Version July 2025
Fibromyalgia (alternative agent) (off-label use):
Note: For mild to moderate symptoms, particularly with sleep disturbance (Ref).
Oral: Immediate release: Initial: 5 to 10 mg once daily before bedtime; may gradually titrate as needed and tolerated up to 10 to 40 mg daily in 1 to 3 divided doses (Ref). If excessive sedation occurs, may divide dose so larger portion is taken at bedtime (eg, 5 mg in morning and 10 or 15 mg at bedtime) (Ref).
Muscle spasm and/or musculoskeletal pain (adjunctive therapy):
Note: For skeletal muscle spasm and/or pain (eg, low back pain, neck pain) with muscle spasm, usually in combination with a nonsteroidal anti-inflammatory drug (NSAID) and/or acetaminophen (Ref). In general, muscle relaxants should be used temporarily (eg, for a few days or intermittently for a few days when needed; up to 4 weeks’ duration when necessary) (Ref).
Oral: Immediate release: Initial: 5 mg 3 times daily scheduled or as needed with one of the doses administered at bedtime (Ref). May increase dose based on response and tolerability up to 10 mg 3 times daily as needed. Once-daily use at bedtime (with daytime NSAID and/or acetaminophen) may be better tolerated (Ref).
Oral: Extended release: Usual: 15 mg once daily; some patients may require up to 30 mg once daily.
Temporomandibular disorder, acute (adjunctive therapy) (off-label use):
Note: Adjunct to an NSAID in select patients with pain on palpation of the lower jaw muscle (Ref).
Oral: Immediate release: Usual: 5 to 10 mg once daily at bedtime for 10 to 14 days; some patients with persistent muscular pain may require an additional 7 days of therapy (Ref).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason A. Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.
Altered kidney function: Mild to severe impairment: No dosage adjustment likely needed based on pharmacokinetic characteristics; however, use with caution due to limited safety and efficacy data (Ref).
Hemodialysis: Unlikely to be dialyzed (Ref): No dosage adjustment likely needed based on pharmacokinetic characteristics; however, use with caution due to limited safety and efficacy data (Ref). Increased risk of altered mental status and fractures has been observed (Ref).
Extended release: Mild to severe impairment: Use not recommended.
Immediate release:
Mild impairment: Initial: 5 mg; use with caution; titrate slowly and consider less frequent dosing.
Moderate to severe impairment: Use not recommended.
Avoid use (Ref).
(For additional information see "Cyclobenzaprine: Pediatric drug information")
Muscle spasm, treatment: Adolescents ≥15 years: Oral: Immediate release tablet: Initial: 5 mg 3 times daily; may increase up to 10 mg 3 times daily if needed. Do not use longer than 2 to 3 weeks.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in the manufacturer's labeling.
Immediate release tablet: Adolescents ≥15 years:
Mild impairment: Initial: 5 mg; use with caution; titrate slowly and consider less frequent dosing
Moderate to severe impairment: Use not recommended
Similar to tricyclic antidepressants, reversible peripheral and central anticholinergic effects may occur with cyclobenzaprine use. These include CNS effects (eg, dizziness, drowsiness, confusion), GI effects (eg, constipation), and GU effects (eg, urinary retention). The anticholinergic CNS effects have been associated with an increased risk of injury and falls in older patients (Ref).
Mechanism: Dose-related; related to the pharmacologic action (ie, inhibition of acetylcholine action at muscarinic receptors; atropine-like effects).
Risk factors:
• Higher doses (Ref)
• Multiple daily dosing (Ref)
• Age ≥65 years (Ref)
• Concurrent administration with other anticholinergic agents
Cyclobenzaprine use is associated with reversible CNS effects such as dizziness, drowsiness, asthenia, and fatigue which may impair the ability to drive or operate machinery (Ref). These effects have been associated with an increased risk of injury and falls in older patients (Ref).
Mechanism: Dose-related; mechanism not fully understood. Sedation may be a result of anticholinergic and other CNS effects (Ref).
Onset: Rapid; typically occurs within the first 3 days of therapy (Ref).
