Cyclobenzaprine hydrochloride

Description

Cyclobenzaprine hydrochloride, USP is a white to off-white, odorless, crystalline powder with the chemical formula C20H21N•HCl and a molecular weight of 311.85. It exhibits a melting point range of 215°C to 219°C and has a pKa of 8.47. The compound 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 is available in three oral tablet formulations: 5 mg, 7.5 mg, and 10 mg. The 5 mg tablets contain inactive ingredients including colloidal silicon dioxide, croscarmellose sodium, hypromellose, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, talc, titanium dioxide, and triacetin. The 7.5 mg tablets include the same inactive ingredients as the 5 mg formulation, with the addition of yellow iron oxide. The 10 mg tablets contain colloidal silicon dioxide, croscarmellose sodium, FD&C Blue No. 2 Aluminium Lake, hypromellose, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, talc, titanium dioxide, triacetin, and yellow iron oxide. It is important to note that the FDA-approved organic impurities test acceptance criterion differs from the USP organic impurities test acceptance criterion for Cyclobenzaprine Hydrochloride Tablets.

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 typically resolve within a 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, USP 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, USP for periods longer than two or 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 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 individuals in the acute recovery phase of myocardial infarction, as well as those with arrhythmias, heart block, 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 associated with its administration, particularly concerning serotonin syndrome and central nervous system (CNS) effects.

Serotonin Syndrome Risk The concomitant use of cyclobenzaprine hydrochloride with serotonergic agents, including selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), tramadol, bupropion, meperidine, verapamil, or monoamine oxidase inhibitors (MAOIs), has been associated with the development of serotonin syndrome, a potentially life-threatening condition. The use of cyclobenzaprine hydrochloride in conjunction with MAO inhibitors is contraindicated. Symptoms of serotonin syndrome may manifest as mental status changes (e.g., confusion, agitation, hallucinations), autonomic instability (e.g., diaphoresis, tachycardia, labile blood pressure, hyperthermia), neuromuscular abnormalities (e.g., tremor, ataxia, hyperreflexia, clonus, muscle rigidity), and gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Should these symptoms occur, immediate discontinuation of cyclobenzaprine hydrochloride and any concomitant serotonergic agents is imperative, along with the initiation of supportive symptomatic treatment. If the clinical decision is made to continue treatment with cyclobenzaprine hydrochloride alongside other serotonergic drugs, careful monitoring is essential, particularly during the initiation of therapy or when adjusting dosages.

CNS Effects and Precautions Cyclobenzaprine hydrochloride shares structural similarities with 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 CNS reactions akin to those observed with tricyclic antidepressants have been reported. These reactions may include, but are not limited to, arrhythmias, sinus tachycardia, and conduction time prolongation, which can lead to severe cardiovascular events such as myocardial infarction and stroke.

CNS Depressant Interactions The administration of cyclobenzaprine hydrochloride may potentiate the effects of alcohol, barbiturates, and other CNS depressants. Healthcare professionals should exercise caution when prescribing cyclobenzaprine hydrochloride to patients who are concurrently using these substances, as the risk of enhanced CNS depression may increase.

In summary, healthcare providers must remain vigilant regarding the potential for serotonin syndrome, CNS effects, and interactions with other depressants when prescribing cyclobenzaprine hydrochloride, ensuring appropriate monitoring and patient education to mitigate these risks.

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, 39% at 10 mg, and 10% for placebo), dry mouth (21% at 5 mg, 27% at 10 mg, and 7% for placebo), fatigue (6% at both 5 mg and 10 mg, and 3% for placebo), and headache (5% at both 5 mg and 10 mg, and 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 infection, pharyngitis, fatigue/tiredness, asthenia, dyspepsia, unpleasant taste, blurred vision, and confusion.

Serious adverse reactions have also been noted. These include syncope and malaise as part of general body reactions, as well as cardiovascular issues such as tachycardia, arrhythmia, vasodilatation, palpitation, and hypotension. Digestive system reactions may involve vomiting, anorexia, gastrointestinal pain, gastritis, thirst, flatulence, edema of the tongue, and abnormal liver function, with rare reports of hepatitis, jaundice, and cholestasis. Hypersensitivity reactions can manifest as anaphylaxis, angioedema, pruritus, facial edema, urticaria, and rash.

Nervous system and psychiatric adverse reactions are particularly noteworthy, 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. Other reactions may involve local weakness in the musculoskeletal system, sweating in the skin, and ageusia or tinnitus in the special senses. Urogenital effects may include urinary frequency and/or retention.

Certain adverse reactions have been reported where a causal relationship is unknown. These include chest pain and edema in the body as a whole, hypertension, myocardial infarction, heart block, and stroke in the cardiovascular system. Digestive issues such as paralytic ileus, tongue discoloration, stomatitis, and parotid swelling have also been noted. Endocrine reactions 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 present as elevation or lowering of blood sugar levels, as well as weight gain or loss. Musculoskeletal complaints may include myalgia, and nervous system and psychiatric reactions can involve decreased or increased libido, abnormal gait, delusions, aggressive behavior, paranoia, peripheral neuropathy, Bell's palsy, alteration in EEG patterns, and extrapyramidal symptoms. Respiratory issues such as dyspnea, skin reactions like photosensitization and alopecia, and urogenital effects including impaired urination, dilatation of the urinary tract, impotence, testicular swelling, gynecomastia, breast enlargement, and galactorrhea have also been reported.

A significant warning regarding serotonin syndrome is warranted, as this potentially life-threatening condition has been reported with the use of cyclobenzaprine hydrochloride in combination with other medications, including 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 hydrochloride is associated with several significant drug interactions that warrant careful consideration.

