Flexeril

Keep all appointments with your doctor.

Do not let anyone else take your medication. Ask your pharmacist any questions you have about refilling your prescription.

It is important for you to keep a written list of all of the prescription and nonprescription (over-the-counter) medicines you are taking, as well as any products such as vitamins, minerals, or other dietary supplements. You should bring this list with you each time you visit a doctor or if you are admitted to a hospital. It is also important information to carry with you in case of emergencies.

Cyclobenzaprine hydrochloride 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, Ndimethyl- 1-propanamine hydrochloride, and has the following structural formula:

FLEXERIL 5 mg (Cyclobenzaprine HCl) is supplied as a 5 mg tablet for oral administration. FLEXERIL 10 mg (Cyclobenzaprine HCl) is supplied as a 10 mg tablet for oral administration.

FLEXERIL tablets contain the following inactive ingredients: hydroxypropyl cellulose, hydroxypropyl methylcellulose, iron oxide, lactose, magnesium stearate, starch, and titanium dioxide. FLEXERIL 5 mg tablets also contain Yellow D&C #10 Aluminum Lake HT, and Yellow FD&C #6 Aluminum Lake.

Cyclobenzaprine HCl relieves skeletal muscle spasm of local origin without interfering with muscle function. It is ineffective in muscle spasm due to central nervous system disease.

Cyclobenzaprine reduced or abolished skeletal muscle hyperactivity in several animal models. 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 brain stem as opposed to spinal cord levels, although its 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 showed 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

Estimates of mean oral bioavailability of cyclobenzaprine range from 33% to 55%. Cyclobenzaprine exhibits linear pharmacokinetics over the dose range 2.5 mg to 10 mg, and is subject to enterohepatic circulation. It is highly bound to plasma proteins. Drug accumulates when dosed three times a day, reaching steady-state within 3-4 days at plasma concentrations about four-fold higher than after a single dose. At steady state in healthy subjects receiving 10 mg t.i.d. (n=18), peak plasma concentration was 25.9 ng/mL (range, 12.8-46.1 ng/mL), and area under the concentration-time (AUC) curve over an 8-hour dosing interval was 177 ng.hr/mL (range, 80-319 ng.hr/mL).

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 is eliminated quite slowly, with an effective half-life of 18 hours (range 8-37 hours; n=18); plasma clearance is 0.7 L/min.

The plasma concentration of cyclobenzaprine is generally higher in the elderly and in patients with hepatic impairment. (See PRECAUTIONS, Use in the Elderly and PRECAUTIONS, Impaired Hepatic Function.)

Elderly

In a pharmacokinetic study in elderly individuals ( ≥ 65yrs old), mean (n=10) steady-state cyclobenzaprine AUC values were approximately 1.7 fold (171.0 ng.hr/mL, range 96.1-255.3) higher than those seen in a group of eighteen younger adults (101.4 ng.hr/mL, range 36.1-182.9) from another study. Elderly male subjects had the highest observed mean increase, approximately 2.4 fold (198.3 ng.hr/mL, range 155.6-255.3 versus 83.2 ng.hr/mL, range 41.1-142.5 for younger males) while levels in elderly females were increased to a much lesser extent, approximately 1.2 fold (143.8 ng.hr/mL, range 96.1-196.3 versus 115.9 ng.hr/mL, range 36.1-182.9 for younger females).

In light of these findings, therapy with FLEXERIL in the elderly should be initiated with a 5 mg dose and titrated slowly upward.

Hepatic Impairment

In a pharmacokinetic study of sixteen 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. Based on the findings, FLEXERIL should be used with caution in subjects with mild hepatic impairment starting with the 5 mg dose and titrating slowly upward. Due to the lack of data in subjects with more severe hepatic insufficiency, the use of FLEXERIL in subjects with moderate to severe impairment is not recommended.

