AMRIX- cyclobenzaprine hydrochloride capsule, extended release
For Healthcare Providers >

1. Patient Information
2. What Is Amrix?
3. Do Not Take Amrix If You:
4. Before You Take Amrix, Tell Your Healthcare Provider If You:
5. Especially Tell Your Healthcare Provider If You Take:
6. How Should I Take Amrix?
7. What Should I Avoid While Taking Amrix?
8. What Are The Possible Side Effects Of Amrix?
9. The Most Common Side Effects Of Amrix Include:
10. How Should I Store Amrix?
11. Active Ingredient:
12. Inactive Ingredients:
13. Distributed By:
14. Manufactured By:

Patient 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.
North Wales, PA 19454

Manufactured By:
Adare Pharmaceuticals, Inc.
Vandalia, OH 45377

AMR-008

US Patent Nos. 7387793, 7754372, 7790199, 7820203, 7829121

AMRIX is a trademark of Teva Pharmaceuticals International GmbH, or its affiliates.

2004-2016 Teva Pharmaceuticals USA, Inc.

All rights reserved.

What Is Amrix? ⮝

AMRIX is a prescription medicine used along with rest and physical therapy to help treat muscle spasm due to acute, painful musculoskeletal problems.

AMRIX should only be used for up to 2 or 3 weeks. It is not known if AMRIX is effective when used for longer periods.

It is not known if AMRIX is safe and effective in children.

Do Not Take Amrix If You: ⮝

are allergic to cyclobenzaprine or any of the ingredients in AMRIX.

Before You Take Amrix, Tell Your Healthcare Provider If You: ⮝

have a history of eye problems including glaucoma

have heart problems or have had a heart attack

have liver problems

have trouble emptying your bladder (urinary retention)

are pregnant or plan to become pregnant. It is not known if AMRIX will harm your unborn baby.

are breastfeeding or plan to breastfeed. It is not known if AMRIX passes into your breast milk. You and your healthcare provider should decide if you will take AMRIX or breastfeed.

AMRIX may affect the way other medicines work, and other medicines may affect how AMRIX works.

Tell your healthcare provider about all the medicines you takeincluding prescription and non-prescription medicines, vitamins, and herbal supplements.

Especially Tell Your Healthcare Provider If You Take: ⮝

a medicine to treat depression, mood, anxiety, psychotic or thought disorders

a pain medicine called tramadol or meperidine

barbiturates or other medicines that depress your central nervous system (CNS depressants)

a medicine that prevents nerve impulses (anticholinergic medicines)

a medicine to help quit smoking called bupropion

a blood pressure medicine called verapamil

Ask your doctor or pharmacist if you are not sure if you take any of the medicines listed above.

Know the medicines you take. Keep a list of your medicines and show it to your healthcare provider or pharmacist when you get a new medicine.

How Should I Take Amrix? ⮝

Take AMRIX exactly as your healthcare provider tells you to take it.

Your healthcare provider will tell you how much AMRIX to take and when to take it.

Your healthcare provider may change your AMRIX dose if needed.

Take AMRIX around the same time every day.

AMRIX should only be taken for short periods (up to two or three weeks).

If you take too much AMRIX, call your doctor or go to the nearest hospital emergency room right away.

What Should I Avoid While Taking Amrix? ⮝

You should not drink alcohol until you know how AMRIX affects you. Taking AMRIX with alcohol or other medicines that depress your central nervous system can slow your thinking and physical response times.

Do not drive, operate machinery, or do other dangerous activities until you know how AMRIX affects you.

What Are The Possible Side Effects Of Amrix? ⮝

AMRIX may cause serious side effects that may lead to heart attack or stroke.Call your healthcare provider right away or go to the nearest hospital emergency room if you have:

irregular or abnormal heartbeats (arrhythmias)

fast heartbeat (tachycardia)

Serotonin syndromeis a serious medical condition that may happen when AMRIX is taken with certain other medicines. Call your healthcare provider right away or go to the nearest hospital emergency room if you become severely ill and have some or all of these symptoms:

agitation, hallucinations, coma or other changes in mental status

coordination problems or muscle twitching (overactive reflexes)

fast heartbeat, high or low blood pressure

sweating or fever

nausea, vomiting, or diarrhea

muscle stiffness or tightness

The Most Common Side Effects Of Amrix Include: ⮝

dry mouth

dizziness

fatigue

constipation

nausea

upset stomach

drowsiness

Tell your healthcare provider if you get any side effect that bothers you or that does not go away.

