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. This drug is intended to improve symptoms such as muscle spasm, pain, tenderness, limitation of motion, and restrictions in activities of daily living.

Cyclobenzaprine hydrochloride tablets should be utilized for short periods, specifically up to 2 or 3 weeks, as there is insufficient evidence to support the effectiveness of prolonged use. Muscle spasms associated with acute, painful musculoskeletal conditions are typically of short duration, and specific therapy for extended periods is seldom warranted.

This medication has not demonstrated efficacy in treating spasticity related to cerebral or spinal cord diseases, nor is it indicated for use in children with cerebral palsy.

Dosage and Administration

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

It is important to note that the use of cyclobenzaprine hydrochloride tablets for periods longer than 2 or 3 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 should not use it due to the risk of severe allergic reactions.

Concomitant use with monoamine oxidase (MAO) inhibitors or within 14 days of their discontinuation is contraindicated, as this combination has been associated with hyperpyretic crisis, seizures, and fatalities in patients receiving cyclobenzaprine or similar tricyclic antidepressants.

The product is also 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.

Additionally, use is 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 Cyclobenzaprine hydrochloride has been associated with the development of serotonin syndrome, a potentially life-threatening condition, particularly when used in conjunction with other serotonergic agents. This includes selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), tramadol, bupropion, meperidine, verapamil, and monoamine oxidase (MAO) inhibitors. The concomitant use of cyclobenzaprine hydrochloride with MAO inhibitors is contraindicated. Clinicians should be vigilant for symptoms indicative of serotonin syndrome, which 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 arise, immediate discontinuation of cyclobenzaprine hydrochloride and any concomitant serotonergic agents is warranted, along with the initiation of supportive symptomatic treatment. If the clinical decision is made to continue treatment with cyclobenzaprine hydrochloride alongside other serotonergic medications, careful observation is essential, particularly during the initiation of therapy or when adjusting dosages.

Central Nervous System Effects Cyclobenzaprine is structurally related to 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 similar to those observed with tricyclic antidepressants have been reported.

Cardiovascular Risks Tricyclic antidepressants, including cyclobenzaprine, have been linked to cardiovascular complications such as arrhythmias, sinus tachycardia, and prolongation of conduction time, which may lead to myocardial infarction and stroke. Healthcare professionals should monitor patients for these potential cardiovascular effects, especially in those with pre-existing heart conditions.

CNS Depressant Interactions Cyclobenzaprine may potentiate the effects of alcohol, barbiturates, and other central nervous system (CNS) depressants. Caution is advised when prescribing cyclobenzaprine to patients who are concurrently using these substances, as the risk of additive CNS depression may increase.

In summary, healthcare professionals should exercise caution when prescribing cyclobenzaprine hydrochloride, particularly in patients with a history of serotonergic drug use, cardiovascular issues, or concurrent use of CNS depressants. Regular monitoring and patient education regarding the signs and symptoms of serotonin syndrome and other potential adverse effects are essential for safe and effective treatment.

Side Effects

Patients may experience a range of adverse reactions while using the medication. Common adverse reactions, occurring in more than 3% of participants, include drowsiness (29% at 5 mg, 38% at 10 mg, compared to 10% in the placebo group), dry mouth (21% at 5 mg, 32% at 10 mg, 7% in placebo), fatigue (6% at both doses), and headache (5% at both doses). Additional common adverse reactions reported in clinical studies include drowsiness (39%) and dry mouth (27%), with lower incidences noted in a surveillance program (16% and 7%, respectively). Dizziness was reported in 11% of clinical studies and 3% in the surveillance program.

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

Postmarketing experience has identified additional adverse reactions with an incidence of less than 1%. These include syncope and malaise (body as a whole), tachycardia, arrhythmia, vasodilatation, palpitation, and hypotension (cardiovascular), as well as vomiting, anorexia, gastrointestinal pain, gastritis, thirst, flatulence, edema of the tongue, abnormal liver function, and rare reports of hepatitis, jaundice, and cholestasis (digestive). Hypersensitivity reactions such as anaphylaxis, angioedema, pruritus, facial edema, urticaria, and rash have also been reported.

Nervous system and psychiatric adverse reactions include 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 include local weakness (musculoskeletal), sweating (skin), ageusia and tinnitus (special senses), and urinary frequency and/or retention (urogenital).