No significant effect on plasma levels or bioavailability of FLEXERIL or aspirin was noted when single or multiple doses of the two drugs were administered concomitantly. Concomitant administration of FLEXERIL and naproxen or diflunisal was well tolerated with no reported unexpected adverse effects. However combination therapy of FLEXERIL with naproxen was associated with more side effects than therapy with naproxen alone, primarily in the form of drowsiness. No well-controlled studies have been performed to indicate that FLEXERIL enhances the clinical effect of aspirin or other analgesics, or whether analgesics enhance the clinical effect of FLEXERIL in acute musculoskeletal conditions.

Clinical Studies

Eight double-blind controlled clinical studies were performed in 642 patients comparing FLEXERIL 10 mg, diazepam, and placebo. Muscle spasm, local pain and tenderness, limitation of motion, and restriction in activities of daily living were evaluated. In three of these studies there was a significantly greater improvement with FLEXERIL than with diazepam, while in the other studies the improvement following both treatments was comparable.

Although the frequency and severity of adverse reactions observed in patients treated with FLEXERIL were comparable to those observed in patients treated with diazepam, dry mouth was observed more frequently in patients treated with FLEXERIL and dizziness more frequently in those treated with diazepam. The incidence of drowsiness, the most frequent adverse reaction, was similar with both drugs.

The efficacy of FLEXERIL 5 mg was demonstrated in two seven-day, double-blind, controlled clinical trials enrolling 1405 patients. One study compared FLEXERIL 5 mg and 10 mg t.i.d. to placebo; and a second study compared FLEXERIL 5 mg and 2.5 mg t.i.d. to placebo. Primary endpoints for both trials were determined by patient-generated data and included global impression of change, medication helpfulness, and relief from starting backache. Each endpoint consisted of a score on a 5-point rating scale (from 0 or worst outcome to 4 or best outcome).

Comparisons of FLEXERIL 5 mg and placebo groups in both trials established the statistically significant superiority of the 5 mg dose for all three primary endpoints at day 8 and, in the study comparing 5 and 10 mg, at day 3 or 4 as well. A similar effect was observed with FLEXERIL 10 mg (all endpoints). Physician-assessed secondary endpoints also showed that FLEXERIL 5 mg was associated with a greater reduction in palpable muscle spasm than placebo.

Analysis of the data from controlled studies shows that FLEXERIL produces clinical improvement whether or not sedation occurs.

Secondary endpoints included a physician's evaluation of the presence and extent of palpable muscle spasm.

Surveillance Program

A post-marketing surveillance program was carried out in 7607 patients with acute musculoskeletal disorders, and included 297 patients treated with FLEXERIL 10 mg for 30 days or longer. The overall effectiveness of FLEXERIL was similar to that observed in the double-blind controlled studies; the overall incidence of adverse effects was less (see ADVERSE REACTIONS).

Flexeril is part of the drug class:

• Other centrally acting agents

If you take too much Flexeril, call your healthcare provider or local Poison Control Center, or seek emergency medical attention right away.

Absorption

Bioavailability

Well absorbed following oral administration110 111 but appears to undergo first-pass metabolism;112 113 115 mean oral bioavailability is 33–55%.101 110 111 113 114 Undergoes enterohepatic circulation.101 110 113

Special Populations

In patients ≥65 years of age, mean steady-state AUC is about 1.7 times greater than AUC in younger adults.101

In patients with mild to moderate hepatic impairment, peak plasma concentration and AUC are twice the values in healthy individuals.101 110

Distribution

Extent

Widely distributed into most body tissues.110

Plasma Protein Binding

About 93%.101 111

Elimination

Metabolism

Extensively metabolized in the liver via oxidation and conjugation.101 110 112 113 115 Oxidative N-demethylation mediated by CYP3A4, 1A2, and (to a lesser extent) 2D6.101 110

Elimination Route

Eliminated mainly in urine as inactive glucuronide metabolites; <1% eliminated as unchanged drug.101 110 112 113