These are not all the possible side effects of AMRIX. For more information, ask your healthcare provider or pharmacist.

Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How Should I Store Amrix? ⮝

Store AMRIX at room temperature, between 59 F to 86 F (15 C to 30 C).

Keep AMRIX in a tightly closed container, and keep AMRIX out of light.

Keep AMRIX and all medicines out of the reach of children.

General information about the safe and effective use of AMRIX.

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use AMRIX for a condition for which it was not prescribed. Do not give AMRIX to other people, even if they have the same symptoms you have. It may harm them.

This Patient Information leaflet summarizes the most important information about AMRIX. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about AMRIX that is written for healthcare professionals.

For more information, go towww.AMRIX.comor call 1-800-896-5855.

Active Ingredient: ⮝

cyclobenzaprine hydrochloride USP

Inactive Ingredients: ⮝

diethyl phthalate NF, ethylcellulose NF (Ethocel Standard 10 Premium), gelatin, OpadryClear YS-1-7006, sugar spheres NF (20-25 mesh), and titanium dioxide.

AMRIX 15 mg capsulesalso contain: D&C yellow #10, FD&C green #3, and FD&C red #40.

AMRIX 30 mg capsulesalso contain: FD&C blue #1, FD&C blue #2, FD&C red #40, and FD&C yellow #6.

Distributed By: ⮝

Teva Pharmaceuticals USA, Inc.

North Wales, PA 19454

Manufactured By: ⮝

Adare Pharmaceuticals, Inc.

Vandalia, OH 45377

AMRPL-003

Revised May 2016

AMRIX is a trademark of Teva Pharmaceuticals International GmbH, or its affiliates.

2004-2016 Teva Pharmaceuticals USA, Inc.

All rights reserved.

1. Description
2. Clinical Pharmacology
3. Clinical Studies
4. Indications And Usage
5. Contraindications
6. Warnings
7. Precautions
8. Adverse Reactions
9. Drug Abuse And Dependence
10. Overdosage
11. Dosage And Administration
12. How Supplied
13. Principal Display Panel
14. Indications And Usage
15. Dosage And Administration
16. Highlights Of Prescribing Information
17. Dosage Forms And Strengths
18. Warnings And Precautions
19. Drug Interactions
20. 1 Indications And Usage
21. 2 Dosage And Administration
22. 3 Dosage Forms And Strengths
23. 4 Contraindications
24. 5 Warnings And Precautions
25. 6 Adverse Reactions
26. 7 Drug Interactions
27. 8 Use In Specific Populations
28. 9 Drug Abuse And Dependence
29. 10 Overdosage
30. 11 Description
31. 12 Clinical Pharmacology
32. 13 Nonclinical Toxicology
33. 14 Clinical Studies
34. 16 How Supplied/storage And Handling
35. Instructions For Use
36. Package/label Display Panel
37. Recent Major Changes
38. Cyclobenzaprine Hydrochloride

Description ⮝

AMRIX (Cyclobenzaprine Hydrochloride Extended-Release Capsules) 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 C20H21N 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:

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.

Clinical Pharmacology ⮝

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 ( ) and alpha ( ) 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.

Pharmacokinetics

Absorption

In a single-dose study comprised of healthy adult males (n=15), the dose adjusted ratios of the arithmetic means of AUC0-168 and AUC0- indicated that exposure of the AMRIX 30 mg was about 16% and 10% higher than that of AMRIX 15 mg, respectively. The dose-adjusted ratios of the arithmetic means of Cmax indicated that the peak plasma concentration of AMRIX 30 mg was about 20% higher than that of AMRIX 15 mg. The half-lives and time to peak plasma cyclobenzaprine concentration were similar for both AMRIX 15 mg and 30 mg. These data are summarized below.