Certain adverse reactions have been reported where a causal relationship is unknown, including chest pain and edema (body as a whole), hypertension, myocardial infarction, heart block, and stroke (cardiovascular), as well as paralytic ileus, tongue discoloration, stomatitis, and parotid swelling (digestive). Endocrine reactions such as inappropriate ADH syndrome, hematologic reactions including purpura, bone marrow depression, leukopenia, eosinophilia, and thrombocytopenia, and metabolic changes like elevation and lowering of blood sugar levels, weight gain or loss have also been noted. Musculoskeletal reactions include myalgia, while nervous system and psychiatric reactions encompass 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, while skin reactions may involve photosensitization and alopecia. Urogenital reactions include impaired urination, dilatation of the urinary tract, impotence, testicular swelling, gynecomastia, breast enlargement, and galactorrhea.

A serious warning regarding serotonin syndrome is noted, which may occur when the medication is used in combination with other drugs such as SSRIs, SNRIs, TCAs, tramadol, bupropion, meperidine, verapamil, or MAO inhibitors. Symptoms may include mental status changes, autonomic instability, neuromuscular abnormalities, and gastrointestinal symptoms.

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 potentially critical manifestations 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) and Serotonergic Drugs Cyclobenzaprine may lead to life-threatening interactions when administered concurrently with MAO inhibitors. It is essential to monitor patients closely when cyclobenzaprine is used alongside other serotonergic medications due to the potential for increased serotonergic effects.

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

Tricyclic Antidepressants (TCAs) Tricyclic antidepressants may interfere with the antihypertensive effects of guanethidine and similar agents. Clinicians should be aware of this interaction and consider monitoring blood pressure in patients receiving both medications. Additionally, TCAs may increase the risk of seizures in patients taking tramadol, necessitating careful patient evaluation and monitoring for seizure activity.

No additional drug interactions or laboratory test interactions have been reported.

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.

Furthermore, 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 any possible 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.

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, while rare, can lead to serious outcomes, including fatalities, particularly when multiple drugs, including alcohol, are involved in a deliberate overdose. Healthcare professionals should be vigilant, as signs and symptoms of toxicity can manifest rapidly following an overdose, 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. Clinically, the most prevalent effects observed in cases of overdose include drowsiness and tachycardia. Other less common symptoms may encompass tremor, agitation, coma, ataxia, hypertension, slurred speech, confusion, dizziness, nausea, vomiting, and hallucinations.

Healthcare providers should be aware of rare but critical manifestations of cyclobenzaprine overdose, which can include cardiac arrest, chest pain, cardiac dysrhythmias, severe hypotension, seizures, and neuroleptic malignant syndrome. Changes in the electrocardiogram, particularly alterations in the QRS axis or width, serve as significant clinical indicators of toxicity.

For the management of suspected cyclobenzaprine overdose, all patients should undergo gastrointestinal decontamination. This includes performing a 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 to a pH of 7.45 to 7.55 is recommended. In instances of central nervous system (CNS) depression, early intubation is advised due to the risk of abrupt deterioration. Seizures should be managed with benzodiazepines or other anticonvulsants.

It is strongly recommended that healthcare professionals contact a poison control center for the most current information regarding treatment protocols and specific management strategies for pediatric patients.

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 demonstrate 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 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.

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.

Animal studies have demonstrated that cyclobenzaprine effectively reduces or abolishes skeletal muscle hyperactivity across various 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 brain stem levels, although its action on spinal cord levels may also contribute to its overall skeletal muscle relaxant activity. The net effect of cyclobenzaprine appears to be a reduction in tonic somatic motor activity, influencing both gamma and alpha motor systems.

Pharmacological studies in animals have indicated 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 has also been 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 reactions reported are 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 noted. 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 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 consist of myalgia. In the Nervous System and Psychiatric categories, decreased or increased libido, abnormal gait, delusions, aggressive behavior, paranoia, peripheral neuropathy, Bell's palsy, alteration in EEG patterns, and extrapyramidal symptoms have been reported. Respiratory reactions include dyspnea. Skin reactions consist of photosensitization and alopecia. Urogenital reactions reported are impaired urination, dilatation of the urinary tract, impotence, testicular swelling, gynecomastia, breast enlargement, and galactorrhea.

Patient Counseling

Healthcare providers should advise patients that cyclobenzaprine 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 elderly patients that they may experience an increased frequency and severity of adverse events associated with 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 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, and instruct 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 will help maintain 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 therefore, cyclobenzaprine should be initiated at a 5 mg dose in this population, with gradual titration recommended.

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 NORTHSTAR RX LLC. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)