Cyclobenzaprine hydrochloride

Description

Cyclobenzaprine hydrochloride, USP is a white to off-white crystalline powder with the molecular 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, alcohol, and methanol; sparingly soluble in isopropanol; slightly soluble in chloroform and methylene chloride; and insoluble in hydrocarbons. When aqueous solutions are made alkaline, the free base separates.

Chemically, cyclobenzaprine hydrochloride 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 hydrochloride is supplied in tablet form for oral administration, specifically as 7.5 mg tablets. Each tablet contains the following inactive ingredients: corn starch, hydroxypropyl cellulose, hypromellose, lactose monohydrate, magnesium stearate, polyethylene glycol, pregelatinized starch, talc, and titanium dioxide.

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 typically resolve within a 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 either 7.5 mg or 10 mg, also taken three times a day.

It is important to note that the use of cyclobenzaprine hydrochloride tablets for durations exceeding two to three weeks is not recommended. For patients who are elderly or have hepatic impairment, 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 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 necessitates careful consideration of several critical warnings and precautions to ensure patient safety.

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, has been associated with 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). Should these symptoms occur, immediate discontinuation of cyclobenzaprine hydrochloride and any concomitant serotonergic agents is imperative, 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 hydrochloride shares structural similarities with tricyclic antidepressants such as amitriptyline and imipramine. In short-term studies involving indications beyond muscle spasm associated with acute musculoskeletal conditions, and typically at doses exceeding those recommended for muscle spasm, serious central nervous system reactions akin to those observed with tricyclic antidepressants have been reported.

Cardiac Risks Tricyclic antidepressants, including cyclobenzaprine hydrochloride, have been linked to various cardiac risks, including arrhythmias, sinus tachycardia, and prolongation of conduction time, which may lead to severe outcomes such as myocardial infarction and stroke.

CNS Depressant Effects Cyclobenzaprine hydrochloride may potentiate the effects of alcohol, barbiturates, and other central nervous system depressants. Healthcare professionals should exercise caution when prescribing cyclobenzaprine hydrochloride to patients who are concurrently using these substances, as the risk of enhanced CNS depressant effects may increase.

Monitoring for these adverse effects and ensuring appropriate patient education regarding the risks associated with cyclobenzaprine hydrochloride is essential for safe therapeutic use.

Side Effects

Patients receiving treatment may experience a range of adverse reactions. The most common adverse reactions, occurring in more than 3% of participants, include drowsiness (29% at 5 mg, 38% at 10 mg, compared to 10% in the placebo group), dry mouth (21% at 5 mg, 32% at 10 mg, and 7% in the placebo group), fatigue (6% at both 5 mg and 10 mg, and 3% in the placebo group), and headache (5% at both dosages, with 8% in the placebo group).

Adverse reactions occurring 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.

Postmarketing experience has identified additional adverse reactions occurring in less than 1% of patients. These include syncope and malaise (body as a whole), tachycardia, arrhythmia, vasodilatation, palpitation, and hypotension (cardiovascular). Digestive system reactions may include 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 such as anaphylaxis, angioedema, pruritus, facial edema, urticaria, and rash have also been reported. Musculoskeletal reactions may include local weakness, while nervous system and psychiatric reactions can 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, and diplopia. Skin reactions may involve sweating, and special senses may be affected by ageusia and tinnitus. Urogenital reactions can include urinary frequency and/or retention.

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

Drug Interactions

Cyclobenzaprine has several significant drug interactions that warrant careful consideration during treatment.

Monoamine Oxidase Inhibitors (MAOIs) Cyclobenzaprine is contraindicated in patients taking MAO inhibitors due to the potential for life-threatening interactions.

Serotonergic Drugs Postmarketing reports indicate that the concomitant use of cyclobenzaprine hydrochloride with other serotonergic agents, such as selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), tramadol, bupropion, meperidine, verapamil, or MAO inhibitors, may lead to serotonin syndrome. If the combination of cyclobenzaprine and other serotonergic drugs is deemed necessary, careful monitoring is recommended, especially during the initiation of therapy or when increasing dosages.

CNS Depressants Cyclobenzaprine hydrochloride may potentiate the effects of alcohol, barbiturates, and other central nervous system (CNS) depressants. Caution is advised when these substances are used concurrently, and dosage adjustments may be necessary to mitigate the risk of excessive sedation.

Antihypertensive Agents Tricyclic antidepressants may interfere with the antihypertensive effects of guanethidine and similar medications. Clinicians should monitor blood pressure and consider alternative treatments if necessary.

Seizure Risk The use of tricyclic antidepressants in conjunction with tramadol may increase the risk of seizures. Patients should be monitored closely for seizure activity, and dosage adjustments may be warranted based on individual risk factors.