Table 1: Summary of Pharmacokinetic Parameters in Healthy Adult Subjects

SD = standard deviation
Parameter Mean SD	AMRIX 15 mg (N=15)	AMRIX 30 mg (N=14)
AUC0-168 (ng hr/mL)	318.3 114.7	736.6 259.4
AUC0- (ng hr/mL)	354.1 119.8	779.9 277.6
Cmax (ng/mL)	8.3 2.2	19.9 5.9
Tmax (hrs)	8.1 2.9	7.1 1.6
t1/2 (hrs)	33.4 10.3	32.0 10.1

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 (Cmax) and a 20% increase in exposure (AUC0-168 and AUC0- ) in the presence of food. No effect, however, was noted in Tlag, Tmax, 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.

In a multiple-dose study utilizing AMRIX 30 mg administered once daily for 7 days in a group of healthy adult volunteers (n=35) a 2.5-fold accumulation of plasma cyclobenzaprine levels was noted at steady-state.

Metabolism and Elimination

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 Cmax or Tmax, 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 (32 hours). Pharmacokinetic characteristics of cyclobenzaprine following multiple-dose administration of AMRIX in the elderly were not evaluated.

Table 2: Summary of Pharmacokinetic Parameters of AMRIX 30 mg Extended-Release Capsules, By Age Group

* Measured over the entire 24 hour period
SD = standard deviation
Parameter Mean SD	AMRIX 30 mg QD
	18 to 45 years (N=18)	65 to 75 years (N=17)
AUC0-168 (ng hr/mL)	715.1 264.2	945.9 255.2
AUC0- (ng hr/mL)	751.2 271.5	1055.2 301.9
Cmax (ng/mL)*	19.2 5.6	19.2 5.1
Tmax (hrs)*	6.8 1.9	8.5 2.3
t1/2 (hrs)	32.4 8.1	49.0 8.3

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 Cmax were approximately double the values seen in the healthy control group. The pharmacokinetics of cyclobenzaprine in subjects with severe hepatic impairment is not known.

Clinical Studies ⮝

Efficacy was assessed in two double-blind, parallel-group, placebo-controlled studies of identical design of AMRIX 15 mg and 30 mg taken once daily 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 3: Subject s Rating of Medication Helpfulness - Study 1105

	Day 4		Day 14
	Number of Subjects (%)		Number of Subjects (%)
	Placebo (N = 64)	AMRIX 30 mg (N = 64)	Placebo (N = 64)	AMRIX 30 mg (N = 64)
Excellent	1 (1.6%)	3 (4.7%)	12 (18.8%)	15 (23.4%)
Very Good	5 (7.8%)	13 (20.3%)	9 (14.1%)	19 (29.7%)
Good	15 (23.4%)	22 (34.4%)	10 (15.6%)	15 (23.4%)
Fair	24 (37.5%)	20 (31.3%)	16 (25.0%)	10 (15.6%)
Poor	10 (15.6%)	5 (7.8%)	9 (14.1%)	4 (6.3%)
Missing	9 (14.1%)	1 (1.6%)	8 (12.5%)	1 (1.6%)

Table 4: Subject's Rating of Medication Helpfulness - Study 1106

	Day 4		Day 14
	Number of Subjects (%)		Number of Subjects (%)
	Placebo (N = 64)	AMRIX 15 mg (N = 63)	Placebo (N = 64)	AMRIX 15 mg (N = 63)
Excellent	1 (1.6%)	2 (3.2%)	10 (15.6%)	13 (20.6%)
Very Good	10 (15.6%)	12 (19.0%)	12 (18.8%)	21 (33.3%)
Good	14 (21.9%)	21 (33.3%)	13 (20.3%)	9 (14.3%)
Fair	16 (25.0%)	17 (27.0%)	14 (21.9%)	10 (15.9%)
Poor	19 (29.7%)	6 (9.5%)	12 (18.8%)	5 (7.9%)
Missing	4 (6.3%)	5 (17.9%)	3 (4.7%)	5 (7.9%)

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 subject-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.

