Cyclobenzaprine Hydrochloride

1 INDICATIONS AND USAGE 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. Cyclobenzaprine hydrochloride extended-release capsules are a muscle relaxant 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. ( 1 ) Limitations of Use: • Cyclobenzaprine hydrochloride extended-release capsules should be used only for short periods (up to 2 or 3 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. ( 1 ) • 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. ( 1 )

2 DOSAGE AND ADMINISTRATION 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. • Recommended adult dose for most patients is 15 mg taken once daily. Some patients may require 30 mg taken once daily ( 2 ) • Recommended to take doses at approximately same time each day ( 2 ) • Instruct patients to swallow cyclobenzaprine hydrochloride extended-release capsules intact or to sprinkle capsule contents on a tablespoon of applesauce and swallow immediately without chewing ( 2 ) • Use for periods longer than 2 or 3 weeks is not recommended ( 2 )

3 DOSAGE FORMS & STRENGTHS Extended-release capsules in the following strengths: • 15 mg: Size ‘4’ capsule, containing white to off white pellets, having orange cap, orange body with ‘T39’ imprinted on the cap and ‘15 mg’ imprinted on the body with black ink. • 30 mg: Size ‘4’ capsule, containing white to off white pellets, having orange cap, Blue body with ‘T40’ imprinted on the cap and ‘30 mg’ imprinted on the body with white ink. • Extended-release capsules: 15 and 30 mg ( 3 )

4 CONTRAINDICATIONS • 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. • Hypersensitivity to any component of this product (4) • Concomitant use of monoamine oxidase (MAO) inhibitors or within 14 days after their discontinuation (4) • During acute recovery phase of myocardial infarction, and in patients with arrhythmias, heart block or conduction disturbances, or congestive heart failure (4) • Hyperthyroidism (4)

6 ADVERSE REACTIONS 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 )] 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 Macleods Pharma USA, Inc., at 1-888-943-3210 or 1-855-926-3384 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 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 …

7 DRUG INTERACTIONS 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)] . • MAO Inhibitors: Life-threatening interactions may occur ( 4 , 7 ) • Serotonergic Drugs: Serotonin syndrome has been reported ( 5.1 , 7 ) • CNS Depressants: Effects of alcohol, barbiturates, and other CNS depressants may be enhanced ( 5.2 , 7 ) • Tramadol: Seizure risk may be enhanced ( 7 ) • Guanethidine: Antihypertensive effect may be blocked ( 7 )

8 USE IN SPECIFIC POPULATIONS 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/m 2 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/m 2 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 )].

12.1 Mechanism of Action Cyclobenzaprine relieves skeletal muscle spasm of local origin without interfering with muscle function. Cyclobenzaprine has not been shown to be effective in muscle spasm due to central nervous system disease. In animal models, cyclobenzaprine reduced or abolished skeletal muscle hyperactivity. 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 the brain stem as opposed to the spinal cord level, although an overlapping action on the latter may contribute to its overall skeletal muscle relaxant activity. Evidence suggests that the net effect of cyclobenzaprine is a reduction of tonic somatic motor activity, influencing both gamma (γ) and alpha (α) motor systems. Pharmacological studies in animals demonstrated 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.

11 DESCRIPTION Cyclobenzaprine hydrochloride extended-release capsules USP are skeletal muscle relaxant which relieves muscle spasm of local origin without interfering with muscle function. The active ingredient in cyclobenzaprine hydrochloride extended-release capsules is cyclobenzaprine hydrochloride, USP. Cyclobenzaprine hydrochloride (HCl) 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 pK a 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 extended-release capsules for oral administration are supplied in 15 and 30 mg strengths. Cyclobenzaprine hydrochloride extended-release capsules contain the following inactive ingredients: colloidal silicon dioxide, ethyl alcohol, ethylcellulose, FDC yellow #6, gelatin, hydroxypropyl cellulose, isopropyl alcohol, potassium hydroxide, sugar spheres (which contain sucrose and corn starch) and titanium dioxide. In addition, red iron oxide is also included in the 15 mg strength. The capsule is imprinted with black ink consisting of: black iron oxide, DC Yellow #10, ethanol, FDC Blue #1, FDC Blue #2, FDC Red #40, methanol, N-butyl alcohol, propylene glycol, and shellac. Structural Formula

