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 g/mol. 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. 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 available in tablet form for oral administration, with dosages of 5 mg and 10 mg. Each tablet contains inactive ingredients including croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate, polyethylene glycol, pregelatinized starch (maize), and titanium dioxide. The 5 mg tablets also contain D&C yellow #10 aluminum lake and FD&C yellow #6 aluminum lake, while the 10 mg tablets include yellow iron oxide. It is important to note that FDA-approved dissolution test specifications may differ from those established by the USP.

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 are typically of 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 10 mg three times a day.

It is important to note that the use of cyclobenzaprine hydrochloride tablets for periods longer than two to three 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 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 combination of cyclobenzaprine (or structurally similar tricyclic antidepressants) and MAO inhibitors.

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, use 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.

It is important to note that cyclobenzaprine hydrochloride may enhance the effects of alcohol, barbiturates, and other central nervous system (CNS) 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 taking anticholinergic medications.

In patients with hepatic impairment, the plasma concentration of cyclobenzaprine is increased, which may heighten 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 recommended in patients with moderate to severe hepatic insufficiency due to insufficient data regarding safety in this population.

Healthcare professionals should remain vigilant regarding these warnings and precautions to mitigate risks associated with the use of cyclobenzaprine hydrochloride.

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

Adverse reactions reported 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.

In addition to these, 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), 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. Musculoskeletal reactions may include local weakness, while nervous system and psychiatric effects can encompass 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 sweating (skin), ageusia and tinnitus (special senses), and urinary frequency and/or retention (urogenital).

Certain adverse reactions have been reported rarely, with an unknown causal relationship. These include 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 effects may involve inappropriate ADH syndrome, while hematologic and lymphatic reactions can include purpura, bone marrow depression, leukopenia, eosinophilia, and thrombocytopenia. Metabolic, nutritional, and immune reactions may manifest as elevation or lowering of blood sugar levels, as well as weight gain or loss. Musculoskeletal effects can include myalgia, and nervous system and psychiatric reactions may involve decreased or increased libido, abnormal gait, delusions, aggressive behavior, paranoia, peripheral neuropathy, Bell’s palsy, alterations in EEG patterns, and extrapyramidal symptoms. Respiratory effects may include dyspnea, while skin reactions can involve photosensitization and alopecia. Urogenital effects may include impaired urination, dilatation of the urinary tract, impotence, testicular swelling, gynecomastia, breast enlargement, and galactorrhea.

A serious warning regarding serotonin syndrome is noted, as this potentially life-threatening condition has been reported with the use of cyclobenzaprine hydrochloride in combination with other medications, such as SSRIs, SNRIs, TCAs, tramadol, bupropion, meperidine, verapamil, or MAO inhibitors. Symptoms of serotonin syndrome 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).

Drug Interactions

Cyclobenzaprine has several significant drug interactions that require careful consideration.

Monoamine Oxidase Inhibitors (MAOIs) Cyclobenzaprine may cause life-threatening interactions when used in conjunction with MAO inhibitors. It is advised that cyclobenzaprine not be administered to patients currently taking MAOIs.

Serotonergic Drugs Postmarketing reports indicate that the combination 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 concomitant use of cyclobenzaprine and other serotonergic drugs is deemed clinically necessary, careful observation is recommended, particularly during the initiation of treatment or when increasing doses.

Central Nervous System (CNS) Depressants Cyclobenzaprine hydrochloride may potentiate the effects of alcohol, barbiturates, and other CNS depressants. Caution is advised when these substances are used concurrently, and monitoring for increased sedation or respiratory depression may be warranted.

Tricyclic Antidepressants (TCAs) TCAs may interfere with the antihypertensive effects of guanethidine and similar compounds. Additionally, the use of TCAs in patients taking tramadol may increase the risk of seizures. Clinicians should consider these interactions when prescribing and may need to adjust dosages or monitor patients closely for adverse effects.

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

The 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 exhibit increased plasma concentrations of cyclobenzaprine, which necessitates careful consideration when prescribing this medication. Due to this pharmacokinetic change, geriatric patients are at a heightened 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 also important to note that this population may experience significant drug-drug and drug-disease interactions, warranting thorough medication reviews and monitoring.

Given these factors, cyclobenzaprine should be prescribed to elderly patients only 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 potential risks. Careful monitoring for adverse effects is advised throughout the treatment course.

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

Patients with renal impairment have not been specifically addressed in the available prescribing information. There are no dosage adjustments, special monitoring requirements, or safety considerations outlined for individuals with reduced kidney function. Healthcare professionals should exercise caution and consider the lack of data when prescribing to 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

Although rare, fatalities may occur as a result of cyclobenzaprine hydrochloride overdosage. It is important to note that multiple drug ingestion, including alcohol, is frequently associated with deliberate cyclobenzaprine overdose.