There were no significant treatment differences between the AMRIX treatment groups and the placebo group in physician's global assessment, in subject-rated restriction in activities of daily living, or quality of night-time sleep.

Indications And Usage ⮝

AMRIX 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.

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.

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.
• During the acute recovery phase of myocardial infarction, and in patients with arrhythmias, heart block conduction disturbances, or congestive heart failure.
• Hyperthyroidism.

Warnings ⮝

AMRIX is closely related to the tricyclic antidepressants, e.g., amitriptyline and imipramine. In short term studies for indications other than muscle spasm associated with acute musculoskeletal conditions, and usually at doses somewhat greater than those recommended for skeletal muscle spasm, some of the more serious central nervous system reactions noted with the tricyclic antidepressants have occurred (see WARNINGS, below, and ADVERSE REACTIONS).

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.

As a result of a 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 subjects with mild, moderate or severe hepatic impairment.

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 elderly.

Precautions ⮝

General

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.

Information for Patients

AMRIX, especially when used with alcohol or other CNS depressants, may impair mental and/or physical abilities required for performance of hazardous tasks, such as operating machinery or driving a motor vehicle.

Drug Interactions

AMRIX may have life-threatening interactions with MAO inhibitors. (See CONTRAINDICATIONS.) AMRIX may enhance the effects of alcohol, barbiturates, and other CNS depressants. Tricyclic antidepressants may block the antihypertensive action of guanethidine and similarly acting compounds. Tricyclic antidepressants may enhance the seizure risk in patients taking tramadol (ULTRAM [tramadol HCl tablets, Ortho-McNeil Pharmaceutical] or ULTRACET [tramadol HCl and acetaminophen tablets, Ortho-McNeil Pharmaceutical]).

Carcinogenesis, Mutagenesis, Impairment of Fertility

In rats treated with cyclobenzaprine for up to 67 weeks at doses of approximately 5 to 40 times the maximum recommended human dose, pale, sometimes enlarged, livers were noted and there was a dose-related hepatocyte vacuolation with lipidosis. In the higher dose groups, this microscopic change was seen after 26 weeks and even earlier in rats that died prior to 26 weeks; at lower doses, the change was not seen until after 26 weeks. Cyclobenzaprine did not affect the onset, incidence, or distribution of neoplasia in an 81-week study in the mouse or in a 105-week study in the rat. At oral doses of up to 10 times the human dose, cyclobenzaprine did not adversely affect the reproductive performance or fertility of male or female rats. Cyclobenzaprine did not demonstrate mutagenic activity in the male mouse at dose levels of up to 20 times the human dose.

A battery of mutagenicity tests using bacterial and mammalian systems for point mutations and cytogenic effects have provided no evidence for a mutagenic potential for cyclobenzaprine. An in vivo mouse bone micronucleus assay, an assessment of chromosomal aberrations (Chinese hamster ovary), and a mammalian microsome reverse mutation assay were negative.

Pregnancy

Pregnancy Category B: Reproduction studies have been performed in rats, mice, and rabbits at doses up to 20 times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to cyclobenzaprine. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because cyclobenzaprine is closely related to the tricyclic antidepressants, some of which are known to be excreted in human milk, caution should be exercised when AMRIX is administered to a nursing woman.

Pediatric Use

Safety and effectiveness of AMRIX has not been studied in pediatric patients.

Use in the Elderly

The plasma concentration and half-life of cyclobenzaprine are substantially increased in the elderly when compared to the general patient population (see CLINICAL PHARMACOLOGY, Pharmacokinetics, Special Populations, Elderly). Accordingly, AMRIX should not be used in the elderly.

Adverse Reactions ⮝

The most common adverse reactions in the two 14-day clinical efficacy trials and in the 7-day repeat-dose pharmacokinetic study are presented in Tables 5 and 6, respectively.

