AMRIX

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 Teva Pharmaceuticals at 1-888-483-8279 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 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 [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 AMRIX 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 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 6.2 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: 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.

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 AMRIX 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)

11 DESCRIPTION AMRIX is a skeletal muscle relaxant which relieves muscle spasm of local origin without interfering with muscle function. The active ingredient in AMRIX 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: AMRIX extended-release capsules for oral administration are supplied in 15 and 30 mg strengths. AMRIX capsules contain the following inactive ingredients: diethyl phthalate NF, ethylcellulose NF (Ethocel Standard 10 Premium), gelatin, Opadry ® Clear YS-1-7006, sugar spheres NF (20-25 mesh), and titanium dioxide. AMRIX 15 mg capsules also contain D&C yellow #10, FD&C green #3, and FD&C red #40. AMRIX 30 mg capsules also contain FD&C blue #1, FD&C blue #2, FD&C red #40, and FD&C yellow #6. Structural Formula

2 DOSAGE AND ADMINISTRATION The recommended adult dose for most patients is one (1) AMRIX 15 mg capsule taken once daily. Some patients may require up to 30 mg/day, given as one (1) AMRIX 30 mg capsule taken once daily or as two (2) AMRIX 15 mg capsules taken once daily. It is recommended that doses be taken at approximately the same time each day. Use of AMRIX for periods longer than two or three weeks is not recommended [ see Indications and Usage (1) ]. Instruct patients to swallow AMRIX capsules intact. Alternatively, the contents of the AMRIX 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 AMRIX 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 AMRIX 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)

1 INDICATIONS AND USAGE AMRIX ® (cyclobenzaprine hydrochloride extended-release capsules) is 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: AMRIX 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. AMRIX has not been found effective in the treatment of spasticity associated with cerebral or spinal cord disease or in children with cerebral palsy. AMRIX is a muscle relaxant indicated as an adjunct to rest and physical therapy for relief of muscle spasm associated with acute, painful musculoskeletal conditions. ( 1 ) Limitations of Use: AMRIX should be used only for short periods (up to 2 or 3 weeks) ( 1 ) AMRIX has not been found effective in the treatment of spasticity or cerebral palsy (1)

9.3 Dependence Pharmacologic similarities among the tricyclic drugs require that certain withdrawal symptoms be considered when AMRIX 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.

9 DRUG ABUSE AND DEPENDENCE 9.3 Dependence Pharmacologic similarities among the tricyclic drugs require that certain withdrawal symptoms be considered when AMRIX 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.

10 OVERDOSAGE 10.1 Manifestations Although rare, deaths may occur from overdosage with AMRIX. 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 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 (6) . 10.2 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 AMRIX 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.

7 DRUG INTERACTIONS Based on its structural similarity to tricyclic antidepressants, AMRIX 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 )