Risk factors:
• Higher doses (Ref)
• Multiple daily dosing (Ref)
• Age ≥65 years (Ref)
• Concurrent administration with ethanol and/or other CNS depressants (Ref)
• Hepatic impairment
Serotonin syndrome has been reported rarely when cyclobenzaprine is concurrently administered with one or more serotonergic agents. Symptoms such as mental status changes (confusion, agitation, psychosis, hallucinations, delusions); autonomic instability (tachycardia, labile blood pressure, hyperthermia); neuromuscular effects (tremor, clonus, myoclonus, muscle rigidity); and GI effects (diaphoresis, nausea, vomiting, diarrhea) have been observed. These effects are typically reversible within 3 days after withdrawal of cyclobenzaprine and/or serotonergic agents and supportive care (Ref). Some reported cases have been life-threatening (Ref).
Mechanism: Non–dose-related; inhibition of serotonin transport and agonist action at serotonin receptors (Ref).
Onset: Rapid; generally occurs within the first 24 hours of concurrent administration with serotonergic agents (Ref).
Risk factors:
• Concurrent use of drugs that increase serotonin synthesis, block serotonin reuptake, and/or impair serotonin metabolism
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
>10%:
Gastrointestinal: Xerostomia (6% to 32%) (table 1)
|
Drug (Cyclobenzaprine) |
Placebo |
Dose |
Dosage Form |
Number of Patients (Cyclobenzaprine) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|
|
32% |
7% |
10 mg 3 times daily |
Immediate-release tablets |
249 |
469 |
|
21% |
7% |
5 mg 3 times daily |
Immediate-release tablets |
464 |
469 |
|
27% |
N/A |
10 mg 3 times daily |
Immediate-release tablets |
N/A |
N/A |
|
14% |
2% |
30 mg once daily |
Extended-release capsules |
126 |
128 |
|
6% |
2% |
15 mg once daily |
Extended-release capsules |
127 |
128 |
Nervous system: Dizziness (3% to 11%) (table 2), drowsiness (1% to 39%) (table 3)
|
Drug (Cyclobenzaprine) |
Placebo |
Dose |
Dosage Form |
Number of Patients (Cyclobenzaprine) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|
|
11% |
N/A |
10 mg 3 times daily |
Immediate-release tablets |
N/A |
N/A |
|
6% |
2% |
30 mg once daily |
Extended-release capsules |
126 |
128 |
|
3% |
2% |
15 mg once daily |
Extended-release capsules |
127 |
128 |
|
Drug (Cyclobenzaprine) |
Placebo |
Dose |
Dosage Form |
Number of Patients (Cyclobenzaprine) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|
|
39% |
N/A |
10 mg 3 times daily |
Immediate-release tablets |
N/A |
N/A |
|
38% |
10% |
10 mg 3 times daily |
Immediate-release tablets |
249 |
469 |
|
29% |
10% |
5 mg 3 times daily |
Immediate-release tablets |
464 |
469 |
|
2% |
0% |
30 mg once daily |
Extended-release capsules |
126 |
128 |
|
1% |
0% |
15 mg once daily |
Extended-release capsules |
127 |
128 |
1% to 10%:
Gastrointestinal: Abdominal pain (1% to 3%), acid regurgitation (1% to 3%), constipation (1% to 3%) (table 4), diarrhea (1% to 3%), dyspepsia (4%), nausea (3%), unpleasant taste (1% to 3%)
|
Drug (Cyclobenzaprine) |
Placebo |
Dose |
Dosage Form |
Number of Patients (Cyclobenzaprine) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|
|
3% |
0% |
30 mg once daily |
Extended-release capsules |
126 |
128 |
|
1% |
0% |
15 mg once daily |
Extended-release capsules |
127 |
128 |
Nervous system: Confusion (1% to 3%), decreased mental acuity (1% to 3%), fatigue (3% to 6%) (table 5), headache (1% to 3%), irritability (1% to 3%), nervousness (1% to 3%)
|
Drug (Cyclobenzaprine) |
Placebo |
Dose |
Dosage Form |
Number of Patients (Cyclobenzaprine) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|
|
6% |
3% |
5 mg 3 times daily |
Immediate-release tablets |
464 |
469 |
|
6% |
3% |
10 mg 3 times daily |
Immediate-release tablets |
249 |
469 |
|
3% |
2% |
15 mg once daily |
Extended-release capsules |
127 |
128 |
|
3% |
2% |
30 mg once daily |
Extended-release capsules |
126 |
128 |
Neuromuscular & skeletal: Asthenia (1% to 3%)
Ophthalmic: Blurred vision (1% to 3%)
Respiratory: Pharyngitis (1% to 3%), upper respiratory tract infection (1% to 3%)
Postmarketing:
Cardiovascular: Cardiac arrhythmia, facial edema, hypotension, palpitations, syncope, tachycardia (may be associated with serotonin syndrome; (Ref)), vasodilation