Table 5: Incidence of the Most Common Adverse Reactions Occurring in 3% of Subjects in Any Treatment Group in the Two Phase 3, Double-Blind AMRIX Trials

	AMRIX 15 mg N=127	AMRIX 30 mg N=126	Placebo N=128
Dry mouth	6%	14%	2%
Dizziness	3%	6%	2%
Fatigue	3%	3%	2%
Constipation	1%	3%	0%
Somnolence	1%	2%	0%
Nausea	3%	3%	1%
Dyspepsia	0%	4%	1%

Table 6: Incidence of the Most Common Adverse Reactions Occurring in 3% of Subjects in Any Treatment Group in the Seven-Day Pharmacokinetic Study of AMRIX

	AMRIX 30 mg N = 36
Somnolence	100%
Dry mouth	58%
Headache NOS	17%
Dizziness	19%
Vision blurred	3%
Nausea	8%
Dysgeusia	6%
Palpitations	6%
Tremor	6%
Dry throat	8%
Acne NOS	6%
Disturbance in attention	6%
Insomnia	0

In a postmarketing surveillance program (7607 patients treated with cyclobenzaprine 10 mg TID), the adverse reactions reported most frequently 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:

Table 7: Most Common Adverse Reactions from Postmarketing Surveillance Program

	Clinical Studies cyclobenzaprine 10 mg TID	Surveillance Program cyclobenzaprine 10 mg TID
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 TID 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.
Skin: Sweating.
Special Senses: Ageusia; tinnitus.
Urogenital: Urinary frequency and/or retention.

Causal Relationship Unknown

Other reactions, reported rarely for cyclobenzaprine 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; alopecia.
Urogenital: Impaired urination; dilatation of urinary tract; impotence; testicular swelling; gynecomastia; breast enlargement; galactorrhea.

Drug Abuse And 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.

Overdosage ⮝

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 acute oral LD50 of cyclobenzaprine 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 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 pCO2 <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.

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).

Dosage Considerations for Special Patient Populations: AMRIX should not be used in the elderly or in patients with impaired hepatic function. (see WARNINGS)

How Supplied ⮝

AMRIX extended-release capsules are available in 15 mg strengths, packaged in bottles of 30 capsules. AMRIX 15 mg capsules (NDC 54868-6022-0) 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.

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].

KEEP THIS AND ALL MEDICATION OUT OF THE REACH OF CHILDREN. IN CASE OF ACCIDENTAL OVERDOSE, SEEK PROFESSIONAL ASSISTANCE OR CONTACT A POISON CONTROL CENTER IMMEDIATELY.

Distributed by:
Cephalon, Inc.
Frazer, PA 19355

Manufactured by:
Eurand Inc.
Vandalia, Ohio 45377
AMRIX is a trademark of Cephalon, Inc. or its affiliates.

U.S. Patent No. 7,387,793

2004, 2006, 2007, 2008 Cephalon, Inc., or its affiliates. All rights reserved.

PI-40018-01
Revised December 2008

Relabeling and Repackaging by:
Physicians Total Care, Inc.
Tulsa, Oklahoma 74146

Primary Display Panel for Amrix ER Capsules

15 mg

AMRIX cyclobenzaprine hydrochloride capsule, extended release

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:54868-6022(NDC:63459-700) Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength cyclobenzaprine hydrochloride (UNII: 0VE05JYS2P) (Cyclobenzaprine - UNII:69O5WQQ5TI) cyclobenzaprine hydrochloride 15 mg

Inactive Ingredients Ingredient Name Strength DIETHYL PHTHALATE (UNII: UF064M00AF) ETHYLCELLULOSE (10 MPA.S) (UNII: 3DYK7UYZ62) GELATIN (UNII: 2G86QN327L) SUCROSE (UNII: C151H8M554) TITANIUM DIOXIDE (UNII: 15FIX9V2JP) D&C YELLOW NO. 10 (UNII: 35SW5USQ3G) FD&C GREEN NO. 3 (UNII: 3P3ONR6O1S) FD&C RED NO. 40 (UNII: WZB9127XOA) STARCH, CORN (UNII: O8232NY3SJ)

Product Characteristics Color ORANGE Score no score Shape CAPSULE Size 14mm Flavor Imprint Code 15mg;Cephalon Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:54868-6022-0 30 in 1 BOTTLE, PLASTIC

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA021777 04/16/2009

Labeler - Physicians Total Care, Inc. (194123980)

Establishment
Name	Address	ID/FEI	Business Operations
Physicians Total Care, Inc.		194123980	relabel(54868-6022)

Revised: 8/2012 Document Id: 902dee94-2e89-4ada-96b2-36cc4d1eb34f 34391-3 Set id: c18058a0-9c69-49cf-8454-db3b98427808 Version: 3 Effective Time: 20120806 Physicians Total Care, Inc.

