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. When aqueous solutions are made alkaline, the free base separates.

Chemically, cyclobenzaprine HCl is designated as 3-(5H–dibenzoa,dcyclohepten-5-ylidene)-N,N-dimethyl-1-propanamine hydrochloride. The structural formula is provided in the accompanying documentation.

Cyclobenzaprine HCl, USP is available in two oral tablet formulations: 5 mg and 10 mg. The 5 mg tablets contain the following inactive ingredients: lactose monohydrate, microcrystalline cellulose, pregelatinized starch, colloidal silicon dioxide, magnesium stearate, and opadry beige (composed of hypromellose 6cP, titanium dioxide, PEG 400, iron oxide yellow, and iron oxide red). The 10 mg tablets include lactose monohydrate, microcrystalline cellulose, pregelatinized starch, colloidal silicon dioxide, magnesium stearate, and opadry yellow (composed of 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 only for short durations, specifically up to two or three weeks, as there is insufficient evidence to support its effectiveness for prolonged use. Muscle spasms related to acute, painful musculoskeletal conditions are typically of short duration, and specific therapy for extended 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 dosage 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 exceeding two to three weeks is not recommended.

For patients with hepatic impairment or for elderly patients, consideration should be given to less frequent dosing 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 complications.

Use is also contraindicated in patients with hyperthyroidism, as it may exacerbate the condition.

Warnings and Precautions

The use of Cyclobenzaprine Hydrochloride is associated with significant warnings that healthcare professionals must consider to ensure patient safety.

Serotonin Syndrome Risk 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 can 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 these symptoms occur, it is imperative to discontinue treatment with Cyclobenzaprine Hydrochloride and any concomitant serotonergic agents immediately, and to initiate supportive symptomatic treatment.

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 higher than those recommended for muscle spasm, serious central nervous system reactions similar to those observed with tricyclic antidepressants have been reported.

Cardiovascular Concerns Tricyclic antidepressants, which share a pharmacological profile with Cyclobenzaprine, have been associated with arrhythmias, sinus tachycardia, and prolongation of conduction time, potentially leading to myocardial infarction and stroke. Therefore, caution is advised when prescribing Cyclobenzaprine, particularly in patients with pre-existing cardiovascular conditions.

CNS Depressant Interaction Cyclobenzaprine Hydrochloride may potentiate the effects of alcohol, barbiturates, and other central nervous system depressants. Healthcare professionals should advise patients to avoid the use of these substances concurrently to mitigate the risk of enhanced sedation and respiratory depression.

In summary, careful consideration of these warnings and precautions is essential when prescribing Cyclobenzaprine Hydrochloride to ensure patient safety and minimize the risk of adverse effects.

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, dry mouth, and dizziness.

Less common adverse reactions, with an incidence between 1% and 3%, encompass 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.

Additional adverse reactions, reported in less than 1% of patients, are categorized by system:

Body as a Whole: Syncope and malaise.

Cardiovascular: Tachycardia, arrhythmia, vasodilatation, palpitations, and hypotension.

Digestive: Vomiting, anorexia, gastrointestinal pain, gastritis, thirst, flatulence, edema of the tongue, abnormal liver function, and rare reports of hepatitis, jaundice, and cholestasis.

Hypersensitivity: Anaphylaxis, angioedema, pruritus, facial edema, urticaria, and rash.

Musculoskeletal: Local weakness.

Nervous System and Psychiatric: 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.

Skin: Sweating.

Special Senses: Ageusia and tinnitus.

Urogenital: Urinary frequency and/or retention.

Certain adverse reactions have an unknown causal relationship with the medication. These include:

Body as a Whole: Chest pain and edema.

Cardiovascular: Hypertension, myocardial infarction, heart block, and stroke.

Digestive: Paralytic ileus, tongue discoloration, stomatitis, and parotid swelling.

Endocrine: Inappropriate ADH syndrome.

Hematic and Lymphatic: Purpura, bone marrow depression, leukopenia, eosinophilia, and thrombocytopenia.

Metabolic, Nutritional and Immune: Elevation and lowering of blood sugar levels, and weight gain or loss.