Dermatologic: Diaphoresis (may be associated with serotonin syndrome; (Ref)), pruritus, skin rash, urticaria
Endocrine & metabolic: Increased thirst
Gastrointestinal: Ageusia, anorexia, cholestasis, flatulence, gastritis, gastrointestinal pain, vomiting
Genitourinary: Urinary frequency, urinary retention (Ref)
Hepatic: Hepatitis (rare), jaundice
Hypersensitivity: Anaphylaxis, angioedema, tongue edema
Nervous system: Abnormal dreams, abnormal sensory symptoms, abnormality in thinking, agitation (may be associated with serotonin syndrome; (Ref)), anxiety, ataxia, clonus (may be associated with serotonin syndrome; (Ref)), delusion (may be associated with serotonin syndrome; (Ref)), depressed mood, disorientation, dysarthria, excitement, hallucination (may be associated with serotonin syndrome; (Ref)), hyperthermia (may be associated with serotonin syndrome; (Ref)), hypertonia, insomnia, malaise, myoclonus (may be associated with serotonin syndrome; (Ref)), paresthesia, psychosis, seizure, serotonin syndrome (Ref), vertigo
Neuromuscular & skeletal: Muscle rigidity (may be associated with serotonin syndrome; (Ref)), muscle twitching, tremor (may be associated with serotonin syndrome; (Ref))
Ophthalmic: Diplopia
Otic: Tinnitus
Hypersensitivity to cyclobenzaprine or any component of the formulation; during or within 14 days of MAO inhibitors; hyperthyroidism; heart failure; arrhythmias; heart block or conduction disturbances; acute recovery phase of MI
Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Concerns related to adverse effects:
• Toxicity: Cyclobenzaprine shares the toxic potentials of the tricyclic antidepressants, including prolongation of conduction time, arrhythmias, and tachycardia; the usual precautions of tricyclic antidepressant therapy should be observed.
Disease-related concerns:
• Hepatic impairment: Use with caution in patients with mild hepatic impairment; plasma concentrations increased twofold in presence of mild impairment. Not recommended in moderate to severe hepatic impairment. ER capsules not recommended in patients with hepatic impairment of any severity (mild, moderate, or severe).
• Ophthalmic conditions: Use with caution in patients with certain ophthalmic conditions (eg, increased intraocular pressure, angle-closure glaucoma) as anticholinergic effects may exacerbate underlying condition.
• Urinary frequency/hesitancy: Use with caution in patients with urinary frequency/hesitancy as anticholinergic effects may exacerbate underlying condition.
Special populations:
• Older adult: ER capsules not recommended for use in older adults.
Other warnings/precautions:
• Appropriate use: Limit therapy to 2 to 3 weeks; efficacy has not been established for longer periods of use.
Not effective in the treatment of spasticity due to cerebral or spinal cord disease or in children with cerebral palsy.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Capsule Extended Release 24 Hour, Oral, as hydrochloride:
Amrix: 15 mg [contains fd&c red #40 (allura red ac dye), quinoline yellow (d&c yellow #10)]
Amrix: 30 mg [contains fd&c blue #1 (brilliant blue), fd&c blue #2 (indigotine,indigo carmine), fd&c red #40 (allura red ac dye), fd&c yellow #6 (sunset yellow)]
Generic: 15 mg, 30 mg
Tablet, Oral, as hydrochloride:
Fexmid: 7.5 mg [DSC]
Generic: 5 mg, 7.5 mg, 10 mg
Yes
Capsule ER 24 Hour Therapy Pack (Amrix Oral)
15 mg (per each): $76.19
30 mg (per each): $76.19
Capsule ER 24 Hour Therapy Pack (Cyclobenzaprine HCl ER Oral)
15 mg (per each): $39.71 - $45.28
30 mg (per each): $39.71 - $45.28
Tablets (Cyclobenzaprine HCl Oral)
5 mg (per each): $1.64 - $1.73
7.5 mg (per each): $4.81 - $7.54
10 mg (per each): $0.26 - $2.98
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral, as hydrochloride:
Flexeril: 10 mg [contains corn starch, fd&c yellow #6(sunset yellow)alumin lake]
Generic: 10 mg
Oral: Extended release: Swallow whole and administer at the same time each day. Alternatively, the contents of the capsule may be sprinkled onto a tablespoon of applesauce and consume immediately without chewing; rinse mouth to ensure all contents have been swallowed; discard any unused portion of capsule.