Principal Display Panel ⮝

AMRIX cyclobenzaprine hydrochloride capsule, extended release

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:21695-723(NDC:63459-0700) Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength cyclobenzaprine hydrochloride (UNII: 0VE05JYS2P) (Cyclobenzaprine - UNII:69O5WQQ5TI) Cyclobenzaprine 15 mg

Inactive Ingredients Ingredient Name Strength diethyl phthalate (UNII: UF064M00AF) ETHYLCELLULOSES (UNII: 7Z8S9VYZ4B) gelatin (UNII: 2G86QN327L) SUCROSE (UNII: C151H8M554) titanium dioxide (UNII: 15FIX9V2JP) D&C YELLOW NO. 10 (UNII: 35SW5USQ3G) FD&C GREEN NO. 3 (UNII: 3P3ONR6O1S) FD&C RED NO. 40 (UNII: WZB9127XOA) STARCH, CORN (UNII: O8232NY3SJ)

Product Characteristics Color ORANGE Score no score Shape CAPSULE Size 14mm Flavor Imprint Code 15mg;Cephalon Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:21695-723-14 14 in 1 BOTTLE 2 NDC:21695-723-28 28 in 1 BOTTLE 3 NDC:21695-723-60 60 in 1 BOTTLE

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA021777 10/01/2007

Labeler - Rebel Distributors Corp. (118802834)

Establishment
Name	Address	ID/FEI	Business Operations
Rebel Distributors Corp.		118802834	RELABEL, REPACK

Revised: 9/2010 Document Id: 555ff988-280c-4272-bf1f-a911fe2e584d 34391-3 Set id: 555ff988-280c-4272-bf1f-a911fe2e584d Version: 1 Effective Time: 20100908 Rebel Distributors Corp.

Indications And Usage ⮝

AMRIX 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.

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.

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).

Dosage Considerations for Special Patient Populations: AMRIX should not be used in the elderly or in patients with impaired hepatic function. (see WARNINGS)

Highlights Of Prescribing Information ⮝

These highlights do not include all the information needed to use AMRIX safely and effectively. See full prescribing information for AMRIX.

AMRIX (cyclobenzaprine hydrochloride extended-release capsules), for oral use

Initial U.S. Approval: 1977

Dosage Forms And Strengths ⮝

Extended-release capsules: 15 and 30 mg (3)

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)

Drug Interactions ⮝

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)

See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.

Revised: 11/2017

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.

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.

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.

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.

5 Warnings And Precautions ⮝

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 AMRIX 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 AMRIX 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 AMRIX 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)]. AMRIX 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 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.

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 [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

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:

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.

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)]

8 Use In Specific Populations ⮝

8.1 Pregnancy

Pregnancy Category B: There are no adequate and well-controlled studies of AMRIX in pregnant women. Because animal reproduction studies are not always predictive of human response, AMRIX should be used during pregnancy only if clearly needed.

No treatment-related effects on embryofetal development were observed in mice and rabbits at approximately 3 and 15 times the maximum recommended human dose (MRHD), respectively (on a mg/m2 basis at maternal doses of 20 mg/kg/day in both mice and rabbits).

Nonteratogenic Effects

Cyclobenzaprine has been shown to adversely affect pup postnatal development when dams were treated with the drug during pregnancy and lactation periods in rats. This study found that cyclobenzaprine decreased pup body weight and survival at approximately 3 times the MRHD (on a mg/m2 basis at maternal doses of 10 and 20 mg/kg/day in rats).

