Cyclobenzaprine hydrochloride

Description

Cyclobenzaprine hydrochloride, USP is a white, crystalline tricyclic amine salt with the molecular formula C20H21N • HCl and a molecular weight of 311.9. It has a melting point of 217ºC and a pKa of 8.47 at 25ºC. The compound is freely soluble in water and alcohol, sparingly soluble in isopropanol, and insoluble in hydrocarbon solvents. Chemically, it is designated as 3-(5H-dibenzoa,dcyclohepten-5-ylidene)-N,N-dimethyl-1-propanamine hydrochloride. Cyclobenzaprine hydrochloride is supplied as 5 mg or 10 mg tablets for oral administration. Each tablet contains the following inactive ingredients: croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate, polyethylene glycol, pregelatinized starch (maize), and titanium dioxide. The 5 mg tablets also contain D&C yellow #10 aluminum lake and FD&C yellow #6 aluminum lake, while the 10 mg tablets contain yellow iron oxide.

Uses and Indications

Cyclobenzaprine hydrochloride tablets, USP are indicated as an adjunct to rest and physical therapy for the relief of muscle spasm associated with acute, painful musculoskeletal conditions. The therapeutic effects are characterized by the alleviation of muscle spasm and its associated signs and symptoms, including pain, tenderness, limitation of motion, and restrictions in activities of daily living.

This medication is intended for short-term use, specifically for periods not exceeding two to three weeks. There is insufficient evidence to support the effectiveness of cyclobenzaprine hydrochloride for prolonged use, as muscle spasms related to acute, painful musculoskeletal conditions are typically of short duration. Therefore, specific therapy for extended periods is seldom warranted.

Cyclobenzaprine hydrochloride tablets, USP have not demonstrated efficacy in treating spasticity associated with cerebral or spinal cord diseases, nor are they indicated for use in children with cerebral palsy.

Dosage and Administration

The recommended dose of cyclobenzaprine hydrochloride tablets for most patients is 5 mg administered three times a day. Based on individual patient response, the dosage may be increased to 10 mg three times a day.

It is important to note that the use of cyclobenzaprine hydrochloride tablets for periods longer than two to three weeks is not recommended. For patients who are hepatically impaired or elderly, less frequent dosing should be considered to ensure safety and efficacy.

Contraindications

Use of this product is contraindicated in the following situations:

Patients with hypersensitivity to any component of this product.

Concomitant use with monoamine oxidase (MAO) inhibitors or within 14 days of their discontinuation is contraindicated due to the risk of hyperpyretic crisis, seizures, and fatalities associated with cyclobenzaprine or structurally similar tricyclic antidepressants.

The product should not be used in the acute recovery phase of myocardial infarction, or in patients with arrhythmias, heart block, conduction disturbances, or congestive heart failure, as these conditions may exacerbate cardiovascular risks.

Additionally, the product is contraindicated in patients with hyperthyroidism.

Warnings and Precautions

The use of cyclobenzaprine hydrochloride carries significant warnings and precautions that healthcare professionals must consider to ensure patient safety.

Warnings

The development of potentially life-threatening serotonin syndrome has been reported with cyclobenzaprine hydrochloride, particularly when used in conjunction with other serotonergic agents, including selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), tramadol, bupropion, meperidine, verapamil, or monoamine oxidase inhibitors (MAOIs). The concomitant use of cyclobenzaprine hydrochloride with MAO inhibitors is contraindicated.

Symptoms of serotonin syndrome may manifest as mental status changes (e.g., confusion, agitation, hallucinations), autonomic instability (e.g., diaphoresis, tachycardia, labile blood pressure, hyperthermia), neuromuscular abnormalities (e.g., tremor, ataxia, hyperreflexia, clonus, muscle rigidity), and gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Should any of these reactions occur, treatment with cyclobenzaprine hydrochloride and any concomitant serotonergic agents must be discontinued immediately, and supportive symptomatic treatment should be initiated.

Cyclobenzaprine is structurally related to tricyclic antidepressants such as amitriptyline and imipramine. In short-term studies for indications other than muscle spasm associated with acute musculoskeletal conditions, and typically at doses exceeding those recommended for skeletal muscle spasm, serious central nervous system reactions similar to those observed with tricyclic antidepressants have been noted. Additionally, tricyclic antidepressants are known to produce arrhythmias, sinus tachycardia, and prolongation of conduction time, which may lead to myocardial infarction and stroke.