Muscle spasm: As an adjunct to rest and physical therapy for short-term (2 to 3 weeks) relief of muscle spasm associated with acute, painful musculoskeletal conditions.
Fibromyalgia; Temporomandibular disorder, acute
Cyclobenzaprine may be confused with cycloSERINE, cyproheptadine
Flexeril may be confused with Floxin
Beers Criteria: Cyclobenzaprine is identified in the Beers Criteria as a potentially inappropriate medication to be avoided in patients 65 years and older (independent of diagnosis or condition) because most muscle relaxants are poorly tolerated in older adults due to anticholinergic effects caused by some muscle relaxants, risk of sedation, and an increased risk of fracture. Cyclobenzaprine has strong anticholinergic properties. In addition, efficacy is questionable at doses tolerated by geriatric patients (Beers Criteria [AGS 2023]).
Pharmacy Quality Alliance (PQA): Cyclobenzaprine (as a single agent or as part of a combination product) is identified as a high-risk medication in patients 65 years and older on the PQA’s, Use of High-Risk Medications in the Elderly (HRM) performance measure, a safety measure used by the Centers for Medicare and Medicaid Services (CMS) for Medicare plans (PQA 2017).
Flexin: Brand name for cyclobenzaprine [Chile], but also the brand name for diclofenac [Argentina] and orphenadrine [Israel]
Flexin [Chile] may be confused with Floxin brand name for flunarizine [Thailand], norfloxacin [South Africa], ofloxacin [US, Canada], and pefloxacin [Philippines]; Fluoxine brand name for fluoxetine [Thailand]; Flexinol brand name for methocarbamol and paracetamol [India]
Substrate of CYP1A2 (Minor), CYP2D6 (Minor), CYP3A4 (Minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential;
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program by clicking on the “Launch drug interactions program” link above.
Acetylcholinesterase Inhibitors: May decrease therapeutic effects of Agents with Clinically Relevant Anticholinergic Effects. Agents with Clinically Relevant Anticholinergic Effects may decrease therapeutic effects of Acetylcholinesterase Inhibitors. Risk C: Monitor
Aclidinium: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk X: Avoid
Acrivastine: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk C: Monitor
Acrivastine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Alcohol (Ethyl): CNS Depressants may increase CNS depressant effects of Alcohol (Ethyl). Risk C: Monitor
Alizapride: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Amantadine: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk C: Monitor
Amisulpride (Oral): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Articaine: May increase CNS depressant effects of CNS Depressants. Management: Consider reducing the dose of articaine if possible when used in patients who are also receiving CNS depressants. Monitor for excessive CNS depressant effects with any combined use. Risk D: Consider Therapy Modification
Azelastine (Nasal): May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Benperidol: Agents with Clinically Relevant Anticholinergic Effects may decrease therapeutic effects of Benperidol. Risk C: Monitor
Benperidol: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Benztropine: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Benztropine. Risk C: Monitor
Biperiden: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Biperiden. Risk C: Monitor
Blonanserin: CNS Depressants may increase CNS depressant effects of Blonanserin. Management: Use caution if coadministering blonanserin and CNS depressants; dose reduction of the other CNS depressant may be required. Strong CNS depressants should not be coadministered with blonanserin. Risk D: Consider Therapy Modification
Bornaprine: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Bornaprine. Risk C: Monitor
Botulinum Toxin-Containing Products: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk C: Monitor
Botulinum Toxin-Containing Products: Muscle Relaxants (Centrally Acting) may increase adverse/toxic effects of Botulinum Toxin-Containing Products. Specifically, the risk for increased muscle weakness may be enhanced. Risk C: Monitor
Brexanolone: CNS Depressants may increase CNS depressant effects of Brexanolone. Risk C: Monitor
Brimonidine (Topical): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Bromopride: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Bromperidol: May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Buclizine: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Buclizine. Risk C: Monitor
Buclizine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Buprenorphine: CNS Depressants may increase CNS depressant effects of Buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine at lower doses in patients already receiving CNS depressants. Risk D: Consider Therapy Modification
BusPIRone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Cannabinoid-Containing Products: Agents with Clinically Relevant Anticholinergic Effects may increase tachycardic effects of Cannabinoid-Containing Products. Risk C: Monitor
Cannabinoid-Containing Products: CNS Depressants may increase CNS depressant effects of Cannabinoid-Containing Products. Risk C: Monitor
Cetirizine (Systemic): May increase CNS depressant effects of CNS Depressants. Management: Consider avoiding this combination if possible. If required, monitor for excessive sedation or CNS depression, limit the dose and duration of combination therapy, and consider CNS depressant dose reductions. Risk D: Consider Therapy Modification