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

In a pharmacokinetic study involving elderly individuals aged 65 years and older, it was observed that the mean steady-state area under the curve (AUC) values for cyclobenzaprine were approximately 1.7 times higher than those recorded in younger adult populations. Notably, elderly male subjects exhibited the most significant increase, with AUC values approximately 2.4 times higher, while elderly female subjects demonstrated a lesser increase, approximately 1.2 times higher.

Given these findings, it is recommended that therapy with cyclobenzaprine hydrochloride in geriatric patients be initiated at a lower dose of 5 mg. Furthermore, careful titration of the dosage should be conducted, allowing for a gradual upward adjustment to ensure safety and efficacy in this population. Monitoring for potential adverse effects is advised, considering the altered pharmacokinetics observed in elderly patients.

Pregnancy

Reproduction studies have been conducted in rats, mice, and rabbits at doses up to 20 times the human dose of cyclobenzaprine hydrochloride, 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 hydrochloride should be used during pregnancy only if clearly needed. Healthcare professionals are advised to weigh the potential benefits against the 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 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 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 hydrochloride, while rare, can lead to serious outcomes, including fatalities. It is important to note that instances of deliberate overdose often involve the co-ingestion of multiple substances, including alcohol, which complicates the clinical picture.

Given the complexities associated with the management of cyclobenzaprine overdose, it is imperative for healthcare professionals to consult a poison control center for the most current treatment recommendations. This ensures that the management approach is aligned with the latest clinical guidelines and evidence.

Signs and symptoms of toxicity can manifest rapidly following an overdose. Therefore, immediate hospital monitoring is essential to assess the patient's condition and initiate appropriate interventions.

The acute oral LD50 values for cyclobenzaprine hydrochloride have been established at approximately 338 mg/kg in mice and 425 mg/kg in rats, indicating the potential for significant toxicity at high doses. Prompt recognition and management of overdose symptoms are critical to improving patient outcomes.

Nonclinical Toxicology

In rats treated with cyclobenzaprine hydrochloride for up to 67 weeks at doses ranging from approximately 5 to 40 times the maximum recommended human dose, observations included pale and occasionally enlarged livers, along with dose-related hepatocyte vacuolation accompanied by lipidosis. In higher dose groups, these microscopic changes were evident after 26 weeks, and in some cases, even earlier in rats that succumbed 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, indicating no carcinogenic potential.

Reproductive performance and fertility were not adversely affected in male or female rats administered oral doses of cyclobenzaprine up to 10 times the human dose, suggesting no impairment of fertility.

Additionally, cyclobenzaprine did not exhibit mutagenic activity in male mice at dose levels of up to 20 times the human dose, further supporting its safety profile in nonclinical 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 noted include anaphylaxis, angioedema, pruritus, facial edema, urticaria, and rash. Musculoskeletal reactions include local weakness. Nervous system and psychiatric events reported are 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 reactions reported are urinary frequency and/or retention.

Additionally, other reactions have been reported rarely for cyclobenzaprine hydrochloride under circumstances where a causal relationship could not be established, or reported for other tricyclic drugs, and are listed to serve as alerting information to physicians. 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 reported include elevation and lowering of blood sugar levels, as well as weight gain or loss. Musculoskeletal reactions include myalgia. Nervous system and psychiatric reactions consist of 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 reported are photosensitization and alopecia. 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 hydrochloride, particularly when used in conjunction with alcohol or other central nervous system (CNS) depressants, may impair their mental and physical abilities necessary for performing hazardous tasks, including operating machinery or driving a motor vehicle.

In elderly patients, it is important to communicate that the frequency and severity of adverse events associated with cyclobenzaprine may be increased, regardless of whether other medications are being taken concurrently. Therefore, healthcare providers should recommend initiating treatment with a 5 mg dose in this population and emphasize the need for 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).

It is essential for healthcare providers to inform patients about 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 various package configurations, with specific NDC numbers available for identification. It is essential to store the product at a temperature range of 20° to 25° C (68° to 77° F), in accordance with USP controlled room temperature guidelines. Proper storage conditions must be maintained to ensure the integrity and efficacy of the product.

Additional Clinical Information

No additional information is available regarding laboratory tests or the route, method, and frequency of administration for cyclobenzaprine hydrochloride.

Clinicians should be aware that while cyclobenzaprine hydrochloride has not been reported to cause withdrawal symptoms, abrupt cessation after prolonged use may lead to nausea, headache, and malaise, which are not indicative of addiction. Patients should be counseled on the potential for impaired mental and physical abilities when using cyclobenzaprine hydrochloride, particularly in conjunction with alcohol or other CNS depressants, which may affect their ability to perform hazardous tasks such as driving or operating machinery. Additionally, there is a risk of serotonin syndrome when cyclobenzaprine hydrochloride 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 advised to seek immediate medical attention if they occur.

Postmarketing experience indicates that the overall effectiveness of cyclobenzaprine hydrochloride aligns with findings from double-blind 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 Aidarex Pharmaceuticals LLC. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)