8.3 Nursing Mothers

It is not known whether this drug is excreted in human milk. Because cyclobenzaprine is closely related to the tricyclic antidepressants, some of which are known to be excreted in human milk, caution should be exercised when AMRIX is administered to a nursing woman.

8.4 Pediatric Use

Safety and effectiveness of AMRIX has 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)]

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 ⮝

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.

10.1 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 (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 pCO2 <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.

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 C20H21N 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:

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.

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 ( ) and alpha ( ) 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), Cmax, AUC0-168h and AUC0- increased in an approximately dose-proportional manner from 15 mg to 30 mg. The time to peak plasma cyclobenzaprine concentration (Tmax) 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 (Cmax) and a 20% increase in exposure (AUC0-168h and AUC0- ) in the presence of food. No effect, however, was noted in Tmax 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 Cmax or Tmax, 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 Cmax were approximately double the values seen in the healthy control group. The pharmacokinetics of cyclobenzaprine in subjects with severe hepatic impairment is not known.

13 Nonclinical Toxicology ⮝

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies were conducted in CD-1 mice and Sprague-Dawley rats with 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 (2 times the MRHD on a mg/m2 basis). In a 105-week carcinogenicity study, malignant astrocytoma was seen in 3 of 50 male rats at 10 mg/kg/day (3 times the MRHD on a mg/m2 basis). There were no tumor findings in female mice or rats.

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.

Cyclobenzaprine HCl had no effects on fertility and reproductive performance in male or female rats at oral doses up to 20 mg/kg/day (6 times the MRHD on a mg/m2 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/m2 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/m2 basis) was euthanized in week 17. Morbidity for this animal was attributed to findings of chronic pancreatitis, cholecystitis, cholangitis, and focal liver necrosis.

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.

16 How Supplied/storage And Handling ⮝

Product: 50090-1101

NDC: 50090-1101-2 30 CAPSULE, EXTENDED RELEASE in a BOTTLE

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

Package/label Display Panel ⮝

NDC 63459-701-60
amrix (Cyclobenzaprine Hydrochloride Extended-Release Capsules)
30 mg
TEVA Rx ONLY
60 Capsules

AMRIX cyclobenzaprine hydrochloride capsule, extended release

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:63459-700 Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength CYCLOBENZAPRINE HYDROCHLORIDE (UNII: 0VE05JYS2P) (CYCLOBENZAPRINE - UNII:69O5WQQ5TI) CYCLOBENZAPRINE HYDROCHLORIDE 15 mg

Inactive Ingredients Ingredient Name Strength DIETHYL PHTHALATE (UNII: UF064M00AF) ETHYLCELLULOSE (10 MPA.S) (UNII: 3DYK7UYZ62) GELATIN (UNII: 2G86QN327L) HYPROMELLOSE 2910 (6 MPA.S) (UNII: 0WZ8WG20P6) POLYETHYLENE GLYCOL 400 (UNII: B697894SGQ) POLYETHYLENE GLYCOL 8000 (UNII: Q662QK8M3B) SUCROSE (UNII: C151H8M554) STARCH, CORN (UNII: O8232NY3SJ) TITANIUM DIOXIDE (UNII: 15FIX9V2JP) D&C YELLOW NO. 10 (UNII: 35SW5USQ3G) FD&C GREEN NO. 3 (UNII: 3P3ONR6O1S) FD&C RED NO. 40 (UNII: WZB9127XOA)

Product Characteristics Color ORANGE Score no score Shape CAPSULE Size 14mm Flavor Imprint Code 15;mg;C;Cephalon Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:63459-700-22 5 in 1 CARTON 10/02/2007 10/31/2018 1 NDC:63459-700-02 2 in 1 BLISTER PACK; Type 0: Not a Combination Product 2 NDC:63459-700-15 10 in 1 CARTON 10/02/2007 05/31/2015 2 NDC:63459-700-11 1 in 1 BLISTER PACK; Type 0: Not a Combination Product 3 NDC:63459-700-60 60 in 1 BOTTLE; Type 0: Not a Combination Product 10/02/2007