Half-life

About 18 hours (range: 8–37 hours).101 110

• CNS depressant with sedative and skeletal muscle relaxant effects.101 a

• Precise mechanism of action not known.101 a Does not directly relax skeletal muscle and, unlike neuromuscular blocking agents, does not depress neuronal conduction, neuromuscular transmission, or muscle excitability.101 a

• Like tricyclic antidepressants, potentiates the effects of norepinephrine and has anticholinergic effects.101 a

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of cyclobenzaprine extended-release capsules in the pediatric population. Safety and efficacy have not been established.

Geriatric

Because of the possibility of higher blood levels in the elderly as compared to younger adults, use of cyclobenzaprine extended-release capsules is not recommended in the elderly.

Pregnancy

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Amifampridine
• Amisulpride
• Bepridil
• Cisapride
• Dronedarone
• Furazolidone
• Iproniazid
• Isocarboxazid
• Levomethadyl
• Linezolid
• Mesoridazine
• Methylene Blue
• Moclobemide
• Pargyline
• Phenelzine
• Pimozide
• Piperaquine
• Procarbazine
• Rasagiline
• Safinamide
• Saquinavir
• Selegiline
• Sparfloxacin
• Terfenadine
• Thioridazine
• Tranylcypromine
• Ziprasidone

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Alfentanil
• Almotriptan
• Amineptine
• Amiodarone
• Amitriptyline
• Amitriptylinoxide
• Amoxapine
• Amphetamine
• Anagrelide
• Aripiprazole
• Aripiprazole Lauroxil
• Arsenic Trioxide
• Artemether
• Asenapine
• Balofloxacin
• Bedaquiline
• Benzphetamine
• Besifloxacin
• Bromazepam
• Buprenorphine
• Buserelin
• Butriptyline
• Ciprofloxacin
• Citalopram
• Clarithromycin
• Clomipramine
• Clozapine
• Codeine
• Crizotinib
• Dabrafenib
• Degarelix
• Delamanid
• Desipramine
• Deslorelin
• Desvenlafaxine
• Deutetrabenazine
• Dextroamphetamine
• Dibenzepin
• Dihydrocodeine
• Disopyramide
• Dofetilide
• Dolasetron
• Domperidone
• Donepezil
• Dothiepin
• Doxepin
• Doxylamine
• Droperidol
• Duloxetine
• Efavirenz
• Enoxacin
• Erythromycin
• Escitalopram
• Fentanyl
• Flecainide
• Flibanserin
• Fluconazole
• Flumequine
• Fluoxetine
• Fluvoxamine
• Foscarnet
• Gatifloxacin
• Gemifloxacin
• Gonadorelin
• Goserelin
• Granisetron
• Halofantrine
• Histrelin
• Hydrocodone
• Hydromorphone
• Hydroxychloroquine
• Hydroxytryptophan
• Hydroxyzine
• Ibutilide
• Iloperidone
• Imipramine
• Iprindole
• Ivabradine
• Ketoconazole
• Lapatinib
• Leuprolide
• Levofloxacin
• Levomilnacipran
• Levorphanol
• Lisdexamfetamine
• Lofepramine
• Lomefloxacin
• Lorcaserin
• Lumefantrine
• Melitracen
• Meperidine
• Methadone
• Methamphetamine
• Metronidazole
• Milnacipran
• Mirtazapine
• Morphine
• Morphine Sulfate Liposome
• Moxifloxacin
• Nadifloxacin
• Nafarelin
• Nefazodone
• Nilotinib
• Norfloxacin
• Nortriptyline
• Ofloxacin
• Ondansetron
• Opipramol
• Oxycodone
• Oxymorphone
• Paliperidone
• Palonosetron
• Panobinostat
• Paroxetine
• Pasireotide
• Pazopanib
• Pazufloxacin
• Pefloxacin
• Periciazine
• Pimavanserin
• Pitolisant
• Pixantrone
• Posaconazole
• Propizepine
• Protriptyline
• Prulifloxacin
• Quetiapine
• Quinidine
• Ranolazine
• Remifentanil
• Ribociclib
• Rufloxacin
• Sertraline
• Sevoflurane
• Sibutramine
• Sodium Oxybate
• Sodium Phosphate
• Sotalol
• Sufentanil
• Sulpiride
• Sunitinib
• Tacrolimus
• Tapentadol
• Telithromycin
• Tetrabenazine
• Tianeptine
• Tiotropium
• Tizanidine
• Tramadol
• Trazodone
• Trimipramine
• Triptorelin
• Vandetanib
• Vemurafenib
• Venlafaxine
• Verapamil
• Vilazodone
• Vinflunine
• Voriconazole
• Vortioxetine
• Zolpidem
• Zuclopenthixol