12 CLINICAL PHARMACOLOGY 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. 12.3 Pharmacokinetics Absorption Following single-dose administration of AMRIX 15 mg and 30 mg in healthy adult subjects (n=15) , C max, AUC 0-168h and AUC 0-∞ increased in an approximately dose-proportional manner from 15 mg to 30 mg. The time to peak plasma cyclobenzaprine concentration (T max ) was 7 to 8 hours for both doses of AMRIX. A food effect study conducted in healthy adult subjects (n=15) utilizing a single dose of AMRIX 30 mg demonstrated a statistically significant increase in bioavailability when AMRIX 30 mg was given with food relative to the fasted state. There was a 35% increase in peak plasma cyclobenzaprine concentration (C max ) and a 20% increase in exposure (AUC 0-168h and AUC 0-∞ ) in the presence of food. No effect, however, was noted in T max or the shape of the mean plasma cyclobenzaprine concentration versus time profile. Cyclobenzaprine in plasma was first detectable in both the fed and fasted states at 1.5 hours. When the contents of AMRIX capsules were administered by sprinkling on applesauce, it was found to be bioequivalent to the same dose when administered as an intact capsule. In a multiple-dose study utilizing AMRIX 30 mg administered once daily for 7 days in a group of healthy adult subjects (n=35), a 2.5-fold accumulation of plasma cyclobenzaprine levels was noted at steady-state. Metabolism and Excretion Cyclobenzaprine is extensively metabolized and is excreted primarily as glucuronides via the kidney. Cytochromes P-450 3A4, 1A2, and, to a lesser extent, 2D6, mediate N-demethylation, one of the oxidative pathways for cyclobenzaprine. Cyclobenzaprine has an elimination half-life of 32 hours (range 8-37 hours; n=18); plasma clearance is 0.7 L/min following single-dose administration of AMRIX. Special Populations Elderly Although there were no notable differences in C max or T max , cyclobenzaprine plasma AUC is increased by 40% and the plasma half-life of cyclobenzaprine is prolonged in elderly subjects greater than 65 years of age (50 hours) after dosing with AMRIX compared to younger subjects 18 to 45 years of age (32 hours). Pharmacokinetic characteristics of cyclobenzaprine following multiple-dose administration of AMRIX in the elderly were not evaluated. Hepatic Impairment In a pharmacokinetic study of immediate-release cyclobenzaprine in 16 subjects with hepatic impairment (15 mild, 1 moderate per Child-Pugh score), both AUC and C max were approximately double the values seen in the healthy control group. The pharmacokinetics of cyclobenzaprine in subjects with severe hepatic impairment is not known.

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.

12.3 Pharmacokinetics Absorption Following single-dose administration of AMRIX 15 mg and 30 mg in healthy adult subjects (n=15) , C max, AUC 0-168h and AUC 0-∞ increased in an approximately dose-proportional manner from 15 mg to 30 mg. The time to peak plasma cyclobenzaprine concentration (T max ) was 7 to 8 hours for both doses of AMRIX. A food effect study conducted in healthy adult subjects (n=15) utilizing a single dose of AMRIX 30 mg demonstrated a statistically significant increase in bioavailability when AMRIX 30 mg was given with food relative to the fasted state. There was a 35% increase in peak plasma cyclobenzaprine concentration (C max ) and a 20% increase in exposure (AUC 0-168h and AUC 0-∞ ) in the presence of food. No effect, however, was noted in T max or the shape of the mean plasma cyclobenzaprine concentration versus time profile. Cyclobenzaprine in plasma was first detectable in both the fed and fasted states at 1.5 hours. When the contents of AMRIX capsules were administered by sprinkling on applesauce, it was found to be bioequivalent to the same dose when administered as an intact capsule. In a multiple-dose study utilizing AMRIX 30 mg administered once daily for 7 days in a group of healthy adult subjects (n=35), a 2.5-fold accumulation of plasma cyclobenzaprine levels was noted at steady-state. Metabolism and Excretion Cyclobenzaprine is extensively metabolized and is excreted primarily as glucuronides via the kidney. Cytochromes P-450 3A4, 1A2, and, to a lesser extent, 2D6, mediate N-demethylation, one of the oxidative pathways for cyclobenzaprine. Cyclobenzaprine has an elimination half-life of 32 hours (range 8-37 hours; n=18); plasma clearance is 0.7 L/min following single-dose administration of AMRIX. Special Populations Elderly Although there were no notable differences in C max or T max , cyclobenzaprine plasma AUC is increased by 40% and the plasma half-life of cyclobenzaprine is prolonged in elderly subjects greater than 65 years of age (50 hours) after dosing with AMRIX compared to younger subjects 18 to 45 years of age (32 hours). Pharmacokinetic characteristics of cyclobenzaprine following multiple-dose administration of AMRIX in the elderly were not evaluated. Hepatic Impairment In a pharmacokinetic study of immediate-release cyclobenzaprine in 16 subjects with hepatic impairment (15 mild, 1 moderate per Child-Pugh score), both AUC and C max were approximately double the values seen in the healthy control group. The pharmacokinetics of cyclobenzaprine in subjects with severe hepatic impairment is not known.

