Cyclobenzaprine hydrochloride

Description

Cyclobenzaprine hydrochloride, USP is a white, crystalline tricyclic amine salt with the chemical designation of 3-(5H-dibenzoa,dcyclohepten-5-ylidene)-N,N-dimethyl-1-propanamine hydrochloride. It has a molecular formula of C20H21N • HCl and a molecular weight of 311.9 g/mol. The compound exhibits a melting point of 217ºC and a pKa of 8.47 at 25ºC. Cyclobenzaprine hydrochloride is freely soluble in water and alcohol, sparingly soluble in isopropanol, and insoluble in hydrocarbon solvents; alkaline conditions in aqueous solutions lead to the separation of the free base.

This medication is supplied in tablet form for oral administration, available in dosages of 5 mg and 10 mg. 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 tablets also include D&C yellow #10 aluminum lake and FD&C yellow #6 aluminum lake, while the 10 mg tablets contain 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 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 certain medications can lead to the development of serotonin syndrome, a potentially life-threatening condition. This risk is particularly pronounced when cyclobenzaprine is used alongside selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), tramadol, bupropion, meperidine, verapamil, or monoamine oxidase inhibitors (MAOIs). Notably, the use of cyclobenzaprine hydrochloride in conjunction with MAO inhibitors is contraindicated.

Symptoms of serotonin syndrome may manifest as mental status changes, including confusion, agitation, and hallucinations; autonomic instability, such as diaphoresis, tachycardia, labile blood pressure, and hyperthermia; neuromuscular abnormalities, including tremor, ataxia, hyperreflexia, clonus, and muscle rigidity; and gastrointestinal symptoms like nausea, vomiting, and diarrhea. Should any of these symptoms arise, it is imperative to discontinue treatment with cyclobenzaprine hydrochloride and any concomitant serotonergic agents immediately, followed by the initiation of supportive symptomatic treatment.

Cyclobenzaprine is structurally related to 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. 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 regarding these warnings and precautions to mitigate risks associated with cyclobenzaprine hydrochloride therapy.

Side Effects

Patients receiving cyclobenzaprine hydrochloride 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% for both 5 mg and 10 mg, 3% for placebo), and headache (5% for 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.

Less frequent adverse reactions, occurring in less than 1% of patients, encompass a variety of systems. Notable reactions 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 documented.

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 less frequent reactions involve sweating (skin), ageusia and tinnitus (special senses), and urinary frequency and/or retention (urogenital).

Certain adverse reactions have an unknown causal relationship with cyclobenzaprine. 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 reactions such as inappropriate ADH syndrome, hematologic issues like purpura, bone marrow depression, leukopenia, eosinophilia, and thrombocytopenia, and metabolic changes including elevation and lowering of blood sugar levels, weight gain or loss, and myalgia (musculoskeletal) have also been reported. Additionally, nervous system and psychiatric reactions such as 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 issues like dyspnea, skin reactions such as photosensitization and alopecia, and urogenital concerns including impaired urination, dilatation of the urinary tract, impotence, testicular swelling, gynecomastia, breast enlargement, and galactorrhea have also been observed.

The development of serotonin syndrome, a potentially life-threatening condition, has been reported in patients using cyclobenzaprine in combination with other medications, including selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (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).

Overall, the incidence of adverse reactions among patients in the surveillance program was found to be lower than that observed in controlled clinical studies. It is important to note that in elderly patients, the frequency and severity of adverse events associated with the use of cyclobenzaprine, with or without concomitant medications, is increased.

Drug Interactions

Cyclobenzaprine has several significant drug interactions that warrant careful consideration.

Monoamine Oxidase Inhibitors (MAOIs) Cyclobenzaprine may cause life-threatening interactions when used in conjunction with MAO inhibitors. Due to the potential for severe adverse effects, concurrent use of cyclobenzaprine and MAOIs is contraindicated.

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 use of cyclobenzaprine with these drugs is deemed necessary, careful monitoring is recommended, especially during the initiation of treatment or when increasing dosages.

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

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

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 exhibit increased plasma concentrations of cyclobenzaprine, necessitating 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, there is a potential for cardiac events in this population, which could lead to falls or other serious complications.

