FLEXERIL

Clinical safety rating: caution

Comprehensive clinical and safety monograph for FLEXERIL (FLEXERIL).

How it works

Cyclobenzaprine is a centrally acting muscle relaxant that acts primarily at the brainstem, reducing tonic somatic motor activity via inhibition of descending serotonergic pathways. It is structurally related to tricyclic antidepressants and exhibits anticholinergic, sedative, and analgesic effects.

What the body does with it

Metabolism	Primarily hepatic via CYP3A4, CYP1A2, and CYP2D6; undergoes N-demethylation and glucuronidation. Active metabolite: norcyclobenzaprine.
Excretion	Primarily hepatic; approximately 50% excreted in urine as metabolites, less than 1% unchanged; 40% excreted in feces via bile.
Half-life	Terminal elimination half-life is 18 hours (range 8–37 hours) with clinical context: requires dose adjustment in hepatic impairment; steady-state reached in ~3–5 days.
Protein binding	~93% bound to plasma proteins, primarily albumin.
Volume of Distribution	~14 L/kg (range 10–20 L/kg), indicating extensive tissue distribution.
Bioavailability	Oral: ~33% due to extensive first-pass metabolism.
Onset of Action	Oral: 1 hour. No parenteral route approved.
Duration of Action	12–24 hours; clinical note: muscle relaxant effects may persist beyond half-life due to redistribution.

Classification & Brands

Dosing & administration

10 mg to 15 mg orally three times a day; maximum daily dose: 30 mg.

Dosage form	TABLET
Renal impairment	No specific dosage adjustment guidelines; use with caution in renal impairment due to potential for increased side effects.
Liver impairment	Contraindicated in hepatic impairment; Child-Pugh class A, B, C: no safe dosage established.
Pediatric use	Not recommended for use in children under 15 years old; safety and efficacy not established.
Geriatric use	Use lower starting dose (e.g., 5 mg) and titrate slowly; increased risk of sedation and anticholinergic effects. May not be well tolerated; consider alternative therapy.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

Comprehensive clinical and safety monograph for FLEXERIL (FLEXERIL).

Breastfeeding	Excreted in breast milk in small amounts (M/P ratio not established). Clinical relevance uncertain; however, due to potential for adverse effects in nursing infants, caution is advised. Alternative therapies preferred, especially when nursing a premature or low-birth-weight infant.
Teratogenic Risk	Pregnancy Category B. Animal studies have not demonstrated fetal risk, but no adequate human studies in pregnant women. Use only if clearly needed. First trimester: no known risk. Second trimester: no known risk. Third trimester: potential for neonatal adverse effects such as respiratory depression and withdrawal if used near term.

Warnings & precautions

■ FDA Black Box Warning

None

Side Effect Profile

Serious Effects

Absolute Contraindications

["Concurrent use of MAOIs or within 14 days of MAOI therapy","Acute recovery phase of myocardial infarction","Arrhythmias, heart block, or congestive heart failure","Hyperthyroidism"]

Clinical Precautions

Precautions

["Should not be used for longer than 2-3 weeks (acute use only)","May impair mental or physical abilities required for driving or operating machinery","Central nervous system depression additive with alcohol and other CNS depressants","Anticholinergic effects: caution in patients with angle-closure glaucoma, urinary retention, or prostatic hypertrophy","Cardiovascular effects: risk of arrhythmias, especially in patients with preexisting cardiac disease (tachycardia, QT prolongation)","Serotonin syndrome risk when used with MAOIs, SSRIs, SNRIs, or other serotonergic drugs","Hepatic impairment: lower doses recommended"]

Clinical Tips & Counseling

Drug interactions

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FLEXERIL

Clinical safety rating: caution

Comprehensive clinical and safety monograph for FLEXERIL (FLEXERIL).

How it works

What the body does with it

Metabolism	Primarily hepatic via CYP3A4, CYP1A2, and CYP2D6; undergoes N-demethylation and glucuronidation. Active metabolite: norcyclobenzaprine.
Excretion	Primarily hepatic; approximately 50% excreted in urine as metabolites, less than 1% unchanged; 40% excreted in feces via bile.
Half-life	Terminal elimination half-life is 18 hours (range 8–37 hours) with clinical context: requires dose adjustment in hepatic impairment; steady-state reached in ~3–5 days.
Protein binding	~93% bound to plasma proteins, primarily albumin.
Volume of Distribution	~14 L/kg (range 10–20 L/kg), indicating extensive tissue distribution.
Bioavailability	Oral: ~33% due to extensive first-pass metabolism.
Onset of Action	Oral: 1 hour. No parenteral route approved.
Duration of Action	12–24 hours; clinical note: muscle relaxant effects may persist beyond half-life due to redistribution.

Classification & Brands

Dosing & administration

10 mg to 15 mg orally three times a day; maximum daily dose: 30 mg.

Dosage form	TABLET
Renal impairment	No specific dosage adjustment guidelines; use with caution in renal impairment due to potential for increased side effects.
Liver impairment	Contraindicated in hepatic impairment; Child-Pugh class A, B, C: no safe dosage established.
Pediatric use	Not recommended for use in children under 15 years old; safety and efficacy not established.
Geriatric use	Use lower starting dose (e.g., 5 mg) and titrate slowly; increased risk of sedation and anticholinergic effects. May not be well tolerated; consider alternative therapy.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

Comprehensive clinical and safety monograph for FLEXERIL (FLEXERIL).

Breastfeeding	Excreted in breast milk in small amounts (M/P ratio not established). Clinical relevance uncertain; however, due to potential for adverse effects in nursing infants, caution is advised. Alternative therapies preferred, especially when nursing a premature or low-birth-weight infant.
Teratogenic Risk	Pregnancy Category B. Animal studies have not demonstrated fetal risk, but no adequate human studies in pregnant women. Use only if clearly needed. First trimester: no known risk. Second trimester: no known risk. Third trimester: potential for neonatal adverse effects such as respiratory depression and withdrawal if used near term.

Warnings & precautions

■ FDA Black Box Warning

None

Side Effect Profile

Serious Effects

Absolute Contraindications

["Concurrent use of MAOIs or within 14 days of MAOI therapy","Acute recovery phase of myocardial infarction","Arrhythmias, heart block, or congestive heart failure","Hyperthyroidism"]