Cyclobenzaprine hydrochloride

Description

Cyclobenzaprine hydrochloride, USP is a white, crystalline tricyclic amine salt with the molecular formula C20H21N • HCl and a molecular weight of 311.9. It has a melting point of 217ºC and a pKa of 8.47 at 25ºC. The compound is freely soluble in water and alcohol, sparingly soluble in isopropanol, and insoluble in hydrocarbon solvents. Chemically, it is designated as 3-(5H-dibenzoa,dcyclohepten-5-ylidene)-N,N-dimethyl-1-propanamine hydrochloride. Cyclobenzaprine hydrochloride is supplied as 5 mg or 10 mg tablets for oral administration. Each tablet contains the following inactive ingredients: croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate, polyethylene glycol, pregelatinized starch (maize), and titanium dioxide. The 5 mg tablet also contains D&C yellow #10 aluminum lake and FD&C yellow #6 aluminum lake, while the 10 mg tablet contains yellow iron oxide.

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, typically not exceeding two to three 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, USP are not indicated for the treatment of spasticity associated with cerebral or spinal cord disease, nor are they effective in pediatric patients with cerebral palsy.

Dosage and Administration

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

Cyclobenzaprine hydrochloride tablets are not recommended for use beyond two to three weeks. For patients with hepatic impairment or 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 this 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. This is due to the potential for hyperpyretic crisis, seizures, and fatalities associated with the concurrent administration of cyclobenzaprine or structurally similar tricyclic antidepressants.

The product is contraindicated in patients in the acute recovery phase of myocardial infarction, as well as those with arrhythmias, heart block or conduction disturbances, or congestive heart failure, due to the risk of exacerbating these conditions.

Additionally, the use of this product is contraindicated in patients with hyperthyroidism, as it may worsen the condition.

Warnings and Precautions

The use of cyclobenzaprine hydrochloride carries significant warnings and precautions that healthcare professionals must consider to ensure patient safety.

Warnings

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 potentially life-threatening serotonin syndrome. 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 any of these symptoms occur, treatment with cyclobenzaprine hydrochloride and any concomitant serotonergic agents must be discontinued immediately, and supportive symptomatic treatment should be initiated.

Cyclobenzaprine is structurally related to tricyclic antidepressants such as amitriptyline and imipramine. In short-term studies for 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. Additionally, tricyclic antidepressants are known to cause arrhythmias, sinus tachycardia, and prolongation of conduction time, which may lead to myocardial infarction and stroke.

Furthermore, cyclobenzaprine hydrochloride may potentiate the effects of alcohol, barbiturates, and other central nervous system depressants, necessitating caution in patients who consume these substances.

General Precautions

Due to its atropine-like properties, cyclobenzaprine hydrochloride should be administered with caution in patients with a history of urinary retention, angle-closure glaucoma, or increased intraocular pressure, as well as in those receiving anticholinergic medications.

In patients with hepatic impairment, the plasma concentration of cyclobenzaprine is elevated, increasing susceptibility to the sedative effects of the drug. For patients with mild hepatic impairment, it is recommended to initiate treatment with a 5 mg dose and to titrate slowly. The use of cyclobenzaprine hydrochloride is not advised in patients with moderate to severe hepatic insufficiency due to insufficient data regarding safety in this population.

Healthcare professionals should remain vigilant for any adverse reactions and adjust treatment protocols accordingly to mitigate risks associated with cyclobenzaprine hydrochloride.

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% for placebo), dry mouth (21% at 5 mg, 32% at 10 mg, versus 7% for placebo), fatigue (6% for both 5 mg and 10 mg, 3% for placebo), and headache (5% for both dosages, 8% for placebo).

Adverse reactions 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/tiredness, asthenia, dyspepsia, unpleasant taste, blurred vision, and confusion.

Postmarketing experience has revealed 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.

Nervous system and psychiatric reactions include seizures, ataxia, vertigo, dysarthria, tremors, hypertonia, convulsions, muscle twitching, disorientation, insomnia, depressed mood, abnormal sensations, anxiety, agitation, psychosis, abnormal thinking and dreaming, hallucinations, excitement, paresthesia, 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. These include chest pain and edema (body as a whole), hypertension, myocardial infarction, heart block, and stroke (cardiovascular), paralytic ileus, tongue discoloration, stomatitis, and parotid swelling (digestive), inappropriate ADH syndrome (endocrine), purpura, bone marrow depression, leukopenia, eosinophilia, and thrombocytopenia (hematic and lymphatic), as well as fluctuations in blood sugar levels, weight gain or loss (metabolic, nutritional, and immune), myalgia (musculoskeletal), decreased or increased libido, abnormal gait, delusions, aggressive behavior, paranoia, peripheral neuropathy, Bell’s palsy, alterations in EEG patterns, and extrapyramidal symptoms (nervous system and psychiatric). 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.