Chloral Hydrate/Chloral Betaine: CNS Depressants may increase CNS depressant effects of Chloral Hydrate/Chloral Betaine. Management: Consider alternatives to the use of chloral hydrate or chloral betaine and additional CNS depressants. If combined, consider a dose reduction of either agent and monitor closely for enhanced CNS depressive effects. Risk D: Consider Therapy Modification
Chlormethiazole: May increase CNS depressant effects of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used. Risk D: Consider Therapy Modification
Chlorphenesin Carbamate: May increase adverse/toxic effects of CNS Depressants. Risk C: Monitor
Chlorprothixene: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Chlorprothixene. Risk C: Monitor
Cimetropium: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Cimetropium. Risk X: Avoid
CloZAPine: Agents with Clinically Relevant Anticholinergic Effects may increase constipating effects of CloZAPine. Management: Consider alternatives to this combination whenever possible. If combined, monitor closely for signs and symptoms of gastrointestinal hypomotility and consider prophylactic laxative treatment. Risk D: Consider Therapy Modification
CNS Depressants: May increase adverse/toxic effects of CNS Depressants. Risk C: Monitor
Cyclizine: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk C: Monitor
Dantrolene: May increase adverse neuromuscular effects of Muscle Relaxants (Centrally Acting). Specifically, neuromuscular block may be potentiated. Risk C: Monitor
Daridorexant: May increase CNS depressant effects of CNS Depressants. Management: Dose reduction of daridorexant and/or any other CNS depressant may be necessary. Use of daridorexant with alcohol is not recommended, and the use of daridorexant with any other drug to treat insomnia is not recommended. Risk D: Consider Therapy Modification
Darifenacin: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Darifenacin. Risk C: Monitor
DexmedeTOMIDine: CNS Depressants may increase CNS depressant effects of DexmedeTOMIDine. Management: Monitor for increased CNS depression during coadministration of dexmedetomidine and CNS depressants, and consider dose reductions of either agent to avoid excessive CNS depression. Risk D: Consider Therapy Modification
Dicyclomine: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Dicyclomine. Risk C: Monitor
Difelikefalin: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Difenoxin: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Dihydralazine: CNS Depressants may increase hypotensive effects of Dihydralazine. Risk C: Monitor
Dimethindene (Systemic): Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Dimethindene (Systemic). Risk C: Monitor
Dimethindene (Topical): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Dothiepin: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Doxylamine: CNS Depressants may increase CNS depressant effects of Doxylamine. Risk C: Monitor
DroNABinol: Agents with Clinically Relevant Anticholinergic Effects may increase tachycardic effects of DroNABinol. Risk X: Avoid
DroPERidol: May increase CNS depressant effects of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (eg, opioids, barbiturates) with concomitant use. Risk D: Consider Therapy Modification
Eluxadoline: Agents with Clinically Relevant Anticholinergic Effects may increase constipating effects of Eluxadoline. Risk X: Avoid
Emedastine (Systemic): May increase CNS depressant effects of CNS Depressants. Management: Consider avoiding this combination if possible. If required, monitor for excessive sedation or CNS depression, limit the dose and duration of combination therapy, and consider CNS depressant dose reductions. Risk C: Monitor
Entacapone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Esketamine (Nasal): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Fesoterodine: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Fesoterodine. Risk C: Monitor
Flunarizine: CNS Depressants may increase CNS depressant effects of Flunarizine. Risk X: Avoid
Flunitrazepam: CNS Depressants may increase CNS depressant effects of Flunitrazepam. Management: Reduce the dose of CNS depressants when combined with flunitrazepam and monitor patients for evidence of CNS depression (eg, sedation, respiratory depression). Use non-CNS depressant alternatives when available. Risk D: Consider Therapy Modification
FluPHENAZine: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk C: Monitor
Gastrointestinal Agents (Prokinetic): Agents with Clinically Relevant Anticholinergic Effects may decrease therapeutic effects of Gastrointestinal Agents (Prokinetic). Risk C: Monitor
Gepotidacin: May decrease anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk C: Monitor
Glucagon: Agents with Clinically Relevant Anticholinergic Effects may increase adverse/toxic effects of Glucagon. Specifically, the risk of gastrointestinal adverse effects may be increased. Risk C: Monitor
Glycopyrrolate (Oral Inhalation): Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Glycopyrrolate (Oral Inhalation). Risk X: Avoid
Glycopyrrolate (Systemic): Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Glycopyrrolate (Systemic). Risk C: Monitor
Glycopyrronium (Topical): May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk X: Avoid
HydrOXYzine: May increase CNS depressant effects of CNS Depressants. Management: Consider a decrease in the CNS depressant dose, as appropriate, when used together with hydroxyzine. Increase monitoring of signs/symptoms of CNS depression in any patient receiving hydroxyzine together with another CNS depressant. Risk D: Consider Therapy Modification
Ipratropium (Nasal): May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk C: Monitor
Ipratropium (Oral Inhalation): May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk X: Avoid
Itopride: Agents with Clinically Relevant Anticholinergic Effects may decrease therapeutic effects of Itopride. Risk C: Monitor