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3 DOSAGE FORMS AND STRENGTHS Extended-release capsules in the following strengths: 15 mg: Capsules are orange/orange and are embossed in blue ink with “15 mg” on the body, and Cephalon “C” logo, “Cephalon,” and a dashed band on the cap. 30 mg: Capsules are blue/red and are embossed in white ink with “30 mg” on the body, and Cephalon “C” logo, “Cephalon,” and a dashed band on the cap. Extended-release capsules: 15 and 30 mg (3)

AMRIX Cyclobenzaprine Hydrochloride CYCLOBENZAPRINE HYDROCHLORIDE CYCLOBENZAPRINE DIETHYL PHTHALATE ETHYLCELLULOSE (10 MPA.S) GELATIN HYPROMELLOSE 2910 (6 MPA.S) POLYETHYLENE GLYCOL 400 POLYETHYLENE GLYCOL 8000 SUCROSE STARCH, CORN TITANIUM DIOXIDE D&C YELLOW NO. 10 FD&C GREEN NO. 3 FD&C RED NO. 40 15;mg;C;Cephalon AMRIX Cyclobenzaprine Hydrochloride CYCLOBENZAPRINE HYDROCHLORIDE CYCLOBENZAPRINE DIETHYL PHTHALATE ETHYLCELLULOSE (10 MPA.S) GELATIN HYPROMELLOSE 2910 (6 MPA.S) POLYETHYLENE GLYCOL 400 POLYETHYLENE GLYCOL 8000 SUCROSE STARCH, CORN TITANIUM DIOXIDE FD&C BLUE NO. 1 FD&C BLUE NO. 2 FD&C RED NO. 40 FD&C YELLOW NO. 6 30;mg;C;Cephalon

13.2 Animal Toxicology and/or Pharmacology In a 67-week study with rats that received cyclobenzaprine at oral doses of 10, 20, or 40 mg/kg/day (3 to 15 times the MRHD on mg/m 2 basis), there were findings in the liver consisting of midzonal vacuolation with lipidosis for males and midzonal and centrilobular hepatocytic enlargement for females. In addition, there were findings of centrilobular coagulative necrosis. In the higher dose groups, these microscopic changes were seen after 26 weeks and even earlier in rats that died prior to 26 weeks; at lower doses, these changes were not seen until after 26 weeks. In a 26-week study with Cynomolgus monkeys that received cyclobenzaprine at oral of doses of 2.5, 5, 10, or 20 mg/kg/day, one monkey at 20 mg/kg/day (15 times the MRHD on mg/m 2 basis) was euthanized in week 17. Morbidity for this animal was attributed to findings of chronic pancreatitis, cholecystitis, cholangitis, and focal liver necrosis.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Long-term studies were conducted in CD-1 mice and Sprague-Dawley rats with oral cyclobenzaprine to evaluate its carcinogenic potential. In an 81-week carcinogenicity study, metastatic hemangiosarcoma was seen in 3 of 21 male mice at 10 mg/kg/day (approximately 2 times the maximum recommended human dose (MRHD) of 30 mg/day on a mg/m 2 basis). In a 105-week carcinogenicity study, malignant astrocytoma was seen in 3 of 50 male rats at 10 mg/kg/day (approximately 3 times the MRHD on a mg/m 2 basis). There were no tumor findings in female mice or rats. Mutagenesis Cyclobenzaprine HCl was not mutagenic or clastogenic in the following assays: an in vitro Ames bacterial mutation assay, in vitro Chinese hamster ovary (CHO) cell chromosomal aberration test, and in vivo mouse bone marrow micronucleus assay. Impairment of Fertility Cyclobenzaprine HCl, when administered 70 and 14 days prior to mating to male and female rats, respectively, had no effects on fertility or reproductive performance at oral doses up to 20 mg/kg/day (approximately 6.5 times the MRHD on a mg/m 2 basis).

