Cyclobenzaprine

Pronunciation

Class: Centrally Acting Skeletal Muscle Relaxants
VA Class: MS200
Chemical Name: 3-(5H-dibenzo[a,d]cyclohepten-5-ylidine)-N,N-dimethyl-1-propanamine hydrochloride
Molecular Formula: C20H21N·HCl
CAS Number: 6202-23-9
Brands: Flexeril

Introduction

Centrally acting skeletal muscle relaxant; structurally and pharmacologically related to tricyclic antidepressants.101

Uses for Cyclobenzaprine

Muscular Conditions

Adjunct to rest and physical therapy for the relief of muscular spasm associated with acute, painful musculoskeletal conditions.101

If pharmacologic therapy is required for acute low back pain (usually a benign and self-limiting condition105 106 108 ), an analgesic (e.g., acetaminophen, NSAIA) generally is recommended.104 105 106 108 117 Skeletal muscle relaxants may be used alone or in combination with analgesics for short-term relief; however, consider high incidence of adverse effects (e.g., CNS effects).104 106 107 108 Use skeletal muscle relaxants with caution and weigh risks against benefits.104 106 107 108

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Various skeletal muscle relaxants appear to have comparable efficacy for low back pain relief.104 106 108 109

Insufficient evidence to indicate whether cyclobenzaprine enhances the effects of aspirin or other analgesics, or vice versa, in the management of painful musculoskeletal conditions.101

Cyclobenzaprine is ineffective for the treatment of cerebral or spinal disease-associated spasticity or in children with cerebral palsy.101

Cyclobenzaprine Dosage and Administration

Administration

Administer orally.101

Dosage

Available as cyclobenzaprine hydrochloride; dosage expressed in terms of the salt.101

Pediatric Patients

Muscular Conditions
Oral

Adolescents ≥15 years of age: 5 mg 3 times daily; may increase dosage to 10 mg 3 times daily depending on response.101

Adults

Muscular Conditions
Oral

5 mg 3 times daily; may increase dosage to 10 mg 3 times daily depending on response.101

Prescribing Limits

Pediatric Patients

Muscular Conditions
Oral

Do not administer for more than 2–3 weeks.101

Adults

Muscular Conditions
Oral

Do not administer for more than 2–3 weeks.101

Special Populations

Hepatic Impairment

Initiate with caution in patients with mild hepatic impairment.101 Consider less frequent dosing; start with 5-mg dose and increase slowly.101

Use not recommended in patients with moderate or severe hepatic impairment.101

Geriatric Patients

Consider less frequent dosing; start with 5-mg dose and increase slowly.101

Cautions for Cyclobenzaprine

Contraindications

  • Known hypersensitivity to cyclobenzaprine or any ingredient in the formulation.101

  • Concomitant or recent (within 14 days) therapy with MAO inhibitor.101

  • Acute recovery phase of MI.101

  • Arrhythmias, heart block or conduction disorders, or CHF.101

  • Hyperthyroidism.101

Warnings/Precautions

Warnings

Similarity to Tricyclic Antidepressants

Shares the toxic potentials of tricyclic antidepressants; observe the usual precautions associated with tricyclic antidepressant therapy.101 a

Cardiac Effects

Arrhythmias, sinus tachycardia, prolongation of the conduction time leading to MI, and stroke reported with tricyclic antidepressants.101

CNS Effects

May cause serious CNS effects, especially when recommended dosage is exceeded.101

Performance of activities requiring mental alertness or physical coordination may be impaired.101

Concurrent use of other CNS depressants may potentiate CNS depression.101 (See Interactions: Specific Drugs.)

General Precautions

Anticholinergic Effects

Potential for adverse anticholinergic effects.101 Use with caution in patients with history of urinary retention, angle-closure glaucoma, or increased intraocular pressure or in patients receiving anticholinergic drugs.101

Specific Populations

Pregnancy

Category B.101 a

Lactation

Not known whether cyclobenzaprine is distributed into milk; however, distribution into milk is likely, since other tricyclic drugs distribute into milk.101 b Use with caution.101 a b

Pediatric Use

Safety and efficacy not established in children <15 years of age.101

Geriatric Use

Increased plasma concentrations.101

Increased frequency and severity of adverse effects (with or without concomitant drug therapy).101 Increased risk of adverse CNS effects (e.g., hallucinations, confusion, sedation), adverse cardiovascular effects resulting in falls or other sequelae, and interactions with other drugs or diseases.101

Use only if clearly needed.101 Cautious dosing recommended.101 (See Geriatric Patients under Dosage and Administration.)

Hepatic Impairment

Increased plasma concentrations and susceptibility to sedation.101

Initiate with caution in patients with mild hepatic impairment.101 (See Hepatic Impairment under Dosage and Administration.)

Use not recommended in patients with moderate or severe hepatic impairment.101

Common Adverse Effects

Drowsiness, dry mouth, dizziness, fatigue, headache.101

Interactions for Cyclobenzaprine

Metabolized by CYP3A4, 1A2, and (to a lesser extent) 2D6.101

Shares the drug interaction potential of tricyclic antidepressants; consider the usual interactions of tricyclic antidepressant therapy.101

Specific Drugs

Drug

Interaction

Comments

Aspirin

No substantial change in plasma concentrations or bioavailability of either drug101

CNS depressants (e.g., alcohol, barbiturates)

Additive effects101

Hypotensive agents (e.g., guanethidine)

May block uptake and antihypertensive effects of guanethidine and other similarly acting drugs101

MAO inhibitors

Possible hyperpyretic crisis, seizures, and death101

Cyclobenzaprine contraindicated in patients currently or recently (within 14 days) receiving MAO inhibitor101