Ixabepilone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Kava Kava: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Ketotifen (Systemic): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Kratom: May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Lemborexant: May increase CNS depressant effects of CNS Depressants. Management: Dosage adjustments of lemborexant and of concomitant CNS depressants may be necessary when administered together because of potentially additive CNS depressant effects. Close monitoring for CNS depressant effects is necessary. Risk D: Consider Therapy Modification
Levocetirizine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Levosulpiride: Agents with Clinically Relevant Anticholinergic Effects may decrease therapeutic effects of Levosulpiride. Risk X: Avoid
Lisuride: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Lofepramine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Lofexidine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Loxapine: CNS Depressants may increase CNS depressant effects of Loxapine. Management: Consider reducing the dose of CNS depressants administered concomitantly with loxapine due to an increased risk of respiratory depression, sedation, hypotension, and syncope. Risk D: Consider Therapy Modification
Magnesium Sulfate: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Maprotiline: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Maprotiline. Risk C: Monitor
Melitracen [INT]: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Melperone: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk C: Monitor
Mequitazine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Metergoline: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Methotrimeprazine: CNS Depressants may increase CNS depressant effects of Methotrimeprazine. Methotrimeprazine may increase CNS depressant effects of CNS Depressants. Management: Reduce the usual dose of CNS depressants by 50% if starting methotrimeprazine until the dose of methotrimeprazine is stable. Monitor patient closely for evidence of CNS depression. Risk D: Consider Therapy Modification
Methoxyflurane: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Methscopolamine: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Methscopolamine. Risk C: Monitor
Metoclopramide: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
MetyroSINE: CNS Depressants may increase sedative effects of MetyroSINE. Risk C: Monitor
Minocycline (Systemic): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Mirabegron: Agents with Clinically Relevant Anticholinergic Effects may increase adverse/toxic effects of Mirabegron. Risk C: Monitor
Monoamine Oxidase Inhibitors: Cyclobenzaprine may increase serotonergic effects of Monoamine Oxidase Inhibitors. This could result in serotonin syndrome. Risk X: Avoid
Moxonidine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Nabilone: May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Nalfurafine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Nitroglycerin: Agents with Clinically Relevant Anticholinergic Effects may decrease absorption of Nitroglycerin. Specifically, anticholinergic agents may decrease the dissolution of sublingual nitroglycerin tablets, possibly impairing or slowing nitroglycerin absorption. Risk C: Monitor
Noscapine: CNS Depressants may increase adverse/toxic effects of Noscapine. Risk X: Avoid
OLANZapine: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of OLANZapine. Risk C: Monitor
Olopatadine (Nasal): May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Ombitasvir, Paritaprevir, and Ritonavir: May decrease serum concentration of Cyclobenzaprine. Risk C: Monitor
Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir: May decrease serum concentration of Cyclobenzaprine. Risk C: Monitor
Opicapone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Opioid Agonists: CNS Depressants may increase CNS depressant effects of Opioid Agonists. Management: Avoid concomitant use of opioid agonists and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider Therapy Modification
Opipramol: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk C: Monitor
Opipramol: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Orphenadrine: CNS Depressants may increase CNS depressant effects of Orphenadrine. Risk X: Avoid
Oxatomide: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk X: Avoid
Oxomemazine: May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Oxybate Salt Products: CNS Depressants may increase CNS depressant effects of Oxybate Salt Products. Management: Consider alternatives to this combination when possible. If combined, dose reduction or discontinuation of one or more CNS depressants (including the oxybate salt product) should be considered. Interrupt oxybate salt treatment during short-term opioid use Risk D: Consider Therapy Modification
OxyBUTYnin: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of OxyBUTYnin. Risk C: Monitor
OxyCODONE: CNS Depressants may increase CNS depressant effects of OxyCODONE. Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider Therapy Modification
Paliperidone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Paraldehyde: CNS Depressants may increase CNS depressant effects of Paraldehyde. Risk X: Avoid
Perampanel: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Perazine: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk C: Monitor
Periciazine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Perphenazine: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Perphenazine. Risk C: Monitor
Pipamperone: May increase adverse/toxic effects of CNS Depressants. Risk C: Monitor
Piribedil: CNS Depressants may increase CNS depressant effects of Piribedil. Risk C: Monitor