It is important to note that cyclobenzaprine hydrochloride may enhance the effects of alcohol, barbiturates, and other central nervous system depressants, necessitating caution in patients who consume these substances.

General Precautions

Due to its atropine-like action, cyclobenzaprine hydrochloride should be administered with caution in patients with a history of urinary retention, angle-closure glaucoma, or increased intraocular pressure, as well as in those taking anticholinergic medications.

In patients with hepatic impairment, the plasma concentration of cyclobenzaprine is increased, which may heighten susceptibility to the sedative effects of the drug. Therefore, cyclobenzaprine hydrochloride should be initiated at a 5 mg dose in subjects with mild hepatic impairment, with careful titration. The use of cyclobenzaprine hydrochloride is not recommended in patients with moderate to severe hepatic insufficiency due to insufficient data regarding safety in this population.

Healthcare professionals are advised to remain vigilant for any adverse reactions and to monitor patients accordingly when prescribing cyclobenzaprine hydrochloride.

Side Effects

Patients may experience a range of adverse reactions while using the medication. Common adverse reactions, occurring in more than 3% of participants, include drowsiness (29% at 5 mg, 38% at 10 mg, compared to 10% for placebo), dry mouth (21% at 5 mg, 32% at 10 mg, 7% for placebo), fatigue (6% at both 5 mg and 10 mg, 3% for placebo), and headache (5% at both 5 mg and 10 mg, 8% for placebo).

Adverse reactions reported in 1% to 3% of patients include abdominal pain, acid regurgitation, constipation, diarrhea, dizziness, nausea, irritability, decreased mental acuity, nervousness, upper respiratory infections, pharyngitis, fatigue/tiredness, asthenia, dyspepsia, unpleasant taste, blurred vision, and confusion.

Less frequent adverse reactions, occurring in less than 1% of patients, encompass a variety of systems. Notable reactions include syncope and malaise (body as a whole), tachycardia, arrhythmia, vasodilatation, palpitation, and hypotension (cardiovascular), as well as vomiting, anorexia, gastrointestinal pain, gastritis, thirst, flatulence, edema of the tongue, abnormal liver function, and rare reports of hepatitis, jaundice, and cholestasis (digestive). Hypersensitivity reactions such as anaphylaxis, angioedema, pruritus, facial edema, urticaria, and rash have also been reported.

Nervous system and psychiatric reactions include seizures, ataxia, vertigo, dysarthria, tremors, hypertonia, convulsions, muscle twitching, disorientation, insomnia, depressed mood, abnormal sensations, anxiety, agitation, psychosis, abnormal thinking and dreaming, hallucinations, excitement, paresthesia, diplopia, and serotonin syndrome. Other less frequent reactions involve sweating (skin), ageusia and tinnitus (special senses), and urinary frequency and/or retention (urogenital).

Certain adverse reactions have been reported with an unknown causal relationship, including chest pain and edema (body as a whole), hypertension, myocardial infarction, heart block, and stroke (cardiovascular), as well as paralytic ileus, tongue discoloration, stomatitis, and parotid swelling (digestive). Endocrine reactions such as inappropriate ADH syndrome, hematologic reactions including purpura, bone marrow depression, leukopenia, eosinophilia, and thrombocytopenia, and metabolic changes like elevation and lowering of blood sugar levels, weight gain or loss have also been noted. Musculoskeletal reactions include myalgia, while nervous system and psychiatric reactions may involve decreased or increased libido, abnormal gait, delusions, aggressive behavior, paranoia, peripheral neuropathy, Bell’s palsy, alteration in EEG patterns, and extrapyramidal symptoms. Respiratory reactions such as dyspnea, skin reactions including photosensitization and alopecia, and urogenital issues like impaired urination, dilatation of the urinary tract, impotence, testicular swelling, gynecomastia, breast enlargement, and galactorrhea have also been reported.

