capsules for periods longer than two or three weeks is not recommended [SEE INDICATIONS AND USAGE (1)]. Instruct patients to swallow cyclobenzaprine hydrochloride extended-release capsules intact. Alternatively, the contents of the cyclobenzaprine hydrochloride extended-release capsule may be sprinkled over applesauce and then swallowed. This method is appropriate only for patients able to reliably swallow the applesauce without chewing. Other foods have not been tested and should not be substituted for applesauce. Instruct the patient to: Sprinkle the contents of the capsule onto a tablespoon of applesauce and consume immediately without chewing. Rinse the mouth to ensure all of the contents have been swallowed. Discard any unused portion of the cyclobenzaprine hydrochloride extended-release capsules after the contents have been sprinkled on applesauce.

Hypersensitivity to any component of this product. These adverse reactions may manifest as an anaphylactic reaction, urticaria, facial and/or tongue swelling, or pruritus. Discontinue cyclobenzaprine hydrochloride extended-release capsules if a hypersensitivity reaction is suspected. 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 with MAO inhibitor drugs. During the acute recovery phase of myocardial infarction, and in patients with arrhythmias, heart block or conduction disturbances, or congestive heart failure. Hyperthyroidism.

5.1 Serotonin Syndrome The development of a potentially life-threatening serotonin syndrome has been reported with cyclobenzaprine 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 extended-release capsules with MAO inhibitors is contraindicated [SEE CONTRAINDICATIONS (4)]. 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 extended-release capsules 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 extended-release capsules and other serotonergic drugs is clinically warranted, careful observation is advised, particularly during treatment initiation or dose increases. 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 [SEE CONTRAINDICATIONS (4)]. Cyclobenzaprine hydrochloride extended-release capsules may enhance the effects of alcohol, barbiturates, and other CNS depressants. 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 cyclobenzaprine hydrochloride extended-release capsules. 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 cyclobenzaprine hydrochloride extended-release capsules in elderly subjects as compared to young adults, use of cyclobenzaprine hydrochloride extended-release capsules 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 cyclobenzaprine hydrochloride extended-release capsules, use of cyclobenzaprine hydrochloride extended-release capsules 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, cyclobenzaprine hydrochloride extended-release capsules 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.

Based on its structural similarity to tricyclic antidepressants, cyclobenzaprine hydrochloride extended-release capsules may have life-threatening interactions with MAO inhibitors [SEE CONTRAINDICATIONS (4)], may enhance the effects of alcohol, barbiturates, and other CNS depressants, may enhance the seizure risk in patients taking tramadol, or may block the antihypertensive action of guanethidine and similarly acting compounds. Postmarketing cases of serotonin syndrome have been reported during combined use of cyclobenzaprine and other drugs, such as SSRIs, SNRIs, TCAs, tramadol, bupropion, meperidine, verapamil, or MAO inhibitors [SEE WARNINGS AND PRECAUTIONS (5.1)].