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA021777 10/02/2007

AMRIX cyclobenzaprine hydrochloride capsule, extended release

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:63459-701 Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength CYCLOBENZAPRINE HYDROCHLORIDE (UNII: 0VE05JYS2P) (CYCLOBENZAPRINE - UNII:69O5WQQ5TI) CYCLOBENZAPRINE HYDROCHLORIDE 30 mg

Inactive Ingredients Ingredient Name Strength DIETHYL PHTHALATE (UNII: UF064M00AF) ETHYLCELLULOSE (10 MPA.S) (UNII: 3DYK7UYZ62) GELATIN (UNII: 2G86QN327L) HYPROMELLOSE 2910 (6 MPA.S) (UNII: 0WZ8WG20P6) POLYETHYLENE GLYCOL 400 (UNII: B697894SGQ) POLYETHYLENE GLYCOL 8000 (UNII: Q662QK8M3B) SUCROSE (UNII: C151H8M554) STARCH, CORN (UNII: O8232NY3SJ) TITANIUM DIOXIDE (UNII: 15FIX9V2JP) FD&C BLUE NO. 1 (UNII: H3R47K3TBD) FD&C BLUE NO. 2 (UNII: L06K8R7DQK) FD&C RED NO. 40 (UNII: WZB9127XOA) FD&C YELLOW NO. 6 (UNII: H77VEI93A8)

Product Characteristics Color BLUE, RED Score no score Shape CAPSULE Size 14mm Flavor Imprint Code 30;mg;C;Cephalon Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:63459-701-60 60 in 1 BOTTLE; Type 0: Not a Combination Product 11/01/2007

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA021777 10/01/2007

Labeler - Cephalon, Inc. (183236314)

Revised: 5/2019 Document Id: 803f5c94-ba0f-40ad-9dae-d439a5a07086 34391-3 Set id: 3902123b-1365-ac3c-0934-afff9eeeb1bd Version: 20 Effective Time: 20190521 Cephalon, Inc.

Recent Major Changes ⮝

Dosage and Administration (2) 05/2016

Cyclobenzaprine Hydrochloride ⮝

AMRIX cyclobenzaprine hydrochloride capsule, extended release

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:50090-1101(NDC:63459-700) Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength CYCLOBENZAPRINE HYDROCHLORIDE (UNII: 0VE05JYS2P) (CYCLOBENZAPRINE - UNII:69O5WQQ5TI) CYCLOBENZAPRINE HYDROCHLORIDE 15 mg

Inactive Ingredients Ingredient Name Strength DIETHYL PHTHALATE (UNII: UF064M00AF) ETHYLCELLULOSE (10 MPA.S) (UNII: 3DYK7UYZ62) GELATIN, UNSPECIFIED (UNII: 2G86QN327L) HYPROMELLOSE 2910 (6 MPA.S) (UNII: 0WZ8WG20P6) POLYETHYLENE GLYCOL 400 (UNII: B697894SGQ) POLYETHYLENE GLYCOL 8000 (UNII: Q662QK8M3B) SUCROSE (UNII: C151H8M554) STARCH, CORN (UNII: O8232NY3SJ) TITANIUM DIOXIDE (UNII: 15FIX9V2JP) D&C YELLOW NO. 10 (UNII: 35SW5USQ3G) FD&C GREEN NO. 3 (UNII: 3P3ONR6O1S) FD&C RED NO. 40 (UNII: WZB9127XOA)

Product Characteristics Color ORANGE Score no score Shape CAPSULE Size 14mm Flavor Imprint Code 15;mg;C;Cephalon Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:50090-1101-2 30 in 1 BOTTLE; Type 0: Not a Combination Product 11/28/2014

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA021777 10/02/2007

Labeler - A-S Medication Solutions (830016429)

Establishment
Name	Address	ID/FEI	Business Operations
A-S Medication Solutions		830016429	RELABEL(50090-1101) , REPACK(50090-1101)

Revised: 11/2017 Document Id: 89bb20a0-9a04-4800-b335-ced9b9401ea8 34391-3 Set id: 40e794ba-2c0f-420c-977c-d29b4c945673 Version: 3 Effective Time: 20171108 A-S Medication Solutions