A serious warning regarding serotonin syndrome is pertinent, as this potentially life-threatening condition has been observed when the medication is used in combination with other drugs, including SSRIs, SNRIs, TCAs, tramadol, bupropion, meperidine, verapamil, or MAO inhibitors. Symptoms may include mental status changes (e.g., confusion, agitation, hallucinations), autonomic instability (e.g., diaphoresis, tachycardia, labile blood pressure, hyperthermia), neuromuscular abnormalities (e.g., tremor, ataxia, hyperreflexia, clonus, muscle rigidity), and gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).

In cases of overdose, common effects include drowsiness and tachycardia, while less frequent manifestations may involve tremor, agitation, coma, ataxia, hypertension, slurred speech, confusion, dizziness, nausea, vomiting, and hallucinations. Rare but critical manifestations can include cardiac arrest, chest pain, cardiac dysrhythmias, severe hypotension, seizures, and neuroleptic malignant syndrome.

Drug Interactions

Cyclobenzaprine has the potential to cause life-threatening interactions when administered concurrently with monoamine oxidase inhibitors (MAOIs). It is essential to exercise careful observation when cyclobenzaprine is used alongside other serotonergic agents, including selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and tramadol, due to the increased risk of serotonin syndrome.

Additionally, cyclobenzaprine hydrochloride may potentiate the effects of alcohol, barbiturates, and other central nervous system (CNS) depressants. Clinicians should consider monitoring patients for enhanced sedation and respiratory depression when these substances are co-administered.

Tricyclic antidepressants (TCAs) may interfere with the antihypertensive efficacy of guanethidine and similar agents, necessitating careful blood pressure monitoring and potential dosage adjustments of antihypertensive medications.

Furthermore, the use of TCAs in conjunction with tramadol may elevate the risk of seizures. It is advisable to monitor patients closely for seizure activity and consider alternative therapies if necessary.

Packaging & NDC

The table below lists all NDC Code configurations of Cyclobenzaprine Hydrochloride, the U.S. brand-name prescription product. Columns show Packaging, Formulation Type, and Active Ingredient Strength.

Pediatric Use

Safety and effectiveness of cyclobenzaprine hydrochloride in pediatric patients below 15 years of age have not been established. Therefore, caution is advised when considering the use of this medication in this age group.

Geriatric Use

Elderly patients may experience increased plasma concentrations of cyclobenzaprine, which necessitates careful consideration when prescribing this medication. Due to this heightened concentration, geriatric patients are at an elevated risk for central nervous system (CNS) adverse events, including hallucinations and confusion. Additionally, there is a concern for cardiac events in this population, which may lead to falls or other serious complications.

Given these risks, cyclobenzaprine should only be prescribed to elderly patients when clearly indicated. When initiating treatment in this demographic, it is recommended that cyclobenzaprine hydrochloride be started at a lower dose of 5 mg, with a gradual titration to achieve the desired therapeutic effect.

Healthcare providers should remain vigilant for potential drug-drug and drug-disease interactions that may be more pronounced in geriatric patients. Continuous monitoring for adverse effects and overall patient response is essential to ensure safety and efficacy in this vulnerable population.

Pregnancy

Pregnancy Category B. Reproduction studies have been conducted in rats, mice, and rabbits at doses up to 20 times the human dose, demonstrating no evidence of impaired fertility or harm to the fetus associated with cyclobenzaprine hydrochloride. However, there are no adequate and well-controlled studies in pregnant women. Due to the limitations of animal reproduction studies in predicting human response, cyclobenzaprine hydrochloride should be used during pregnancy only if clearly needed. Healthcare professionals are advised to weigh the potential benefits against any possible risks when considering this medication for pregnant patients.

Lactation

It is not known whether this drug is excreted in human milk. Due to the structural similarity of cyclobenzaprine to tricyclic antidepressants, some of which are known to be excreted in human milk, caution should be exercised when administering cyclobenzaprine hydrochloride to lactating mothers. The potential effects on breastfed infants have not been established, and healthcare professionals should consider the risks and benefits of treatment in nursing women.

Renal Impairment

Patients with renal impairment have not been specifically addressed in the available data regarding dosage adjustments, special monitoring, or safety considerations. Therefore, healthcare professionals should exercise caution when prescribing this medication to individuals with reduced kidney function, as the lack of information necessitates careful clinical judgment. Regular monitoring of renal function may be advisable in these patients to ensure safety and efficacy.

