Cyclobenzaprine hydrochloride

Description

Cyclobenzaprine hydrochloride, USP is a tricyclic amine salt presented as a white to off-white, odourless, crystalline powder. Its molecular formula is C20H21N • HCl, and it has a molecular weight of 311.9. The compound has a melting point of 217°C and a pKa of 8.47 at 25°C. It is freely soluble in water, alcohol, and methanol; sparingly soluble in isopropanol; slightly soluble in chloroform and methylene chloride; and insoluble in n-hexane. Chemically, it is designated as 3-(5H-dibenzoa,dcyclohepten-5-ylidene)-N,N-dimethyl-1-propanamine hydrochloride.

Cyclobenzaprine hydrochloride tablets, USP are available in strengths of 5 mg, 7.5 mg, and 10 mg for oral administration. Each tablet contains cyclobenzaprine hydrochloride along with inactive ingredients, which include crospovidone, hypromellose, lactose anhydrous, macrogol, magnesium stearate, polysorbate 80, pregelatinized starch, silicified microcrystalline cellulose, and titanium dioxide. The 5 mg and 10 mg tablets also contain D&C Yellow #10 Aluminum Lake and FD&C Yellow #6 Sunset Yellow FCF Aluminum Lake, while the 5 mg tablets additionally contain FD&C Blue #2/INDIGO Carmine Aluminum Lake.

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 benefits 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, typically not exceeding 2 to 3 weeks, as there is insufficient evidence to support its effectiveness for prolonged treatment. Muscle spasms related to acute, painful musculoskeletal conditions are generally of limited duration, and specific therapy beyond this timeframe is rarely necessary.

Cyclobenzaprine hydrochloride tablets have not demonstrated efficacy in treating spasticity associated with cerebral or spinal cord diseases, nor are they indicated for use in pediatric patients 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 2 to 3 weeks is not recommended. For patients who are elderly or have hepatic impairment, 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 complications.

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

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 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.

Central Nervous System Effects Cyclobenzaprine hydrochloride shares structural similarities with 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 are closely related to cyclobenzaprine, have been associated with cardiovascular complications, including arrhythmias, sinus tachycardia, and prolongation of conduction time, which may lead to myocardial infarction and stroke.

CNS Depressant Interactions Cyclobenzaprine hydrochloride may potentiate the effects of alcohol, barbiturates, and other central nervous system depressants. Healthcare professionals should exercise caution when prescribing cyclobenzaprine to patients who are consuming these substances, as the risk of enhanced sedation and respiratory depression may be increased.

Monitoring parameters should include assessment of mental status, cardiovascular function, and any signs of serotonin syndrome, particularly in patients receiving concomitant medications that may interact with cyclobenzaprine hydrochloride.

Side Effects

Patients receiving treatment have reported a range of adverse reactions, categorized by frequency and seriousness.

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% for both 5 mg and 10 mg, 3% for placebo), and headache (5% for both 5 mg and 10 mg, 8% for placebo).

Adverse reactions reported in 1% to 3% of patients encompass 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.

Additional adverse reactions include serious events such as syncope and malaise, cardiovascular issues like tachycardia, arrhythmia, vasodilatation, palpitations, and hypotension. Digestive system reactions may involve vomiting, anorexia, diarrhea, gastrointestinal pain, gastritis, thirst, flatulence, edema of the tongue, abnormal liver function, and rare cases of hepatitis, jaundice, and cholestasis. Hypersensitivity reactions can manifest as anaphylaxis, angioedema, pruritus, facial edema, urticaria, and rash.

Nervous system and psychiatric adverse reactions are notable, including seizures, ataxia, vertigo, dysarthria, tremors, hypertonia, convulsions, muscle twitching, disorientation, insomnia, depressed mood, anxiety, agitation, psychosis, abnormal thinking and dreaming, hallucinations, excitement, paresthesia, diplopia, and serotonin syndrome. Other reactions may involve local weakness in the musculoskeletal system, sweating in the skin, ageusia and tinnitus in the special senses, and urinary frequency and/or retention in the urogenital system.

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

A significant warning regarding serotonin syndrome is warranted, as this potentially life-threatening condition has been reported in patients using cyclobenzaprine hydrochloride in conjunction with other medications, 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 is associated with significant drug interactions that warrant careful consideration.

Monoamine Oxidase Inhibitors (MAOIs) Cyclobenzaprine may lead to life-threatening interactions when administered concurrently with MAO inhibitors. It is essential to monitor patients closely for signs of serotonin syndrome, particularly when cyclobenzaprine is used alongside other serotonergic medications.

Central Nervous System (CNS) Depressants The concomitant use of cyclobenzaprine with alcohol, barbiturates, and other CNS depressants may enhance the sedative effects of these substances. Caution is advised, and dosage adjustments may be necessary to mitigate the risk of excessive sedation.

Tricyclic Antidepressants (TCAs) Tricyclic antidepressants may interfere with the antihypertensive effects of guanethidine and similar agents. Additionally, the use of TCAs in patients taking tramadol may increase the risk of seizures. Monitoring for these interactions is recommended to ensure patient safety.

No specific drug interactions or laboratory test interactions have been reported beyond those mentioned.

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 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, necessitating careful consideration when prescribing this medication. In a pharmacokinetic study involving individuals aged 65 years and older, the mean steady-state area under the curve (AUC) values for cyclobenzaprine were found to be approximately 1.7-fold higher than those observed in younger adults. Notably, elderly male subjects exhibited the most significant increase, with mean levels approximately 2.4-fold higher, while elderly females showed a lesser increase of about 1.2-fold.