Pizotifen: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Potassium Chloride: Agents with Clinically Relevant Anticholinergic Effects may increase ulcerogenic effects of Potassium Chloride. Management: Patients on drugs with substantial anticholinergic effects should avoid using any solid oral dosage form of potassium chloride. Risk X: Avoid
Potassium Citrate: Agents with Clinically Relevant Anticholinergic Effects may increase ulcerogenic effects of Potassium Citrate. Management: Patients on drugs with substantial anticholinergic effects should avoid using any solid oral dosage form of potassium citrate. Risk X: Avoid
Pramipexole: CNS Depressants may increase sedative effects of Pramipexole. Risk C: Monitor
Pramlintide: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. These effects are specific to the GI tract. Risk X: Avoid
Procarbazine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Promethazine: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Promethazine. Risk C: Monitor
Propantheline: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Propantheline. Risk C: Monitor
Propiverine: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk C: Monitor
QuiNIDine: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk C: Monitor
Ramosetron: Agents with Clinically Relevant Anticholinergic Effects may increase constipating effects of Ramosetron. Risk C: Monitor
Revefenacin: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Revefenacin. Risk X: Avoid
Rilmenidine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Rivastigmine: Agents with Clinically Relevant Anticholinergic Effects may decrease therapeutic effects of Rivastigmine. Rivastigmine may decrease therapeutic effects of Agents with Clinically Relevant Anticholinergic Effects. Management: Use of rivastigmine with an anticholinergic agent is not recommended unless clinically necessary. If the combination is necessary, monitor for reduced anticholinergic effects. Risk D: Consider Therapy Modification
Ropeginterferon Alfa-2b: CNS Depressants may increase adverse/toxic effects of Ropeginterferon Alfa-2b. Specifically, the risk of neuropsychiatric adverse effects may be increased. Management: Avoid coadministration of ropeginterferon alfa-2b and other CNS depressants. If this combination cannot be avoided, monitor patients for neuropsychiatric adverse effects (eg, depression, suicidal ideation, aggression, mania). Risk D: Consider Therapy Modification
ROPINIRole: CNS Depressants may increase sedative effects of ROPINIRole. Risk C: Monitor
Rotigotine: CNS Depressants may increase sedative effects of Rotigotine. Risk C: Monitor
Scopolamine: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Scopolamine. Risk C: Monitor
Secretin: Agents with Clinically Relevant Anticholinergic Effects may decrease therapeutic effects of Secretin. Management: Avoid concomitant use of anticholinergic agents and secretin. Discontinue anticholinergic agents at least 5 half-lives prior to administration of secretin. Risk D: Consider Therapy Modification
Serotonergic Agents (High Risk): Cyclobenzaprine may increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor
Sofpironium: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Sofpironium. Risk X: Avoid
Suvorexant: CNS Depressants may increase CNS depressant effects of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Risk D: Consider Therapy Modification
Thalidomide: CNS Depressants may increase CNS depressant effects of Thalidomide. Risk X: Avoid
Thiazide and Thiazide-Like Diuretics: Agents with Clinically Relevant Anticholinergic Effects may increase serum concentration of Thiazide and Thiazide-Like Diuretics. Risk C: Monitor
Thiothixene: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Thiothixene. Risk C: Monitor
Tiapride: Agents with Clinically Relevant Anticholinergic Effects may decrease therapeutic effects of Tiapride. Risk C: Monitor
Tiotropium: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Tiotropium. Risk X: Avoid
Tolperisone: May increase adverse/toxic effects of Muscle Relaxants (Centrally Acting). Management: Monitor for increased sedation or CNS effects if tolperisone is combined with other centrally acting muscle relaxants. Consider decreasing the tolperisone dose if these agents are combined. Risk D: Consider Therapy Modification
Tolterodine: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Tolterodine. Risk C: Monitor
Topiramate: Agents with Clinically Relevant Anticholinergic Effects may increase adverse/toxic effects of Topiramate. Risk C: Monitor
Trimeprazine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Trimethobenzamide: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Trimethobenzamide. Risk C: Monitor
Trospium: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Trospium. Risk C: Monitor
Umeclidinium: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk X: Avoid
Valerian: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Zolpidem: CNS Depressants may increase CNS depressant effects of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Risk D: Consider Therapy Modification
Zuclopenthixol: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Zuclopenthixol. Risk C: Monitor
Zuranolone: May increase CNS depressant effects of CNS Depressants. Management: Consider alternatives to the use of zuranolone with other CNS depressants or alcohol. If combined, consider a zuranolone dose reduction and monitor patients closely for increased CNS depressant effects. Risk D: Consider Therapy Modification
Food increases bioavailability (peak plasma concentrations increased by 35% and area under the curve by 20%) of the extended release capsule. Management: Monitor for increased effects if taken with food.