Hepatic Impairment

Patients with hepatic impairment have not been specifically studied in relation to the use of this medication. Consequently, there are no established dosage adjustments, special monitoring requirements, or precautions outlined for individuals with compromised liver function. It is recommended that healthcare providers exercise caution when prescribing this medication to patients with hepatic impairment, given the lack of data on its safety and efficacy in this population. Regular monitoring of liver function may be prudent in these cases, although specific parameters are not defined in the available information.

Overdosage

In cases of cyclobenzaprine hydrochloride overdosage, although rare, fatalities may occur. Signs and symptoms of toxicity can develop rapidly, necessitating immediate hospital monitoring.

Clinical Manifestations

The most common effects associated with cyclobenzaprine overdose include drowsiness and tachycardia. Other less frequent manifestations may present as tremor, agitation, coma, ataxia, hypertension, slurred speech, confusion, dizziness, nausea, vomiting, and hallucinations. Rare but critical manifestations include cardiac arrest, chest pain, cardiac dysrhythmias, severe hypotension, seizures, and neuroleptic malignant syndrome. Clinically significant changes in the electrocardiogram, particularly alterations in the QRS axis or width, serve as important indicators of cyclobenzaprine toxicity.

Initial Management

Upon suspicion of overdose, it is imperative to obtain an electrocardiogram (ECG) and initiate cardiac monitoring immediately to protect against potentially critical manifestations. The patient's airway should be secured, and an intravenous line established. Gastric decontamination is essential, which includes large volume gastric lavage followed by the administration of activated charcoal. If the patient is unconscious, airway protection must be prioritized prior to lavage, and emesis is contraindicated.

Monitoring and Supportive Care

Continuous observation with cardiac monitoring is necessary, focusing on signs of central nervous system (CNS) or respiratory depression, hypotension, cardiac dysrhythmias, and seizures. If any signs of toxicity arise during this monitoring period, extended observation is warranted. It is important to note that monitoring plasma drug levels should not dictate patient management, and dialysis is likely ineffective due to the low plasma concentrations of cyclobenzaprine.

In cases where dysrhythmias or QRS widening is present, serum alkalinization to a pH of 7.45 to 7.55 using intravenous sodium bicarbonate, along with hyperventilation, should be initiated. For patients exhibiting CNS depression, early intubation is advised due to the risk of abrupt deterioration. Seizures should be managed with benzodiazepines or other appropriate anticonvulsants.

Special Considerations

Physostigmine is not recommended except for life-threatening symptoms that do not respond to other therapies, and only after consultation with a poison control center. Given that overdosage is often intentional, a psychiatric referral may be appropriate during the recovery phase. Additionally, it is strongly advised that physicians contact the local poison control center for specific pediatric treatment recommendations in cases of overdose.

Nonclinical Toxicology

In rats treated with cyclobenzaprine hydrochloride for up to 67 weeks at doses approximately 5 to 40 times the maximum recommended human dose, observations included pale and occasionally enlarged livers, along with dose-related hepatocyte vacuolation and lipidosis. In the higher dose groups, these microscopic changes were evident after 26 weeks, and in some cases, even earlier in rats that died prior to the 26-week mark. Conversely, at lower doses, these changes were not observed until after 26 weeks of treatment.

Cyclobenzaprine did not influence the onset, incidence, or distribution of neoplasia in an 81-week study conducted in mice or in a 105-week study in rats. Furthermore, at oral doses of up to 10 times the human dose, cyclobenzaprine did not adversely affect the reproductive performance or fertility of either male or female rats. Additionally, cyclobenzaprine did not exhibit mutagenic activity in male mice at dose levels of up to 20 times the human dose.

Postmarketing Experience

The following adverse reactions have been reported in the postmarketing experience or with an incidence of less than 1% of patients in clinical trials with the 10 mg tablet:

In the category of Body as a Whole, reactions such as syncope and malaise have been noted. Cardiovascular events include tachycardia, arrhythmia, vasodilatation, palpitation, and hypotension. Digestive system reactions encompass vomiting, anorexia, diarrhea, gastrointestinal pain, gastritis, thirst, flatulence, edema of the tongue, abnormal liver function, and rare reports of hepatitis, jaundice, and cholestasis.

