Cyclobenzaprine Hydrochloride

Description

Cyclobenzaprine hydrochloride, USP is a white, crystalline tricyclic amine salt with the empirical formula C20H21N•HCl and a molecular weight of 311.9 g/mol. It has a melting point of 217˚C and a pKa of 8.47 at 25˚C. 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 HCl, USP is available in two strengths for oral administration: 5 mg and 10 mg tablets. The 5 mg tablets contain the following inactive ingredients: lactose monohydrate, microcrystalline cellulose, pregelatinized starch, colloidal silicon dioxide, magnesium stearate, and opadry beige (which includes hypromellose 6cP, titanium dioxide, PEG 400, iron oxide yellow, and iron oxide red). The 10 mg tablets contain lactose monohydrate, microcrystalline cellulose, pregelatinized starch, colloidal silicon dioxide, magnesium stearate, and opadry yellow (which includes hypromellose 3cp, hypromellose 6cp, titanium dioxide, PEG 400, iron oxide yellow, and polysorbate 80).

Uses and Indications

Cyclobenzaprine HCl 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 should be utilized for short durations, specifically up to two or three weeks, as there is insufficient evidence to support its effectiveness for extended use. Muscle spasms related to acute, painful musculoskeletal conditions are typically of brief duration, and specific therapy for prolonged periods is rarely necessary.

Cyclobenzaprine HCl is not indicated for the treatment of spasticity associated with cerebral or spinal cord diseases, nor is it effective in pediatric patients with cerebral palsy.

Dosage and Administration

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

It is important to note that the use of cyclobenzaprine HCl tablets USP for periods longer than two or 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 the 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 is contraindicated in the acute recovery phase of myocardial infarction, as well as in patients with arrhythmias, heart block or conduction disturbances, or congestive heart failure, due to potential cardiovascular risks.

Additionally, use is contraindicated in patients with hyperthyroidism.

Warnings and Precautions

The use of Cyclobenzaprine Hydrochloride necessitates careful consideration of potential risks and the implementation of appropriate monitoring strategies.

Serotonin Syndrome The concomitant use of Cyclobenzaprine Hydrochloride 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 (MAO) inhibitors, may lead to the development of serotonin syndrome, a potentially life-threatening condition. The use of Cyclobenzaprine Hydrochloride in conjunction 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). In the event of these symptoms, immediate discontinuation of Cyclobenzaprine Hydrochloride and any concomitant serotonergic agents is required, along with the initiation of supportive symptomatic treatment. If the clinical decision is made to continue treatment with Cyclobenzaprine Hydrochloride alongside other serotonergic drugs, careful observation is essential, particularly during the initiation of therapy or when increasing doses.

CNS Reactions Cyclobenzaprine is structurally related to tricyclic antidepressants such as amitriptyline and imipramine. In short-term studies involving indications other than muscle spasm associated with acute musculoskeletal conditions, and typically at doses exceeding those recommended for muscle spasm, serious central nervous system reactions similar to those observed with tricyclic antidepressants have been reported.

Cardiovascular Risks Tricyclic antidepressants, which share a pharmacological profile with Cyclobenzaprine Hydrochloride, have been associated with arrhythmias, sinus tachycardia, and prolongation of conduction time, potentially leading to myocardial infarction and stroke. Therefore, caution is advised in patients with a history of cardiovascular conditions.

CNS Depressant Effects Cyclobenzaprine Hydrochloride may potentiate the effects of alcohol, barbiturates, and other central nervous system depressants. Healthcare professionals should advise patients regarding the risks of concomitant use of these substances, as it may lead to increased sedation and respiratory depression.

Monitoring parameters should include assessment of mental status, cardiovascular function, and any signs of serotonin syndrome, particularly in patients receiving concomitant serotonergic medications. Regular evaluation of the patient's overall response to treatment is recommended to ensure safety and efficacy.

Side Effects

Patients may experience a range of adverse reactions while using the medication. Common adverse reactions, occurring in more than 3% of patients, include drowsiness, dry mouth, and dizziness.