Outcome data following maternal use of cyclobenzaprine during pregnancy are limited (Fisher 2023; Flannery 1989; Moreira 2014).
Cyclobenzaprine is present in breast milk (Burra 2019).
Data related to the presence of cyclobenzaprine in breast milk are available from a report of 2 lactating patients:
The first patient was taking cyclobenzaprine 5 mg once daily for chronic temporomandibular joint pain for 3 months prior to the study. Breast milk was sampled at multiple times over 24 hours after the dose. The maximum concentration of cyclobenzaprine in breast milk was 6.7 ng/mL. Using an average milk concentration of 2.2 ng/mL, authors of the study calculated the estimated infant dose of cyclobenzaprine via breast milk to be 0.0003 mg/kg/day, providing a relative infant dose (RID) of 0.5% compared to the weight-adjusted maternal dose.
The second patient was taking cyclobenzaprine 10 mg twice daily for 3 years for pain associated with fibromyalgia. Breast milk was sampled over 12 hours after a dose. The maximum concentration of cyclobenzaprine in breast milk was 24.5 ng/mL. Using an average milk concentration of 10.3 ng/mL, authors of the study calculated the estimated infant dose of cyclobenzaprine via breast milk to be 0.0007 mg/kg per 12 hours, providing a RID of 0.5% compared to the weight-adjusted maternal dose.
Adverse events were not observed in either breastfed infant. Until additional data are available, assessment of the infant for adverse events is recommended (Burra 2019). In general, breastfeeding is considered acceptable when the RID of a medication is <10% (Anderson 2016; Ito 2000).
According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of treatment to the mother.
Mental alertness; signs/symptoms of serotonin syndrome (especially during initiation/dose titration) such as mental status changes (eg, agitation, hallucinations), autonomic instability (eg, tachycardia, labile BP, diaphoresis), neuromuscular changes (eg, tremor, rigidity, myoclonus), GI symptoms (eg, nausea, vomiting, diarrhea), and/or seizures.
Centrally-acting skeletal muscle relaxant pharmacologically related to tricyclic antidepressants; reduces tonic somatic motor activity influencing both alpha and gamma motor neurons
Onset of action: Immediate release: Within 1 hour
Duration of action: Immediate release: 12 to 24 hours
Metabolism: Hepatic via CYP3A4, 1A2, and 2D6; may undergo enterohepatic recirculation
Bioavailability: 33% to 55%
Half-life elimination: Normal hepatic function: Range: 8 to 37 hours; Immediate release: 18 hours; Extended release: 32 hours; Impaired hepatic function: 46.2 hours (range: 22.4 to 188 hours) (Winchell 2002)
Time to peak, serum: Immediate release: ~4 hours (Winchell 2002); Extended release: 7 to 8 hours
Excretion: Urine (primarily as glucuronide metabolites); feces (as unchanged drug; Hucker 1978)
Clearance: 0.7 L/minute
Hepatic function impairment: In mild-to-moderate hepatic impairment, AUC and Cmax increased approximately twofold with immediate-release cyclobenzaprine.
Older adult: AUC increased ~2.4-fold in elderly males and ~1.2-fold in elderly females with immediate-release cyclobenzaprine. AUC increased 40% and the plasma half-life is prolonged (50 hours) in elderly subjects with extended-release cyclobenzaprine.
Molecular weight: 311.9.