The following clinically significant reactions are described in greater detail, in other sections. Serotonin Syndrome [see Warnings and Precautions (5.1)] Adverse Cardiovascular Effects [see Warnings and Precautions (5.2)] 6.1 Clinical Trials Experience 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 cyclobenzaprine hydrochloride extended-release capsules in 253 patients in 2 clinical trials. Cyclobenzaprine hydrochloride extended-release capsules were studied in two double-blind, parallel-group, placebo-controlled, active-controlled trials of identical design [SEE CLINICAL STUDIES (14)]. The study population was composed of patients with muscle spasms associated with acute painful musculoskeletal conditions. Patients received 15 mg or 30 mg of cyclobenzaprine hydrochloride extended-release capsules taken orally once daily, cyclobenzaprine immediate-release (IR) 10 mg three times a day, or placebo for 14 days. 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 Cyclobenzaprine Hydrochloride Extended-Release Capsules Trials Placebo Cyclobenzaprine Hydrochloride Extended-Release Capsules 15 mg Cyclobenzaprine Hydrochloride Extended-Release Capsules 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% *cyclobenzaprine hydrochloride extended-release capsules 15 mg QD, cyclobenzaprine hydrochloride extended-release capsules 30 mg QD, or cyclobenzaprine IR tablets TID 6.2 Postmarketing Experience The following adverse reactions have been reported in clinical studies or postmarketing experience with cyclobenzaprine hydrochloride extended-release capsules, 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 (cyclobenzaprine hydrochloride extended-release capsules or cyclobenzaprine IR), in clinical studies of cyclobenzaprine IR (incidence <1%), or in postmarketing experience with other tricyclic drugs: Body as a Whole: Syncope; malaise; chest pain; edema. Cardiovascular: Tachycardia; arrhythmia; vasodilatation; palpitation; hypotension; hypertension; myocardial infarction; heart block; stroke. Digestive: 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. Endocrine: Inappropriate ADH syndrome. Hematologic and Lymphatic: Purpura; bone marrow depression; leukopenia; eosinophilia; thrombocytopenia. Hypersensitivity: Anaphylaxis; angioedema; pruritus; facial edema; urticaria; rash. Metabolic, Nutritional, and Immune: Elevation and lowering of blood sugar levels; weight gain or loss. Musculoskeletal: Local weakness; myalgia. 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; neuroleptic malignant syndrome; decreased or increased libido; abnormal gait; delusions; aggressive behavior; paranoia; peripheral neuropathy; Bell’s palsy; alteration in EEG patterns; extrapyramidal symptoms. Respiratory: Dyspnea. Skin: Sweating; photosensitization; alopecia. Special Senses: Ageusia; tinnitus. Urogenital: Urinary frequency and/or retention; impaired urination; dilatation of urinary tract; impotence; testicular swelling; gynecomastia; breast enlargement; galactorrhea.

8.1 Pregnancy Risk Summary Available data from case reports with cyclobenzaprine hydrochloride extended-release capsules use in pregnancy have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In rats, decreased pup body weight and survival was noted at cyclobenzaprine doses ≥10 mg/kg/day (approximately ≥3 times the maximum recommended human dose (MRHD) of 30 mg/day), when administered orally during pregnancy and lactation (see Data). The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data No adverse embryofetal effects were reported following oral administration of cyclobenzaprine during organogenesis to mice and rabbits at maternal doses up to 20 mg/kg/day (approximately 3 and 15 times the MRHD, respectively, on a mg/m2 basis). Maternal toxicity characterized by decreased body weight gain was observed only in mice at the highest tested dose of 20 mg/kg/day. Decreased pup body weight and survival were reported in a prenatal and postnatal study where pregnant rats were treated orally with cyclobenzaprine during pregnancy and lactation with maternal doses of 10 and 20 mg/kg/day (approximately 3 and 6 times the MRHD on a mg/m2 basis). Maternal toxicity, characterized by a decreased body weight gain, was observed only at the highest tested dose of 20 mg/kg/day. 8.2 Lactation Risk Summary There are no data on the presence of cyclobenzaprine in either human or animal milk, the effects on a breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for cyclobenzaprine hydrochloride extended-release capsules and any potential adverse effects on the breastfed child from cyclobenzaprine hydrochloride extended-release capsules or from the underlying maternal condition. 8.4 Pediatric Use Safety and effectiveness of cyclobenzaprine hydrochloride extended-release capsules have not been studied in pediatric patients. 8.5 Geriatric Use Clinical studies of cyclobenzaprine hydrochloride extended-release capsules did not include sufficient numbers of patients aged 65 and over to determine the safety and efficacy of cyclobenzaprine hydrochloride extended-release capsules in the elderly population. The plasma concentration and half-life of cyclobenzaprine are substantially increased in the elderly when compared to the general patient population. Accordingly, use of cyclobenzaprine hydrochloride extended-release capsules is not recommended in the elderly [SEE WARNINGS AND PRECAUTIONS (5.3) AND CLINICAL PHARMACOLOGY (12.3)]. 8.6 Hepatic Impairment The use of cyclobenzaprine hydrochloride extended-release capsules is not recommended in patients with mild, moderate, or severe hepatic impairment [SEE WARNINGS AND PRECAUTIONS (5.4) and CLINICAL PHARMACOLOGY (12.3)].