Naproxen

Possible increased risk of drowsiness101

Tramadol

Increased risk of seizures101

Cyclobenzaprine Pharmacokinetics

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

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C).101

Actions

  • 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

Advice to Patients

  • Potential for drug to impair mental alertness and physical coordination, particularly when used with alcohol or other CNS depressants.101 Use caution when driving or operating machinery.101

  • Potential for more frequent or severe adverse effects in geriatric patients.101

  • Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.101 a b

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs as well as any concomitant illnesses.101 a b

  • Importance of informing patients of other important precautionary information.101 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Cyclobenzaprine Hydrochloride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

5 mg

Flexeril

McNeil

10 mg*

Flexeril

McNeil

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Amrix 15MG 24-hr Capsules (CEPHALON): 60/$649.99 or 180/$1,930.08

Cyclobenzaprine HCl 10MG Tablets (CADISTA): 30/$13.99 or 60/$16.98

Cyclobenzaprine HCl 15MG 24-hr Capsules (MYLAN): 30/$286.00 or 90/$825.97

Cyclobenzaprine HCl 30MG 24-hr Capsules (WATSON LABS): 30/$345.99 or 90/$1,009.98

Cyclobenzaprine HCl 5MG Tablets (CADISTA): 30/$13.99 or 60/$16.98

Flexeril 10MG Tablets (MCNEIL CONSUMER): 30/$66.48 or 90/$176.60

Flexeril 5MG Tablets (MCNEIL CONSUMER): 30/$60.44 or 90/$168.38

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions November 18, 2012. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

Only references cited for selected revisions after 1984 are available electronically.

100. Gatter RA. Pharmacotherapeutics in fibrositis. Am J Med. 1986; 81(Suppl 3A):63-6. [IDIS 222657] [PubMed 3464210]

101. McNeil. Cyclobenzaprine hydrochloride (Flexeril) tablets prescribing information. Fort Washington, PA: 2003 Feb.

102. Liebelt EL, Francis PD. Cyclic Antidepressants. In: Goldfrank’s Toxicologic Emergencies. 7th Ed. 2002. McGraw-Hill New York, NY.

103. Borenstein DG, Korn S. Efficacy of a low-dose regimen of cyclobenzaprine acute skeletal muscle spasm: results of two placebo-controlled trials. Clin Ther. 2003; 25:1056-73. [IDIS 497263] [PubMed 12809957]

104. van Tulder MW, Touray T, Furlan AD et al. Muscle relaxants for non-specific low back pain. Cochrane Database Syst Rev. 2003; :CD004252. [PubMed 12804507]

105. Roelofs PD, Deyo RA, Koes BW et al. Non-steroidal anti-inflammatory drugs for low back pain. Cochrane Database Syst Rev. 2008; :CD000396. [PubMed 18253976]

106. Chou R, Qaseem A, Snow V et al. Diagnosis and treatment of low back pain: a joint clinical practice guideline from the American College of Physicians and the American Pain Society. Ann Intern Med. 2007; 147:478-91. [PubMed 17909209]

107. Institute for Clinical Systems Improvement. Health care guideline: adult acute and subacute low back pain. 15th ed. Bloomington, MN; 2012 Jan. From the ICSI website

108. Toth PP, Urtis J. Commonly used muscle relaxant therapies for acute low back pain: a review of carisoprodol, cyclobenzaprine hydrochloride, and metaxalone. Clin Ther. 2004; 26:1355-67. [PubMed 15530999]

109. See S, Ginzburg R. Skeletal muscle relaxants. Pharmacotherapy. 2008; 28:207-13. [PubMed 18225966]

110. Winchell GA, King JD, Chavez-Eng CM et al. Cyclobenzaprine pharmacokinetics, including the effects of age, gender, and hepatic insufficiency. J Clin Pharmacol. 2002;42:61-9. IDIS 475544

111. Hucker HB, Stauffer SC, Balletto AJ et al. Physiological disposition and metabolism of cyclobenzaprine in the rat, dog, rhesus monkey, and man. Drug Metab Dispos. 1978; 6:659-72. [IDIS 118762] [PubMed 33029]

112. Hucker HB, Stauffer SC, Albert KS et al. Plasma levels and bioavailability of cyclobenzaprine in human subjects. J Clin Pharmacol. 1977; Nov-Dec:719-27.

113. Till AE, Constanzer ML, Demetriades J et al. Evidence for route dependent biotransformation of cyclobenzaprine hydrochloride. Biopharm Drug Dispos. 1982; 3:19-28. [IDIS 147637] [PubMed 7082776]

114. Nugent LW, Irvin JD, Till AE et al. Cyclobenzaprine hydrochloride: Pharmacokinetics and bioavailability following oral and intramuscular administration. J Clin Pharmacol. 1982; 22(Suppl): 12A.

115. Hucker HB, Stauffer SC. GLC determination of cyclobenzaprine in plasma and urine. J Pharm Sci. 1976; 65:1253-5. [IDIS 70381] [PubMed 978450]

117. Boothby LA, Doering PL, Hatton RC. Carisoprodol: a marginally effective skeletal muscle relaxant with serious abuse potential. Hosp Pharm. 2003; 38:337-45.

a. AHFS Drug Information 2003. McEvoy GK, ed. Cyclobenzaprine hydrochloride. Bethesda, MD: American Society of Health-System Pharmacists; 2004:1330-2.

b. AHFS Drug Information 2003. McEvoy GK, ed. Tricyclic antidepressants general statement. Bethesda, MD: American Society of Health-System Pharmacists; 2004:2234-41.

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