Adverse reactions reported in 1% to 3% of patients encompass a broader spectrum, including abdominal pain, acid regurgitation, constipation, diarrhea, dizziness, nausea, irritability, decreased mental acuity, nervousness, upper respiratory infections, pharyngitis, fatigue, asthenia, dyspepsia, unpleasant taste, blurred vision, headache, confusion, and additional instances of nausea and constipation.

In the post-marketing experience or in clinical trials with an incidence of less than 1%, additional adverse reactions have been documented. These include syncope and malaise as general reactions. Cardiovascular effects may involve tachycardia, arrhythmia, vasodilatation, palpitations, and hypotension. Digestive system reactions can include vomiting, anorexia, gastrointestinal pain, gastritis, thirst, flatulence, edema of the tongue, abnormal liver function, and rare reports of hepatitis, jaundice, and cholestasis. Hypersensitivity reactions may manifest as anaphylaxis, angioedema, pruritus, facial edema, urticaria, and rash.

Nervous system and psychiatric adverse reactions are notable and may include seizures, ataxia, vertigo, dysarthria, tremors, hypertonia, convulsions, muscle twitching, disorientation, insomnia, depressed mood, anxiety, agitation, psychosis, abnormal thinking and dreaming, hallucinations, excitement, paresthesia, and diplopia. Musculoskeletal reactions may present as local weakness, while skin reactions can include sweating. Special senses may be affected, leading to ageusia and tinnitus, and urogenital issues may involve urinary frequency and/or retention.

Certain adverse reactions have been reported rarely, with an unknown causal relationship. These include chest pain and edema as general reactions, hypertension, myocardial infarction, heart block, and stroke in the cardiovascular category. Digestive issues may involve paralytic ileus, tongue discoloration, stomatitis, and parotid swelling. Endocrine reactions can include inappropriate ADH syndrome. Hematic and lymphatic reactions may present as purpura, bone marrow depression, leukopenia, eosinophilia, and thrombocytopenia. Metabolic, nutritional, and immune reactions may involve elevation and lowering of blood sugar levels, as well as weight gain or loss. Musculoskeletal reactions can include myalgia, while nervous system and psychiatric effects may manifest as decreased or increased libido, abnormal gait, delusions, aggressive behavior, paranoia, peripheral neuropathy, Bell's palsy, alterations in EEG patterns, and extrapyramidal symptoms. Respiratory issues may include dyspnea, and skin reactions can involve photosensitization and alopecia. Urogenital reactions may present as impaired urination, dilatation of the urinary tract, impotence, testicular swelling, gynecomastia, breast enlargement, and galactorrhea.

It is important to note that the development of a potentially life-threatening serotonin syndrome has been reported when the medication is used in combination with other drugs, such as selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), tramadol, bupropion, meperidine, verapamil, or MAO inhibitors. Symptoms of serotonin syndrome 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 overdosage, common effects may include drowsiness and tachycardia, while less frequent manifestations can involve tremor, agitation, coma, ataxia, hypertension, slurred speech, confusion, dizziness, nausea, vomiting, and hallucinations. Rare but potentially critical manifestations may include cardiac arrest, chest pain, cardiac dysrhythmias, severe hypotension, seizures, and neuroleptic malignant syndrome.

Drug Interactions

Cyclobenzaprine HCl is associated with significant drug interactions that warrant careful consideration.

Monoamine Oxidase Inhibitors (MAOIs) and Serotonergic Drugs Cyclobenzaprine HCl may produce life-threatening interactions when administered concurrently with MAO inhibitors. Additionally, caution is advised when using cyclobenzaprine with serotonergic agents, including selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), tramadol, bupropion, meperidine, or verapamil. Close monitoring of patients is recommended to mitigate the risk of serotonin syndrome and other adverse effects.