Hypersensitivity reactions reported include anaphylaxis, angioedema, pruritus, facial edema, urticaria, and rash. Musculoskeletal reactions consist of local weakness. In the Nervous System and Psychiatric categories, seizures, ataxia, vertigo, dysarthria, tremors, hypertonia, convulsions, muscle twitching, disorientation, insomnia, depressed mood, abnormal sensations, anxiety, agitation, psychosis, abnormal thinking and dreaming, hallucinations, excitement, paresthesia, diplopia, and serotonin syndrome have been documented. Skin-related reactions include sweating, while special senses reactions involve ageusia and tinnitus. Urogenital reactions reported are urinary frequency and/or retention.

Additionally, other reactions have been reported rarely for cyclobenzaprine hydrochloride, where a causal relationship could not be established, or have been reported for other tricyclic drugs. These include chest pain and edema in the Body as a Whole category; hypertension, myocardial infarction, heart block, and stroke in the Cardiovascular category; and paralytic ileus, tongue discoloration, stomatitis, and parotid swelling in the Digestive category. Endocrine reactions include inappropriate ADH syndrome, while Hematic and Lymphatic reactions consist of purpura, bone marrow depression, leukopenia, eosinophilia, and thrombocytopenia.

Metabolic, Nutritional, and Immune reactions involve elevation and lowering of blood sugar levels, as well as weight gain or loss. Musculoskeletal reactions include myalgia. In the Nervous System and Psychiatric categories, decreased or increased libido, abnormal gait, delusions, aggressive behavior, paranoia, peripheral neuropathy, Bell’s palsy, alteration in EEG patterns, and extrapyramidal symptoms have been reported. Respiratory reactions include dyspnea, while skin reactions encompass photosensitization and alopecia. Urogenital reactions reported are impaired urination, dilatation of the urinary tract, impotence, testicular swelling, gynecomastia, breast enlargement, and galactorrhea.

Patient Counseling

Healthcare providers should advise patients that cyclobenzaprine hydrochloride, particularly when used in conjunction with alcohol or other central nervous system (CNS) depressants, may impair their mental and/or physical abilities necessary for performing hazardous tasks, including operating machinery or driving a motor vehicle.

It is important to inform elderly patients that the frequency and severity of adverse events associated with cyclobenzaprine may be increased, regardless of whether they are taking other medications. For elderly patients, healthcare providers should recommend initiating treatment with a 5 mg dose of cyclobenzaprine hydrochloride and advise a gradual titration upward.

Patients should also be cautioned about the potential risk of serotonin syndrome when cyclobenzaprine hydrochloride is used alongside other medications, such as selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), tramadol, bupropion, meperidine, verapamil, or monoamine oxidase inhibitors (MAOIs).

Healthcare providers should ensure that patients are aware of the signs and symptoms of serotonin syndrome and instruct them to seek immediate medical attention if they experience any of these symptoms.

Storage and Handling

The product is supplied in various package configurations, with specific NDC numbers available upon request. It should be stored at a temperature range of 20° to 25°C (68° to 77°F). Temporary excursions are permitted between 15° to 30°C (59° to 86°F), in accordance with USP Controlled Room Temperature guidelines. Proper storage conditions are essential to maintain the integrity and efficacy of the product.

Additional Clinical Information

Patients using cyclobenzaprine hydrochloride should be aware that the medication may impair mental and physical abilities, particularly when combined with alcohol or other central nervous system (CNS) depressants, which can affect tasks such as operating machinery or driving. In elderly patients, the incidence and severity of adverse events may be heightened; therefore, it is recommended that treatment begins with a 5 mg dose, which should be titrated slowly.

Clinicians should counsel patients on the potential risk of serotonin syndrome when cyclobenzaprine is used alongside other medications, including SSRIs, SNRIs, TCAs, tramadol, bupropion, meperidine, verapamil, or MAO inhibitors. Patients should be informed about the signs and symptoms of serotonin syndrome and advised to seek immediate medical attention if they experience any related symptoms.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Cyclobenzaprine Hydrochloride as submitted by Cardinal Health 107, LLC. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)