It is important to recognize that elderly patients may also experience drug-drug and drug-disease interactions, further complicating their treatment regimen. Therefore, cyclobenzaprine should only be utilized in geriatric patients when it is clearly indicated.

When initiating treatment with cyclobenzaprine hydrochloride in elderly patients, it is recommended to start with a dose of 5 mg, with a gradual titration to higher doses as necessary. This cautious approach is essential to minimize the risk of adverse effects and ensure patient safety. Regular monitoring for any signs of adverse reactions or complications is advised throughout the course of treatment.

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 the risks when considering this medication for pregnant patients.

Lactation

It is not known whether this drug is excreted in human milk. Due to the structural similarity of cyclobenzaprine to tricyclic antidepressants, some of which are known to be excreted in human milk, caution should be exercised when administering cyclobenzaprine hydrochloride to lactating mothers. The potential effects on breastfed infants have not been established, and healthcare professionals should consider the risks and benefits of treatment in nursing women.

Renal Impairment

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

Although rare, cyclobenzaprine hydrochloride overdose can lead to fatalities, particularly in cases involving multiple drug ingestion, including alcohol. The management of such overdoses is complex and subject to change; therefore, it is advisable for healthcare professionals to contact a poison control center for the most current treatment information.

Signs and Symptoms of Overdose

Toxicity symptoms may manifest rapidly following an overdose of cyclobenzaprine. Common effects include drowsiness and tachycardia, while less frequent symptoms 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. Clinically significant changes in the electrocardiogram, particularly alterations in the QRS axis or width, serve as important indicators of cyclobenzaprine toxicity.

Initial Management

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

To mitigate the risk of severe manifestations, it is critical to obtain an electrocardiogram (ECG) and initiate cardiac monitoring immediately. Healthcare providers should ensure airway protection, establish an intravenous line, and commence gastric decontamination. 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 is warranted. 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 cyclobenzaprine.

Advanced Management

A maximal limb-lead QRS duration of ≥0.10 seconds may indicate the severity of the overdose. 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, with hyperventilation as needed. It is crucial to avoid a pH >7.60 or a pCO2 <20 mmHg. 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, and 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 for life-threatening symptoms that have not responded to other treatments, 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. Additionally, there was a dose-related incidence of hepatocyte vacuolation accompanied by lipidosis. In the higher dose groups, this microscopic alteration was evident after 26 weeks, with earlier occurrences 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

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.

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, abnormal liver function, and 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: Adverse events 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: Increased sweating has been observed.

Special Senses: Reports of ageusia and tinnitus have been noted.

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

Additionally, other reactions reported rarely for cyclobenzaprine hydrochloride, where a causal relationship could not be established, or reported for other tricyclic drugs, include the following:

Body as a Whole: Chest pain and edema have been noted.

Cardiovascular: Rare events such as hypertension, myocardial infarction, heart block, and stroke have been reported.

Digestive: Reports of paralytic ileus, tongue discoloration, stomatitis, and parotid swelling have been documented.

Endocrine: Inappropriate ADH syndrome has been noted.

Hematic and Lymphatic: Adverse events include 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, have been reported.

Musculoskeletal: Myalgia has been documented.

Nervous System and Psychiatric: Reports include decreased or increased libido, abnormal gait, delusions, aggressive behavior, paranoia, peripheral neuropathy, Bell’s palsy, alteration in EEG patterns, and extrapyramidal symptoms.

Respiratory: Instances of dyspnea have been noted.

Skin: Reports of photosensitization and alopecia have been documented.

Urogenital: Adverse events 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 the frequency and severity of adverse events associated with cyclobenzaprine may be increased, regardless of whether they are taking other medications. For elderly patients, healthcare providers should recommend initiating treatment with a 5 mg dose of cyclobenzaprine hydrochloride and advise a gradual titration of the dosage.

Patients should also be cautioned about the potential 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 and instruct them to seek immediate medical attention if they experience any of these symptoms.

Storage and Handling

The product is supplied in various package configurations, with specific NDC numbers available 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). Proper storage conditions are essential to maintain the integrity and efficacy of the product.

Additional Clinical Information

No additional information found.

FDA Insert (PDF)

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

View full prescribing information (PDF)