10 OVERDOSAGE Clinical Presentation Although rare, deaths may occur from overdosage with cyclobenzaprine hydrochloride extended-release capsules. 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 most common effects associated with cyclobenzaprine overdose are drowsiness and tachycardia. Less frequent symptoms include tremor, agitation, coma, ataxia, hypertension, slurred speech, confusion, dizziness, nausea, vomiting, and hallucinations. Rare but potentially critical symptoms of overdose are cardiac arrest, chest pain, cardiac dysrhythmias, severe hypotension, seizures, cases of neuroleptic malignant syndrome and rhabdomyolysis have been reported. 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 ( 6 ) . Treatment of Overdose 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 symptoms 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 extended-release capsules 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 overdosage are similar. It is strongly recommended that the physician contact the local poison control center for specific pediatric treatment.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Cyclobenzaprine hydrochloride extended-release capsules USP are available in 15 and 30 mg strengths, packaged in bottles of 60 capsules. Cyclobenzaprine hydrochloride extended-release capsules USP, 15 mg are available as hard gelatin capsule with dark orange opaque cap and red opaque body imprinted with “T035” in black ink. They are supplied as follows: Bottle of 30 NDC 76420-895-30 (repackaged from NDC 24979-035-04) Bottle of 60 NDC 76420-895-60 (relabeled from NDC 24979-035-04) Bottle of 90 NDC 76420-895-90 (repackaged from NDC 24979-035-04) Bottle of 100 NDC 76420-895-01 (repackaged from NDC 24979-035-04) Cyclobenzaprine hydrochloride extended-release capsules USP, 30 mg are available as hard gelatin capsule with orange opaque cap and white opaque body imprinted with “T036” in black ink. They are supplied as follows: Bottle of 30 NDC 76420-896-30 (repackaged from NDC 24979-036-04) Bottle of 60 NDC 76420-896-60 (relabeled from NDC 24979-036-04) Bottle of 90 NDC 76420-896-90 (repackaged from NDC 24979-036-04) Bottle of 100 NDC 76420-896-01 (repackaged from NDC 24979-036-04) 16.2 Storage and Handling Dispense in a tight, light-resistant container as defined in the USP/NF. Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].

16.1 How Supplied Cyclobenzaprine hydrochloride extended-release capsules USP are available in 15 and 30 mg strengths, packaged in bottles of 60 capsules. Cyclobenzaprine hydrochloride extended-release capsules USP, 15 mg are available as hard gelatin capsule with dark orange opaque cap and red opaque body imprinted with “T035” in black ink. They are supplied as follows: Bottle of 30 NDC 76420-895-30 (repackaged from NDC 24979-035-04) Bottle of 60 NDC 76420-895-60 (relabeled from NDC 24979-035-04) Bottle of 90 NDC 76420-895-90 (repackaged from NDC 24979-035-04) Bottle of 100 NDC 76420-895-01 (repackaged from NDC 24979-035-04) Cyclobenzaprine hydrochloride extended-release capsules USP, 30 mg are available as hard gelatin capsule with orange opaque cap and white opaque body imprinted with “T036” in black ink. They are supplied as follows: Bottle of 30 NDC 76420-896-30 (repackaged from NDC 24979-036-04) Bottle of 60 NDC 76420-896-60 (relabeled from NDC 24979-036-04) Bottle of 90 NDC 76420-896-90 (repackaged from NDC 24979-036-04) Bottle of 100 NDC 76420-896-01 (repackaged from NDC 24979-036-04)