Given these pharmacokinetic findings, it is recommended that therapy with cyclobenzaprine in geriatric patients be initiated at a lower dose of 5 mg, with gradual titration to achieve the desired therapeutic effect.

Additionally, 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. There is also an increased potential for drug-drug and drug-disease interactions in this population. Therefore, cyclobenzaprine should be prescribed to elderly patients only when clearly indicated, and close monitoring for adverse effects is advised throughout the course of treatment.

Pregnancy

Pregnancy Category B indicates that 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 due to cyclobenzaprine. 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 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 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 of these patients.

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 overdosage, although rare, fatalities may occur, particularly in instances of multiple drug ingestion, which often includes alcohol. The onset of signs and symptoms of toxicity can be rapid, necessitating immediate hospital monitoring.

The acute oral LD50 of cyclobenzaprine has been established at approximately 338 mg/kg in mice and 425 mg/kg in rats. The most frequently observed effects of overdose include drowsiness and tachycardia. Other less common symptoms may manifest as tremor, agitation, coma, ataxia, hypertension, slurred speech, confusion, dizziness, nausea, vomiting, and hallucinations. Critical manifestations, though rare, can 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. All patients suspected of an overdose should undergo gastrointestinal decontamination, which includes large volume gastric lavage followed by the administration of activated charcoal. In cases where consciousness is impaired, securing the airway prior to lavage is essential, and emesis is contraindicated.

A maximal limb-lead QRS duration of ≥ 0.10 seconds may indicate the severity of the overdose. For patients exhibiting dysrhythmias and/or QRS widening, serum alkalinization with intravenous sodium bicarbonate should be initiated. In patients presenting with central nervous system (CNS) depression, early intubation is recommended due to the risk of abrupt deterioration. Seizures should be managed with benzodiazepines or other anticonvulsants.

It is strongly advised that healthcare professionals contact a poison control center for the most current information regarding treatment protocols for cyclobenzaprine overdose management.

Nonclinical Toxicology

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 teratogenic effects associated with cyclobenzaprine. However, there are no adequate and well-controlled studies in pregnant women. Due to the limitations of animal reproduction studies in predicting human responses, cyclobenzaprine should be used during pregnancy only if clearly needed.

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. Additionally, cyclobenzaprine did not exhibit mutagenic activity in male mice at dose levels of up to 20 times the human dose.

In long-term studies involving rats treated with cyclobenzaprine for up to 67 weeks at doses 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. These microscopic changes were noted in higher dose groups after 26 weeks and even earlier in rats that died prior to this time frame. Furthermore, 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.

Cyclobenzaprine has been shown to reduce or abolish skeletal muscle hyperactivity in various animal models. It does not act at the neuromuscular junction or directly on skeletal muscle, but primarily exerts its effects within the central nervous system, particularly at the brain stem level, although its action on the spinal cord may contribute to its overall skeletal muscle relaxant activity. 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. Cyclobenzaprine was also observed to cause 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 noted include anaphylaxis, angioedema, pruritus, facial edema, urticaria, and rash. Musculoskeletal reactions include 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 reported. Skin reactions include sweating, while special senses reactions consist of ageusia and tinnitus. Urogenital reactions reported include urinary frequency and/or retention.

Additionally, other reactions have been reported rarely for cyclobenzaprine under circumstances where a causal relationship could not be established, or reported for other tricyclic drugs, and are included for alerting information to physicians. These include Body as a Whole reactions such as chest pain and edema. Cardiovascular events include hypertension, myocardial infarction, heart block, and stroke. Digestive reactions consist of paralytic ileus, tongue discoloration, stomatitis, and parotid swelling. Endocrine reactions include inappropriate ADH syndrome. Hematic and Lymphatic reactions reported are purpura, bone marrow depression, leukopenia, eosinophilia, and thrombocytopenia.

Metabolic, Nutritional, and Immune reactions include 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 noted. Respiratory reactions include dyspnea. Skin reactions consist of photosensitization and alopecia. Urogenital reactions reported 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 may impair mental and 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 patients that the elderly population may experience an increased frequency and severity of adverse events associated with cyclobenzaprine, whether or not they are taking other medications. For elderly patients, healthcare providers should recommend initiating treatment with a 5 mg dose of cyclobenzaprine hydrochloride, with a gradual titration to higher doses as appropriate.

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 (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 a tight, light-resistant container that complies with the standards set forth by the United States Pharmacopeia (USP) and features a child-resistant closure. It is essential to store the product at a temperature range of 20°C to 25°C (68°F to 77°F), in accordance with USP Controlled Room Temperature guidelines. Proper adherence to these storage conditions is crucial for maintaining the integrity and efficacy of the product.

Additional Clinical Information

Patients using cyclobenzaprine should be informed 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 are at an increased risk for adverse events, and treatment should begin with a 5 mg dose, titrated slowly.

Additionally, patients must be cautioned about the potential risk of serotonin syndrome when cyclobenzaprine is used alongside other medications, including SSRIs, SNRIs, TCAs, tramadol, bupropion, meperidine, verapamil, or MAO inhibitors. They should be educated on the signs and symptoms of serotonin syndrome and advised to seek immediate medical attention if these occur.

FDA Insert (PDF)

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

View full prescribing information (PDF)