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Long-term studies were conducted in CD-1 mice and Sprague-Dawley rats with oral cyclobenzaprine to evaluate its carcinogenic potential. In an 81-week carcinogenicity study, metastatic hemangiosarcoma was seen in 3 of 21 male mice at 10 mg/kg/day (approximately 2 times the maximum recommended human dose (MRHD) of 30 mg/day on a mg/m 2 basis). In a 105-week carcinogenicity study, malignant astrocytoma was seen in 3 of 50 male rats at 10 mg/kg/day (approximately 3 times the MRHD on a mg/m 2 basis). There were no tumor findings in female mice or rats. Mutagenesis Cyclobenzaprine HCl was not mutagenic or clastogenic in the following assays: an in vitro Ames bacterial mutation assay, in vitro Chinese hamster ovary (CHO) cell chromosomal aberration test, and in vivo mouse bone marrow micronucleus assay. Impairment of Fertility Cyclobenzaprine HCl, when administered 70 and 14 days prior to mating to male and female rats, respectively, had no effects on fertility or reproductive performance at oral doses up to 20 mg/kg/day (approximately 6.5 times the MRHD on a mg/m 2 basis). 13.2 Animal Toxicology and/or Pharmacology In a 67-week study with rats that received cyclobenzaprine at oral doses of 10, 20, or 40 mg/kg/day (3 to 15 times the MRHD on mg/m 2 basis), there were findings in the liver consisting of midzonal vacuolation with lipidosis for males and midzonal and centrilobular hepatocytic enlargement for females. In addition, there were findings of centrilobular coagulative necrosis. In the higher dose groups, these microscopic changes were seen after 26 weeks and even earlier in rats that died prior to 26 weeks; at lower doses, these changes were not seen until after 26 weeks. In a 26-week study with Cynomolgus monkeys that received cyclobenzaprine at oral of doses of 2.5, 5, 10, or 20 mg/kg/day, one monkey at 20 mg/kg/day (15 times the MRHD on mg/m 2 basis) was euthanized in week 17. Morbidity for this animal was attributed to findings of chronic pancreatitis, cholecystitis, cholangitis, and focal liver necrosis.

NDA021777

AMRIX

Cyclobenzaprine Hydrochloride

63459-700

HUMAN PRESCRIPTION DRUG

ORAL

Package/Label Display Panel NDC 63459-700-60 60 Capsules amrix ® (Cyclobenzaprine Hydrochloride Extended-Release Capsules) 15 mg Rx ONLY teva image

17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information). Instruct patients to swallow AMRIX capsules intact or to sprinkle capsule contents on a tablespoon of applesauce and swallow immediately without chewing. Advise patients to stop taking AMRIX and to notify their physician right away if they experience symptoms of an allergic reaction, such as difficulty breathing, hives, swelling of face or tongue, or itching. Advise patients that AMRIX should not be taken with MAO inhibitors or within 14 days after their discontinuation. Caution patients about the risk of serotonin syndrome with concomitant use of AMRIX and other drugs, such as SSRIs, SNRIs, TCAs, tramadol, bupropion, meperidine, verapamil, or MAO inhibitors. Advise patients of the signs and symptoms of serotonin syndrome [ see Warnings and Precautions (5.1) ] and instruct patients to seek medical care immediately if they experience these symptoms. Advise patients to stop taking AMRIX and to notify their physician right away if they experience arrhythmias or tachycardia. Advise patients that AMRIX may enhance the impairment effects of alcohol. These effects may also be seen if AMRIX is taken with other CNS depressants. Caution patients about operating an automobile or other hazardous machinery until it is reasonably certain that AMRIX therapy will not adversely affect their ability to engage in such activities. Advise patients to take AMRIX at approximately the same time each day. Distributed By: Teva Pharmaceuticals USA, Inc. Parsippany, NJ 07054 Manufactured By: Adare Pharmaceuticals, Inc. Vandalia, OH 45377 AMR-011 Rev. 5/2020 US Patent Nos. 7387793, 7544372, 7790199, 7820203, 7829121, 8877245, 9375410, 9399025 © 2020 Teva Pharmaceuticals USA, Inc. All rights reserved.