Management Recommendations Due to the complexity and evolving nature of overdose management, it is strongly advised that healthcare professionals contact a poison control center for the most current treatment information. Immediate hospital monitoring is essential, as signs and symptoms of toxicity can develop rapidly following an overdose.

Signs and Symptoms The acute oral LD50 of cyclobenzaprine hydrochloride is approximately 338 mg/kg in mice and 425 mg/kg in rats. The most commonly observed effects of overdose include drowsiness and tachycardia. Other less frequent symptoms may include 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. Clinically significant changes in the electrocardiogram, particularly alterations in QRS axis or width, are indicative of cyclobenzaprine toxicity.

Initial Treatment Protocol All patients suspected of cyclobenzaprine hydrochloride overdose should undergo gastrointestinal decontamination. This process should involve large volume gastric lavage followed by the administration of activated charcoal. If the patient's consciousness is impaired, securing the airway is imperative prior to performing lavage, and emesis is contraindicated.

To mitigate the risk of severe manifestations, it is crucial 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. Continuous observation for signs of central nervous system (CNS) or respiratory depression, hypotension, cardiac dysrhythmias, conduction blocks, and seizures is necessary. Should any signs of toxicity arise during this monitoring period, extended observation will be required. It is important to note that monitoring plasma drug levels should not dictate patient management, and dialysis is likely ineffective due to the low plasma concentrations of the drug.

Monitoring and Advanced Interventions A maximal limb-lead QRS duration of ≥0.10 seconds may serve as a critical indicator of overdose severity. For patients exhibiting dysrhythmias and/or QRS widening, serum alkalinization to a pH of 7.45 to 7.55 should be initiated using intravenous sodium bicarbonate, with hyperventilation applied as necessary. A pH greater than 7.60 or a pCO2 less than 20 mmHg is considered undesirable. Dysrhythmias that do not respond to sodium bicarbonate therapy or hyperventilation may be treated with lidocaine, bretylium, or phenytoin, while Type 1A and 1C antiarrhythmics (e.g., quinidine, disopyramide, procainamide) are generally contraindicated.

In cases of CNS depression, early intubation is recommended due to the risk of sudden deterioration. Seizures should be managed with benzodiazepines, or if these are ineffective, alternative anticonvulsants such as phenobarbital or phenytoin may be utilized. The use of physostigmine is not recommended except in life-threatening situations unresponsive to other therapies, and only after consultation with a poison control center.

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. A dose-related hepatocyte vacuolation accompanied by lipidosis was noted, with the microscopic changes appearing in higher dose groups after 26 weeks. In rats that died prior to 26 weeks, these changes were observed even earlier, while at lower doses, the changes were not evident until after 26 weeks.

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. 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 revealed a range of 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.

Body as a Whole: Reports include syncope and malaise.

Cardiovascular: Adverse events such as tachycardia, arrhythmia, vasodilatation, palpitation, and hypotension have been noted.

Digestive: Reactions include vomiting, anorexia, diarrhea, gastrointestinal pain, gastritis, thirst, flatulence, edema of the tongue, and abnormal liver function, with rare cases of hepatitis, jaundice, and cholestasis.

Hypersensitivity: Instances of anaphylaxis, angioedema, pruritus, facial edema, urticaria, and rash have been documented.

Musculoskeletal: Local weakness has been reported.

Nervous System and Psychiatric: A variety of neurological and psychiatric events have been observed, including 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: Increased sweating has been reported.

Special Senses: Ageusia and tinnitus have been noted.

Urogenital: Reports of urinary frequency and/or retention have been documented.

Additionally, other reactions have been reported rarely for cyclobenzaprine hydrochloride, where a causal relationship could not be established, or have been associated with other tricyclic drugs. These include:

Body as a Whole: Chest pain and edema.

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

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

Endocrine: Inappropriate ADH syndrome.

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

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

Musculoskeletal: Myalgia has been reported.

Nervous System and Psychiatric: Changes in libido, abnormal gait, delusions, aggressive behavior, paranoia, peripheral neuropathy, Bell’s palsy, alterations in EEG patterns, and extrapyramidal symptoms have been noted.

Respiratory: Dyspnea has been reported.

Skin: Instances of photosensitization and alopecia have been documented.

Urogenital: Reports of impaired urination, dilatation of the urinary tract, impotence, testicular swelling, gynecomastia, breast enlargement, and galactorrhea have been observed.

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 the frequency and severity of adverse events associated with cyclobenzaprine may be increased, regardless of whether 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 storage conditions are essential to maintain 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 withdrawal symptoms such as nausea, headache, and malaise may occur with abrupt cessation after prolonged use, these symptoms are not indicative of addiction. Patients should be counseled on the potential for impaired mental and physical abilities when cyclobenzaprine hydrochloride is used in conjunction with alcohol or other CNS depressants, particularly regarding hazardous tasks like operating machinery or driving. 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 experience these symptoms. Postmarketing experience indicates that the overall incidence of adverse effects is lower than that observed in controlled clinical studies.

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)