Musculoskeletal: Myalgia.

Nervous System and Psychiatric: Decreased or increased libido, abnormal gait, delusions, aggressive behavior, paranoia, peripheral neuropathy, Bell's palsy, alteration in EEG patterns, and extrapyramidal symptoms.

Respiratory: Dyspnea.

Skin: Photosensitization, alopecia.

Urogenital: Impaired urination, dilatation of the urinary tract, impotence, testicular swelling, gynecomastia, breast enlargement, and galactorrhea.

The development of serotonin syndrome, a potentially life-threatening condition, 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 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, the most common effects observed are drowsiness and tachycardia. Less frequent manifestations may include tremor, agitation, coma, ataxia, hypertension, slurred speech, confusion, dizziness, nausea, vomiting, and hallucinations. Rare but potentially critical manifestations of overdose 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 during concurrent therapy.

Serotonergic Drugs Cyclobenzaprine HCl may lead to life-threatening interactions when used in conjunction with monoamine oxidase inhibitors (MAOIs). Postmarketing reports indicate that the combination of Cyclobenzaprine Hydrochloride with other serotonergic agents, including selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), tramadol, bupropion, meperidine, and verapamil, has been linked to cases of serotonin syndrome. If the use of Cyclobenzaprine Hydrochloride with these serotonergic drugs is deemed necessary, it is essential to implement careful monitoring, particularly during the initiation of treatment or when adjusting dosages.

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. Caution is advised when prescribing Cyclobenzaprine Hydrochloride to patients who are consuming these agents, as the risk of additive CNS depression may increase.

Tricyclic Antidepressants Tricyclic antidepressants may interfere with the antihypertensive effects of guanethidine and similar medications. Additionally, the use of tricyclic antidepressants in patients taking tramadol may elevate the risk of seizures. Clinicians should consider these interactions when managing patients on these medications and may need to adjust dosages or monitor for adverse effects accordingly.

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 a pharmacokinetic study, 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 the most significant increase, with plasma concentrations approximately 2.4 times higher than their younger counterparts, while elderly females showed a lesser increase of about 1.2 times.

Due to these pharmacokinetic differences, elderly patients may be at an elevated 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 minimize the risk of adverse effects and drug interactions, including potential drug-drug and drug-disease interactions that may be more pronounced in this population. Careful monitoring of these patients is essential to ensure safety and efficacy.

Pregnancy

Reproduction studies conducted in rats, mice, and rabbits at doses up to 20 times the human dose have shown no evidence of impaired fertility or harm to the fetus associated with cyclobenzaprine HCl. The drug is classified as Pregnancy Category B. 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 HCl 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 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

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 patients with reduced kidney function, as the lack of information necessitates careful clinical judgment and monitoring.

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 fatalities. It is important to note that deliberate overdose often involves the co-ingestion of multiple substances, including alcohol.

Clinical Presentation

Signs and symptoms of cyclobenzaprine toxicity may 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. A maximal limb-lead QRS duration of ≥0.10 seconds may serve as a key indicator of overdose severity.

Management Recommendations

Management of cyclobenzaprine overdose is complex and evolving. It is strongly advised that healthcare professionals contact a poison control center for the most current treatment protocols. All patients suspected of an overdose should undergo gastrointestinal decontamination, which includes large volume gastric lavage followed by the administration of activated charcoal. If the patient's consciousness is impaired, securing the airway is critical prior to performing lavage, and emesis is contraindicated.

For patients exhibiting dysrhythmias or QRS widening, serum alkalinization should be initiated to achieve a pH of 7.45 to 7.55, utilizing intravenous sodium bicarbonate and hyperventilation as necessary. In cases where dysrhythmias do not respond to sodium bicarbonate therapy or hyperventilation, alternative treatments such as lidocaine, bretylium, or phenytoin may be effective.

In patients with central nervous system depression, early intubation is recommended due to the risk of sudden deterioration. Seizures should be managed with benzodiazepines; if these are ineffective, other anticonvulsants such as phenobarbital or phenytoin may be considered.