CNS Depressants The concomitant use of cyclobenzaprine HCl with alcohol, barbiturates, and other central nervous system (CNS) depressants may enhance the sedative effects of these substances. It is advisable to monitor patients for increased sedation and consider dosage adjustments as necessary.

Tricyclic Antidepressants (TCAs) TCAs may interfere with the antihypertensive effects of guanethidine and similar agents. Clinicians should be aware of this interaction and monitor blood pressure accordingly. Furthermore, the use of TCAs in conjunction with tramadol may elevate the risk of seizures. Patients should be monitored for seizure activity, and dosage adjustments may be warranted based on clinical judgment.

Packaging & NDC

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

Pediatric Use

Safety and effectiveness of cyclobenzaprine HCl 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, defined as those aged 65 years and older, may experience increased plasma concentrations of cyclobenzaprine. In pharmacokinetic studies, mean steady-state area under the curve (AUC) values for cyclobenzaprine in this population were approximately 1.7 times higher than those observed in younger adults. Notably, elderly male subjects exhibited an even greater increase, with AUC values approximately 2.4 times higher than their younger counterparts, while elderly females showed a lesser increase of about 1.2 times.

Due to these elevated plasma levels, elderly patients may be at a heightened risk for central nervous system (CNS) adverse events, including hallucinations and confusion, as well as cardiac events that could lead to falls or other complications. Therefore, cyclobenzaprine should be prescribed to geriatric patients only when clearly indicated.

When initiating treatment in elderly patients, it is recommended to start with a lower dose of 5 mg and to titrate slowly upward, taking into account the patient's response and tolerance. Additionally, less frequent dosing should be considered to mitigate the risk of adverse effects and drug interactions, including those related to concomitant medications and existing health conditions. Careful monitoring of these patients is essential to ensure safety and efficacy.

Pregnancy

Reproduction studies have been conducted in rats, mice, and rabbits at doses up to 20 times the human dose of cyclobenzaprine HCl, revealing no evidence of impaired fertility or harm to the fetus. However, there are no adequate and well-controlled studies in pregnant women. Given that animal reproduction studies are not always predictive of human response, cyclobenzaprine HCl should be used during pregnancy only if clearly needed.

Healthcare professionals are advised to weigh the potential benefits against the risks when considering the use of this medication in 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 HCl 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

There is no specific information available regarding dosage adjustments, special monitoring, or safety considerations for patients with renal impairment. Healthcare professionals should exercise caution when prescribing to patients with reduced kidney function, as the absence of detailed guidance necessitates careful clinical judgment and individualized patient assessment.

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

Overdosage with cyclobenzaprine HCl, while rare, can lead to severe outcomes, including death. It is important to note that deliberate overdose often involves the co-ingestion of multiple substances, including alcohol.

Clinical Presentation and Symptoms Signs and symptoms of cyclobenzaprine toxicity can manifest rapidly following an overdose, necessitating immediate hospital monitoring. The most frequently observed effects include drowsiness and tachycardia. Other less common symptoms may include tremor, agitation, coma, ataxia, hypertension, slurred speech, confusion, dizziness, nausea, vomiting, and hallucinations. Critical manifestations, although rare, can include cardiac arrest, chest pain, cardiac dysrhythmias, severe hypotension, seizures, and neuroleptic malignant syndrome. Clinicians should be vigilant for changes in the electrocardiogram, particularly alterations in the QRS axis or width, as these are significant indicators of toxicity.

Management Protocols All patients suspected of cyclobenzaprine overdose should undergo gastrointestinal decontamination. This includes performing a large volume gastric lavage followed by the administration of activated charcoal. If the patient's consciousness is impaired, securing the airway is essential prior to lavage, and emesis is contraindicated.

A maximal limb-lead QRS duration of ≥0.10 seconds may serve as a critical indicator of overdose severity. For patients exhibiting dysrhythmias or QRS widening, serum alkalinization should be initiated, targeting a pH of 7.45 to 7.55 through intravenous sodium bicarbonate and hyperventilation as necessary. In cases of central nervous system (CNS) depression, early intubation is recommended due to the risk of sudden deterioration.