A boxed warning is included regarding the risk of serotonin syndrome, which can be life-threatening and has been reported 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 (e.g., confusion, agitation, hallucinations), autonomic instability (e.g., diaphoresis, tachycardia, labile blood pressure, hyperthermia), neuromuscular abnormalities (e.g., tremor, ataxia, hyperreflexia, clonus, muscle rigidity), and gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).

In cases of overdosage, common effects 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 can include cardiac arrest, chest pain, cardiac dysrhythmias, severe hypotension, seizures, and neuroleptic malignant syndrome.

Drug Interactions

Cyclobenzaprine has the potential to cause life-threatening interactions when administered concurrently with monoamine oxidase inhibitors (MAOIs). It is essential to exercise careful observation when cyclobenzaprine is used alongside other serotonergic agents, including selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and tricyclic antidepressants (TCAs).

Additionally, cyclobenzaprine hydrochloride may potentiate the effects of alcohol, barbiturates, and other central nervous system (CNS) depressants. Clinicians should consider monitoring patients closely for increased sedation and respiratory depression when these substances are co-administered.

Tricyclic antidepressants may interfere with the antihypertensive efficacy of guanethidine and similar compounds, necessitating careful blood pressure monitoring and potential dosage adjustments of antihypertensive medications.

Furthermore, the use of tricyclic antidepressants may elevate the risk of seizures in patients receiving tramadol. It is advisable to assess the seizure threshold and consider alternative pain management strategies in such cases.

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

Elderly patients may experience increased plasma concentrations of cyclobenzaprine, which necessitates careful consideration when prescribing this medication. Due to this heightened concentration, geriatric patients may be at an elevated risk for central nervous system (CNS) adverse events, including hallucinations and confusion.

Additionally, elderly patients may be more susceptible to cardiac events, which could lead to falls or other serious complications. It is important to be vigilant regarding potential drug-drug and drug-disease interactions in this population, as these factors can further complicate treatment.

Cyclobenzaprine should only be prescribed to elderly patients when clearly indicated. When initiating treatment, it is recommended that cyclobenzaprine hydrochloride be started at a dose of 5 mg, with a gradual titration to achieve the desired therapeutic effect while minimizing the risk of adverse events. Close monitoring of these patients is advised to ensure safety and efficacy.

Pregnancy

Pregnancy Category B. Reproduction studies have been conducted in rats, mice, and rabbits at doses up to 20 times the human dose, demonstrating no evidence of impaired fertility or harm to the fetus associated with cyclobenzaprine hydrochloride. 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 hydrochloride 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 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

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

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 multiple drug ingestion, often involving alcohol, is frequently observed in cases of deliberate overdose.

Signs and Symptoms Toxicity symptoms may manifest rapidly following an overdose, necessitating immediate hospital monitoring. The most prevalent effects include drowsiness and tachycardia. Other less common symptoms may encompass 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. Clinically significant changes in the electrocardiogram, particularly alterations in QRS axis or width, serve as important indicators of cyclobenzaprine toxicity.

Management Procedures Upon suspicion of an overdose, it is imperative to obtain an electrocardiogram (ECG) and initiate cardiac monitoring without delay. The patient's airway should be protected, an intravenous line established, and gastric decontamination commenced. This includes performing large volume gastric lavage followed by the administration of activated charcoal. If the patient is unconscious, securing the airway prior to lavage is crucial, and emesis is contraindicated.

Continuous observation is necessary, focusing on signs of central nervous system (CNS) or respiratory depression, hypotension, cardiac dysrhythmias or conduction blocks, and seizures. Extended monitoring is warranted if any signs of toxicity arise during this period. It is important to note that monitoring plasma drug levels should not dictate patient management. Due to the low plasma concentrations of cyclobenzaprine, dialysis is likely ineffective.

