Cyclobenzaprine HCl Extended-Release Capsules

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/orange and are embossed in white ink with “30 mg” on the body, and Cephalon “C” logo, “Cephalon,” and a dashed band on the cap.

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/orange and are embossed in white ink with “30 mg” on the body, and Cephalon “C” logo, “Cephalon”, and a dashed band on the cap.

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].

Distributed By: Teva Pharmaceuticals USA, Inc., North Wales, PA 19454. Manufactured By: Adare Pharmaceuticals, Inc., Vandalia, OH 45377. Revised August 2015

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 (g) and alpha (a) 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

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 doseproportional 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.

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.

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

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.

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.

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.

Clinical Studies

Efficacy was assessed in two double-blind, parallel-group, active-controlled, placebocontrolled 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*

Table 3: Patients' Rating of Medication Helpfulness - Study 2*

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, patientrated restriction in activities of daily living, or quality of nighttime sleep.

Do not take cyclobenzaprine if you have used an MAO inhibitor such as isocarboxazid (Marplan), tranylcypromine (Parnate), phenelzine (Nardil), or selegiline (Eldepryl, Emsam) within the past 14 days. Serious, life-threatening side effects can occur if you take cyclobenzaprine before the MAO inhibitor has cleared from your body.

Do not use cyclobenzaprine if you have recently had a heart attack, or if you have:

• a heart rhythm disorder;
• congestive heart failure;
• heart block; or
• an overactive thyroid.

Before using cyclobenzaprine, tell your doctor if you are allergic to any drugs, or if you have:

• problems with urination;
• enlarged prostate;
• glaucoma; or
• liver disease.

If you have any of these conditions, you may need a dose adjustment or special tests to safely take cyclobenzaprine.

FDA pregnancy category B. This medication is not expected to be harmful to an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant during treatment.

It is not known whether cyclobenzaprine passes into breast milk or if it could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

Older adults may be more sensitive to the side effects of this medication.

Cyclobenzaprine can cause side effects that may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be awake and alert.

Avoid drinking alcohol, which can increase some of the side effects of cyclobenzaprine.

Cold or allergy medicine, narcotic pain medicine, sleeping pills, and medicine for seizures, depression or anxiety can add to sleepiness caused by cyclobenzaprine. Tell your doctor if you regularly use any of these medicines, or any other muscle relaxer.