Cyclobenzaprine Hydrochloride

INDICATIONS AND USAGE Cyclobenzaprine hydrochloride tablets 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, limitation of motion, and restriction in activities of daily living. Cyclobenzaprine hydrochloride tablets 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 has not been found effective in the treatment of spasticity associated with cerebral or spinal cord disease, or in children with cerebral palsy.

DOSAGE & ADMINISTRATION For most patients, the recommended dose of cyclobenzaprine hydrochloride tablets USP is 5 mg three times a day. Based on individual patient response, the dose may be increased to 10 mg three times a day. Use of cyclobenzaprine hydrochloride tablets USP for periods longer than two or three weeks is not recommended. (see INDICATIONS AND USAGE ). Less frequent dosing should be considered for hepatically impaired or elderly patients (see PRECAUTIONS : Impaired Hepatic Function, and Use in the Elderly ).

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 with MAO inhibitor drugs. Acute recovery phase of myocardial infarction, and patients with arrhythmias, heart block or conduction disturbances, or congestive heart failure. Hyperthyroidism.

ADVERSE REACTIONS Incidence of most common adverse reactions in the 2 double-blind 3 , placebo-controlled 5 mg studies (incidence of > 3% on cyclobenzaprine hydrochloride 5 mg): Cyclobenzaprine Hydrochloride 5 mg Cyclobenzaprine Hydrochloride 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% 3 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, 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 hydrochloride 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 post-marketing 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 hydrochloride 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 : 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; a …

DESCRIPTION Cyclobenzaprine hydrochloride, USP, a skeletal muscle relaxant, is a white, crystalline tricyclic amine salt with the empirical formula C 20 H 21 N•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, N-dimethyl-1-propanamine hydrochloride, and has the following structural formula: Cyclobenzaprine hydrochloride USP, 5 mg is supplied as a 5 mg tablet for oral administration. Cyclobenzaprine hydrochloride USP, 7.5 mg is supplied as a 7.5 mg tablet for oral administration. Cyclobenzaprine hydrochloride USP, 10 mg is supplied as a 10 mg tablet for oral administration. Each 5 mg, 7.5 mg and 10 mg tablet contains cyclobenzaprine hydrochloride and the following inactive ingredients: colloidal silicon dioxide, crospovidone, lactose anhydrous, magnesium stearate, microcrystalline cellulose, OPADRY Orange, OPADRY White, pregelatinized starch, purified water. Opadry components: D&C Yellow #10 Aluminum Lake, FD&C Blue #2/Indigo carmine Aluminum Lake, FD&C Yellow #6/Sunset Yellow FGF Aluminum Lake, Hypromellose, polyethylene glycol/macrogol, red iron oxide, talc, titanium dioxide. FDA approved dissolution specifications differ from that of the USP. image

OVERDOSAGE Although rare, deaths may occur from overdosage with cyclobenzaprine hydrochloride. 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 cyclobenzaprine overdose; therefore, hospital monitoring is required as soon as possible. The acute oral LD 50 of cyclobenzaprine hydrochloride 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, and neuroleptic malignant syndrome. Changes in the electrocardiogram, particularly in QRS axis or width, are clinically significant indicators of cyclobenzaprine toxicity. Other potential effects of overdosage include any of the symptoms listed under ADVERSE 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 an ECG and immediately initiate cardiac monitoring. Protect the patient's airway, establish an intravenous line and initiate gastric decontamination. Observation with cardiac monitoring and observation for signs of CNS or respiratory 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. Dialysis is probably of no value because of low plasma concentrations of the drug. Gastrointestinal Decontamination All patients suspected of an overdose with cyclobenzaprine hydrochloride should receive gastrointestinal decontamination. This should include large volume gastric lavage followed by activated charcoal. If consciousness is impaired, the airway should be secured prior to lavage and emesis is 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 intravenous sodium bicarbonate and hyperventilation (as needed), should be instituted for patients with dysrhythmias and/or QRS widening. A pH >7.60 or a pCO 2 <20 mmHg is undesirable. Dysrhythmias unresponsive to sodium bicarbonate therapy/hyperventilation may respond to lidocaine, bretylium or phenytoin. Type 1A and 1C antiarrhythmics are generally contraindicated (e.g., quinidine, disopyramide, and procainamide). CNS In patients with CNS depression, early intubation is advised because of the potential for abrupt deterioration. Seizures should be controlled with benzodiazepines or, if these are ineffective, other anticonvulsants (e.g. phenobarbital, phenytoin). Physostigmine is not recommended except to treat 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 may attempt suicide by other means during the recovery phase. Psychiatric referral may 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.

HOW SUPPLIED Cyclobenzaprine hydrochloride tablets, USP 5 mg are available as yellow to orange colored, round shaped, biconvex coated tablets debossed with "C5" on one side and "Gr" on the other side. Tablets are supplied in bottles of: Bottles of 100 Tablets with child-resistant closure NDC 64980-655-01 Bottles of 500 Tablets NDC 64980-655-50 Bottles of 1,000 Tablets NDC 64980-655-10 Cyclobenzaprine hydrochloride tablets, USP 7.5 mg are available as white to off-white, round shaped, biconvex coated tablets debossed with "C7.5" on one side and "Gr" on the other side. Tablets are supplied in bottles of: Bottles of 100 Tablets with child-resistant closure NDC 64980-656-01 Bottles of 500 Tablets NDC 64980-656-50 Cyclobenzaprine hydrochloride tablets, USP 10 mg are available as yellow to orange colored, round shaped, biconvex coated tablets debossed with "C10" on one side and "Gr" on the other side. Tablets are supplied in bottles of: Bottles of 100 Tablets with child-resistant closure NDC 64980-657-01 Bottles of 500 Tablets NDC 64980-657-50 Bottles of 1,000 Tablets NDC 64980-657-10