Seizures should be managed with benzodiazepines; if these are ineffective, alternative anticonvulsants such as phenobarbital or phenytoin may be utilized. The use of physostigmine is not advised except in life-threatening situations unresponsive to other treatments, and only after consulting a poison control center.

Psychiatric Considerations Given that overdosage is frequently intentional, there is a risk that patients may attempt suicide by other means during the recovery phase. Therefore, a psychiatric referral may be warranted.

It is important to recognize that the management principles for both child and adult overdosages are similar. Physicians are strongly encouraged to contact the local poison control center for specific guidance on pediatric treatment.

Nonclinical Toxicology

Reproduction studies conducted in rats, mice, and rabbits at doses up to 20 times the human dose have classified cyclobenzaprine HCl as Pregnancy Category B, revealing no evidence of impaired fertility or teratogenic effects on the fetus. Additionally, at oral doses of up to 10 times the human dose, cyclobenzaprine did not adversely affect the reproductive performance or fertility of male or female rats. Furthermore, cyclobenzaprine did not demonstrate mutagenic activity in male mice at dose levels of up to 20 times the human dose.

In nonclinical studies involving rats treated with cyclobenzaprine HCl for up to 67 weeks at doses ranging from approximately 5 to 40 times the maximum recommended human dose, observations included pale and sometimes enlarged livers, along with dose-related hepatocyte vacuolation and lipidosis. In higher dose groups, these microscopic changes were noted after 26 weeks, and in some cases, even earlier in rats that died prior to 26 weeks. At lower doses, these changes were not observed until after 26 weeks. Importantly, cyclobenzaprine did not affect the onset, incidence, or distribution of neoplasia in an 81-week study in mice or in a 105-week study in rats.

Pharmacological studies in animals indicated that the effects of cyclobenzaprine are similar to those of structurally related tricyclic antidepressants, demonstrating reserpine antagonism, norepinephrine potentiation, potent peripheral and central anticholinergic effects, and sedation. Additionally, cyclobenzaprine was associated with a slight to moderate increase in heart rate in animal studies.

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 include syncope and malaise. Cardiovascular events reported include tachycardia, arrhythmia, vasodilatation, palpitation, and hypotension. Digestive system reactions consist of 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 include anaphylaxis, angioedema, pruritus, facial edema, urticaria, and rash. Musculoskeletal events reported are local weakness. In the Nervous System and Psychiatric categories, 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, and diplopia. Skin reactions include sweating, while special senses reactions consist of ageusia and tinnitus. Urogenital events reported are urinary frequency and/or retention.

Additionally, other reactions have been reported rarely for cyclobenzaprine HCl under circumstances where a causal relationship could not be established, or 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. Hematic and Lymphatic reactions consist of purpura, bone marrow depression, leukopenia, eosinophilia, and thrombocytopenia.

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

Patient Counseling

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

It is important to inform elderly patients that they may experience an increased frequency and severity of adverse events associated with the use of cyclobenzaprine, whether or not they are taking other medications. For this population, healthcare providers should recommend initiating treatment with a 5 mg dose of cyclobenzaprine HCl and advise a gradual titration upward as needed.

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

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

Storage and Handling

The product is supplied in accordance with the National Drug Code (NDC) specifications. It should be stored at a temperature range of 20° to 25°C (68° to 77°F), in compliance 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 HCl 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. Clinicians should note that elderly patients may experience an increased frequency and severity of adverse events; therefore, it is recommended to initiate treatment with a 5 mg dose and to titrate slowly.

Additionally, patients must be cautioned about the risk of serotonin syndrome when cyclobenzaprine is used alongside other medications, including selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), tramadol, bupropion, meperidine, verapamil, or monoamine oxidase inhibitors (MAOIs). Patients should be informed of the signs and symptoms of serotonin syndrome and instructed to seek immediate medical attention if they experience these symptoms.

FDA Insert (PDF)

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

View full prescribing information (PDF)