INSTRUCTIONS FOR USE INSTRUCTIONS FOR USE AMRIX ® (am-rix) (cyclobenzaprine hydrochloride extended-release capsules) Read this Instructions for Use before you prepare your first dose of AMRIX mixed with applesauce using the capsule sprinkle method, each time you get a refill, and as needed. There may be new information. Ask your healthcare provider or pharmacist if you have any questions about how to mix or give a dose of AMRIX using the capsule sprinkle method. Important Information: Do not chew AMRIX capsules or the granules that are in the capsules. The capsule sprinkle method for mixing the contents of AMRIX with applesauce may be used for adults who cannot swallow capsules. Do not use any other food in the place of applesauce. Preparing a dose of AMRIX using the capsule sprinkle method. Before you prepare a dose of AMRIX mixed with applesauce using the capsule sprinkle method, gather the following supplies: paper towels tablespoon applesauce cup of water Step 1: Choose a clean, flat work surface. Place a clean paper towel on the work surface. Then place the other supplies on the paper towel. Step 2: Wash and dry your hands well. Step 3: Check the dose that was prescribed by your healthcare provider. Take out the number of AMRIX capsules needed to prepare your dose. Place them on the paper towel. Step 4: Place enough applesauce to fill your tablespoon. Set the tablespoon down on the paper towel. Step 5: Hold the AMRIX capsule in an upright position (vertical) directly over the tablespoon. Hold each end of the AMRIX capsule between your thumbs and index (pointer) fingers. Step 6: Carefully twist both ends of the AMRIX capsule in opposite directions to open it. Be careful not to spill the capsule contents. Step 7: Sprinkle the contents of the AMRIX capsule onto the applesauce. Check the capsule shells to make sure they are empty. Throw away the empty capsule shells. If the total prescribed dose is more than 1 capsule, repeat Steps 5 through 7 for each capsule. Do not add more applesauce. Then follow the rest of the steps below. Step 8: Pick up the tablespoon and swallow the AMRIX capsule contents and applesauce mixture right away. Do not chew the AMRIX capsule contents and applesauce mixture. Step 9: Rinse your mouth with a sip of water and swallow to make sure that all of the AMRIX granules have been swallowed. Step 10: Throw away any unused AMRIX capsule content and applesauce mixture. Do not keep any AMRIX capsule content and applesauce mixture for future use. How should I store AMRIX? Store AMRIX capsules at room temperature between 68°F to 77°F (20°C to 25°C). Keep AMRIX capsules and all medicines out of the reach of children. This Instructions for Use has been approved by the U.S. Food and Drug Administration. AMRIFU-001 Issued: April 2019 image image image image image image