For patients exhibiting dysrhythmias or QRS widening, serum alkalinization to a pH of 7.45 to 7.55 should be initiated using intravenous sodium bicarbonate, along with hyperventilation as needed. In cases of CNS depression, early intubation is recommended due to the risk of sudden deterioration. Seizures should be managed with benzodiazepines; if these are ineffective, alternative anticonvulsants such as phenobarbital or phenytoin may be utilized.

Physostigmine is not advised except for the treatment of life-threatening symptoms that do not respond to other therapies, and should only be administered in close consultation with a poison control center. The management principles for both child and adult overdoses are similar, and it is strongly recommended that physicians contact the local poison control center for specific pediatric treatment guidance.

Nonclinical Toxicology

In a nonclinical study involving 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. Additionally, there was a dose-related occurrence of hepatocyte vacuolation accompanied by lipidosis. In the higher dose groups, this microscopic alteration was evident after 26 weeks, with earlier manifestations noted in rats that succumbed prior to this time point. 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. Furthermore, at oral doses of up to 10 times the human dose, cyclobenzaprine did not adversely affect the reproductive performance or fertility of either 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.

Postmarketing Experience

Postmarketing experience has identified several adverse reactions reported voluntarily or through surveillance programs, with an incidence of less than 1% of patients in clinical trials involving 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 encompass vomiting, anorexia, diarrhea, gastrointestinal pain, gastritis, thirst, flatulence, edema of the tongue, and abnormal liver function, with rare reports of hepatitis, jaundice, and cholestasis.

Hypersensitivity reactions have included anaphylaxis, angioedema, pruritus, facial edema, urticaria, and rash. Musculoskeletal reactions consist of local weakness.

Nervous system and psychiatric events reported include seizures, ataxia, vertigo, dysarthria, tremors, hypertonia, convulsions, muscle twitching, disorientation, insomnia, depressed mood, abnormal sensations, anxiety, agitation, psychosis, abnormal thinking and dreaming, hallucinations, excitement, paresthesia, diplopia, and serotonin syndrome. Skin reactions noted include sweating, while special senses reactions involve ageusia and tinnitus. Urogenital events reported include urinary frequency and/or retention.

Additionally, other reactions have been reported rarely for cyclobenzaprine hydrochloride, where a causal relationship could not be established, or have been 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, while hematologic and lymphatic reactions consist of purpura, bone marrow depression, leukopenia, eosinophilia, and thrombocytopenia. Metabolic, nutritional, and immune reactions have involved elevation and lowering of blood sugar levels, as well as weight gain or loss. Musculoskeletal reactions include myalgia.

Nervous system and psychiatric reactions reported include decreased or increased libido, abnormal gait, delusions, aggressive behavior, paranoia, peripheral neuropathy, Bell’s palsy, alteration in EEG patterns, and extrapyramidal symptoms. Respiratory reactions include dyspnea. Skin reactions also encompass 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 hydrochloride, particularly when used in conjunction with alcohol or other central nervous system (CNS) depressants, may impair their mental and/or physical abilities necessary for performing hazardous tasks, including operating machinery or driving a motor vehicle.

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

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

Healthcare providers should ensure that patients are aware of the signs and symptoms of serotonin syndrome, which may include changes in mental status, autonomic instability, and neuromuscular abnormalities. Patients should be instructed to seek medical attention immediately if they experience any of these symptoms.

Storage and Handling

The product is supplied in various package configurations, with specific NDC numbers available upon request. It should be stored at a temperature range of 20° to 25°C (68° to 77°F). Temporary excursions are permitted between 15° to 30°C (59° to 86°F), in accordance with USP Controlled Room Temperature guidelines. Proper container requirements must be adhered to, and special handling needs should be followed to ensure product integrity.

Additional Clinical Information

Patients receiving cyclobenzaprine hydrochloride should be informed that the medication may impair mental and physical abilities, particularly when used in conjunction with alcohol or other central nervous system (CNS) depressants. This impairment can affect the performance of hazardous tasks, including operating machinery or driving.

Clinicians should be aware that elderly patients may experience an increased frequency and severity of adverse events associated with cyclobenzaprine. Therefore, it is recommended to initiate treatment in this population with a 5 mg dose, titrating slowly as needed. Additionally, patients must be cautioned about the risk of serotonin syndrome when cyclobenzaprine is used alongside other medications such as SSRIs, SNRIs, TCAs, tramadol, bupropion, meperidine, verapamil, or MAO inhibitors. Patients 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 Major Pharmaceuticals. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)