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following is usually not recommended, but may be unavoidable in some cases. If used together, your doctor may change the dose or how often you use this medicine, or give you special instructions about the use of food, alcohol, or tobacco.

• Tobacco

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

• Congestive heart failure or
• Heart attack, recent or
• Heart block or
• Heart rhythm problems (eg, arrhythmia) or
• Hyperthyroidism (overactive thyroid)—Should not be used in patients with these conditions.

• Glaucoma, angle closure, history of or
• Trouble urinating, history of—Use with caution. May these conditions worse.

• Liver disease—Use with caution. The effects may be increased because of slower removal of the medicine from the body. .

• It is used to calm muscles.
• This medicine is used with rest, PT (physical therapy), pain drugs, and other therapies.

• May be used for the short-term relief of muscle spasm associated with acute, painful, musculoskeletal conditions.
• Improves pain, tenderness, and range of motion associated with muscle spasms and increases a person's ability to perform their day-to-day activities.
• Relieves skeletal muscle spasm without interfering with muscle function.
• The sedative effects of Flexeril may help people sleep who are experiencing insomnia as a result of muscle spasms.
• Flexeril's effects are long-lasting.
• Flexeril has not been associated with addiction; however, abrupt discontinuation may produce symptoms such as nausea, a headache, and a general feeling of discomfort. The dosage of Flexeril is best tapered off slowly on discontinuation.
• Flexeril is available as a generic under the name cyclobenzaprine.

• Flexeril may be taken with or without food.
• Flexeril should be taken in addition to rest and physical therapy.
• The effective dosage of Flexeril varies between individuals. Take Flexeril exactly as directed by your doctor. Talk with your doctor if you experience any worrying side effects or Flexeril is not effective.
• Flexeril is usually only given for a maximum of two to three weeks. Your doctor may advise tapering off the dose slowly when it is time to discontinue it.
• Flexeril is likely to make you sleepy or impair your judgment time. This may be beneficial in aiding sleep; however, you should avoid operating machinery, driving, or performing tasks that require mental alertness while taking this medicine.
• Avoid alcohol while taking this medicine. Alcohol may potentiate the side effects of Flexeril.
• Talk to your doctor or pharmacist before taking any other medications while you are taking Flexeril. Contact your doctor urgently if you experience any mental status changes (such as agitation, hallucinations, coma, delirium), fast heart rate, dizziness, flushing, muscle tremor or rigidity and stomach symptoms (including nausea, vomiting, and diarrhea).
• Tell your doctor if you have a heart condition, thyroid disease, liver disease, glaucoma or a problem with urination before starting treatment.

• Some muscle-relaxing effects may be noted within 20 to 30 minutes of oral administration. The effects of Flexeril last for four to six hours. Flexeril is eliminated from the body relatively slowly (7 to 37 hours).
• 5mg of Flexeril is reportedly as effective as 10mg of Flexeril, with fewer side effects.
• Flexeril is ineffective in muscle spasm due to brain injury or disease.

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