14 CLINICAL STUDIES Efficacy was assessed in two double-blind, parallel-group, active-controlled, placebo-controlled studies of identical design of AMRIX 15 mg and 30 mg taken once daily, between 6:00 and 7:00 PM, cyclobenzaprine 10 mg three times a day, or placebo for 14 days in patients with muscle spasms associated with acute painful musculoskeletal conditions. There were significant differences in the primary efficacy analysis, the patient’s rating of medication helpfulness, between the AMRIX 15 mg group and the placebo group at Days 4 and 14 in one study and between the AMRIX 30 mg group and the placebo group at Day 4 in the second study. Table 2: Patients’ Rating of Medication Helpfulness - Study 1* Day 4 Day 14 Number of Patients (%) Number of Patients (%) Placebo (N = 64) AMRIX 30 mg (N = 64) Placebo (N = 64) AMRIX 30 mg (N = 64) Excellent 1 (2%) 3 (5%) 12 (19%) 15 (23%) Very Good 5 (8%) 13 (20%) 9 (14%) 19 (30%) Good 15 (23%) 22 (34%) 10 (16%) 15 (23%) Fair 24 (38%) 20 (31%) 16 (25%) 10 (16%) Poor 10 (16%) 5 (8%) 9 (14%) 4 (6%) Missing 9 (14%) 1 (2%) 8 (13%) 1 (2%) * Percentages are rounded to the nearest whole percent. Table 3: Patients’ Rating of Medication Helpfulness - Study 2* Day 4 Day 14 Number of Patients (%) Number of Patients (%) Placebo (N = 64) AMRIX 15 mg (N = 63) Placebo (N = 64) AMRIX 15 mg (N = 63) Excellent 1 (2%) 2 (3%) 10 (16%) 13 (21%) Very Good 10 (16%) 12 (19%) 12 (19%) 21 (33%) Good 14 (22%) 21 (33%) 13 (20%) 9 (14%) Fair 16 (25%) 17 (27%) 14 (22%) 10 (16%) Poor 19 (30%) 6 (10%) 12 (19%) 5 (8%) Missing 4 (6%) 5 (8%) 3 (5%) 5 (8%) * Percentages are rounded to the nearest whole percent. In addition, one of the two studies demonstrated significant differences between the AMRIX 30 mg group and the placebo group in terms of patient-rated relief from local pain due to muscle spasm at Day 4 and Day 8, in patient-rated restriction of movement at Day 4 and Day 8, and in patient-rated global impression of change at Day 4, Day 8, and Day 14. In both studies, there were no significant treatment differences between the AMRIX treatment groups and the placebo group in physician's global assessment, patient-rated restriction in activities of daily living, or quality of nighttime sleep.

8.5 Geriatric Use Clinical studies of AMRIX did not include sufficient numbers of patients aged 65 and over to determine the safety and efficacy of AMRIX 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 AMRIX is not recommended in the elderly [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.3)] .

8.4 Pediatric Use Safety and effectiveness of AMRIX have not been studied in pediatric patients.

8.1 Pregnancy Risk Summary Available data from case reports with AMRIX 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 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Available data from case reports with AMRIX 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 AMRIX and any potential adverse effects on the breastfed child from AMRIX or from the underlying maternal condition. 8.4 Pediatric Use Safety and effectiveness of AMRIX have not been studied in pediatric patients. 8.5 Geriatric Use Clinical studies of AMRIX did not include sufficient numbers of patients aged 65 and over to determine the safety and efficacy of AMRIX 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 AMRIX is not recommended in the elderly [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.3)] . 8.6 Hepatic Impairment The use of AMRIX is not recommended in patients with mild, moderate, or severe hepatic impairment [ see Warnings and Precautions (5.4 ) and Clinical Pharmacology ( 12.3 )].

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied AMRIX extended-release capsules are available in 15 and 30 mg strengths, packaged in bottles of 60 capsules. AMRIX 15 mg capsules (NDC 63459-700-60) are orange/orange and are embossed in blue ink with “15 mg” on the body, and Cephalon “C” logo, “Cephalon”, and a dashed band on the cap. AMRIX 30 mg capsules (NDC 63459-701-60) are blue/red and are embossed in white ink with “30 mg” on the body, and Cephalon “C” logo, “Cephalon”, and a dashed band on the cap. 16.2 Storage and Handling Dispense in a tight, light-resistant container as defined in the USP/NF. Store at 25°C (77°F); excursions permitted to 15 - 30°C (59 - 86°F) [see USP Controlled Room Temperature].

16.2 Storage and Handling Dispense in a tight, light-resistant container as defined in the USP/NF. Store at 25°C (77°F); excursions permitted to 15 - 30°C (59 - 86°F) [see USP Controlled Room Temperature].