Physostigmine is not recommended except in life-threatening situations that do not respond to other therapies, and its use should only occur in close consultation with a poison control center.

The management principles for both child and adult overdoses are similar; however, it is imperative that physicians consult the local poison control center for specific pediatric treatment recommendations.

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, oral administration of cyclobenzaprine at doses up to 10 times the human dose did not adversely affect the reproductive performance or fertility of male or female rats. Furthermore, cyclobenzaprine did not exhibit mutagenic activity in male mice at dose levels of up to 20 times the human dose.

In nonclinical toxicology studies, rats treated with cyclobenzaprine HCl for up to 67 weeks at doses ranging from approximately 5 to 40 times the maximum recommended human dose exhibited pale and occasionally enlarged livers, along with dose-related hepatocyte vacuolation and lipidosis. These microscopic changes were observed in higher dose groups after 26 weeks and even earlier in rats that died prior to this time. In contrast, at lower doses, these changes were not evident until after 26 weeks. Importantly, cyclobenzaprine did not influence the onset, incidence, or distribution of neoplasia in an 81-week study in mice or a 105-week study in rats.

Animal pharmacology and toxicology studies indicate that cyclobenzaprine effectively reduces or abolishes skeletal muscle hyperactivity across various animal models. It has been determined that cyclobenzaprine does not act at the neuromuscular junction or directly on skeletal muscle. Instead, it primarily exerts its effects within the central nervous system, particularly at the brain stem level, although its action on the spinal cord may also contribute to its overall skeletal muscle relaxant activity. Evidence suggests that the net effect of cyclobenzaprine is a reduction in tonic somatic motor activity, influencing both gamma (γ) and alpha (α) motor systems. Pharmacological studies in animals have demonstrated similarities between the effects of cyclobenzaprine and those of structurally related tricyclic antidepressants, including 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 such as syncope and malaise have been noted. Cardiovascular events 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 reported include anaphylaxis, angioedema, pruritus, facial edema, urticaria, and rash. Musculoskeletal reactions feature local weakness.

Nervous system and psychiatric events encompass 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.

Skin-related 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 events 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 also include myalgia. Nervous system and psychiatric events reported are 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 also encompass photosensitization and alopecia. Urogenital events 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 HCl may impair mental and/or physical abilities necessary for performing hazardous tasks, such as operating machinery or driving a motor vehicle, particularly when used in conjunction with alcohol or other central nervous system (CNS) depressants.

In elderly patients, it is important to communicate that the frequency and severity of adverse events associated with cyclobenzaprine may be increased, whether or not other medications are being taken concurrently. Therefore, healthcare providers should recommend initiating treatment with a 5 mg dose in this population and advise a gradual titration upward.

Patients should also be cautioned about the risk of serotonin syndrome when cyclobenzaprine hydrochloride 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 (MAO) inhibitors.

It is essential for healthcare providers to inform patients about 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 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

Laboratory tests specific to cyclobenzaprine HCl have not been detailed. Clinicians should be aware that while withdrawal symptoms have not been reported with cyclobenzaprine HCl, abrupt cessation after prolonged use may lead to nausea, headache, and malaise, which are not indicative of addiction.

The recommended dosage for cyclobenzaprine HCl tablets USP is 5 mg taken three times daily, with the possibility of increasing to 10 mg three times daily based on individual patient response. Prolonged use beyond two to three weeks is not advised. Patients should be counseled on the potential for impaired mental and physical abilities when using cyclobenzaprine HCl, particularly in conjunction with alcohol or other CNS depressants. Additionally, there is a risk of serotonin syndrome when cyclobenzaprine HCl is used with certain medications, including SSRIs, SNRIs, TCAs, tramadol, bupropion, meperidine, verapamil, or MAO inhibitors. Patients should be informed of the signs and symptoms of serotonin syndrome and instructed to seek immediate medical attention if they occur. A post-marketing surveillance program involving 7,607 patients indicated that the effectiveness of cyclobenzaprine HCl was consistent with controlled studies, with a lower incidence of adverse effects reported.

FDA Insert (PDF)

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

View full prescribing information (PDF)