Monoamine Oxidase Inhibitors (MAOIs) The concomitant use of cyclobenzaprine hydrochloride with MAO inhibitors may lead to life-threatening interactions. It is advised that these medications not be used together.

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, has been associated with serotonin syndrome. If the use of cyclobenzaprine hydrochloride alongside these drugs is deemed necessary, careful monitoring is recommended, particularly during the initiation of treatment or when increasing dosages.

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 dosage adjustments may be necessary to mitigate the risk of excessive sedation.

Tricyclic Antidepressants (TCAs) TCAs may interfere with the antihypertensive effects of guanethidine and similar agents. Clinicians should be aware of this potential interaction when prescribing these medications together. Additionally, the use of TCAs in patients taking tramadol may increase the risk of seizures, necessitating careful patient selection and monitoring.

In summary, healthcare providers should exercise caution and consider appropriate monitoring and dosage adjustments when prescribing cyclobenzaprine hydrochloride in conjunction with the aforementioned drug classes.

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 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 times higher than those observed in younger adults. Notably, elderly male subjects exhibited the most significant increase, with AUC values approximately 2.4 times higher, while elderly females showed a lesser increase of about 1.2 times.

Given these pharmacokinetic differences, therapy with cyclobenzaprine hydrochloride in geriatric patients should be initiated at a lower dose of 5 mg, with a gradual titration to achieve the desired therapeutic effect. It is also advisable to consider less frequent dosing schedules for this population to mitigate potential risks.

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. Therefore, cyclobenzaprine hydrochloride should be prescribed only when clearly indicated in elderly patients, with close monitoring for any adverse effects throughout the course of treatment.

Pregnancy

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 associated with cyclobenzaprine hydrochloride. The drug is classified as Pregnancy Category B. 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 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 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 considered as part of standard clinical practice.

Overdosage

Although rare, cyclobenzaprine hydrochloride overdosage can lead to fatal outcomes. It is important to note that deliberate overdose often involves the co-ingestion of multiple substances, including alcohol.

Signs and Symptoms

Toxicity symptoms may manifest rapidly following an overdose, necessitating immediate hospital monitoring. The acute oral LD50 of cyclobenzaprine hydrochloride is approximately 338 mg/kg in mice and 425 mg/kg in rats. The most frequently observed effects include drowsiness and tachycardia. Other less common symptoms may include tremor, agitation, coma, ataxia, hypertension, slurred speech, confusion, dizziness, nausea, vomiting, and hallucinations. Critical manifestations, though rare, can include cardiac arrest, chest pain, cardiac dysrhythmias, severe hypotension, seizures, and neuroleptic malignant syndrome. Clinically significant changes in the electrocardiogram, particularly alterations in QRS axis or width, are indicative of cyclobenzaprine toxicity.

Management

All patients suspected of cyclobenzaprine overdose should undergo gastrointestinal decontamination, which includes large volume gastric lavage followed by the administration of activated charcoal. If the patient is unconscious, securing the airway is essential prior to performing lavage, and emesis is contraindicated.

To mitigate the risk of severe complications, it is crucial to obtain an electrocardiogram (ECG) and initiate cardiac monitoring immediately. The patient's airway should be protected, an intravenous line established, and gastric decontamination initiated. Continuous observation for signs of central nervous system (CNS) or respiratory depression, hypotension, cardiac dysrhythmias, conduction blocks, and seizures is necessary. 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, and dialysis is likely ineffective due to the low plasma concentrations of cyclobenzaprine.

A maximal limb-lead QRS duration of ≥0.10 seconds may serve as a key indicator of overdose severity. For patients exhibiting dysrhythmias or QRS widening, serum alkalinization to a pH of 7.45 to 7.55 should be achieved using intravenous sodium bicarbonate and hyperventilation as needed. A pH exceeding 7.60 or a pCO2 below 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 ineffective, other anticonvulsants such as phenobarbital or phenytoin. The use of physostigmine is not advised unless addressing life-threatening symptoms unresponsive to other treatments, and only after consulting a poison control center.

Given that overdosage is often intentional, there is a risk that patients may attempt suicide by other means during the recovery phase, making psychiatric referral a consideration. The management principles for both child and adult overdosages are similar; therefore, it is strongly recommended that physicians contact the local poison control center for specific pediatric treatment guidance.

As the management of overdose is complex and evolving, it is advisable for healthcare professionals to consult a poison control center for the most current treatment recommendations.

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 hydrochloride. However, there are no adequate and well-controlled studies in pregnant women. Due to the limitations of animal reproduction studies in predicting human responses, the use of this drug during pregnancy should be considered only when clearly necessary.

In terms of non-teratogenic effects, cyclobenzaprine did not adversely affect the reproductive performance or fertility of male or female rats at oral doses of up to 10 times the human dose. Additionally, mutagenicity studies indicated that cyclobenzaprine did not demonstrate mutagenic activity in male mice at dose levels of up to 20 times the human dose.

In long-term animal studies, rats treated with cyclobenzaprine hydrochloride for up to 67 weeks at doses ranging from approximately 5 to 40 times the maximum recommended human dose exhibited pale, sometimes enlarged livers, along with dose-related hepatocyte vacuolation and lipidosis. These microscopic changes were observed in higher dose groups after 26 weeks and even earlier in rats that died prior to this time; lower doses did not show these changes until after 26 weeks.

Furthermore, cyclobenzaprine did not influence the onset, incidence, or distribution of neoplasia in an 81-week study in mice or in a 105-week study in rats.

Pharmacological studies in animals have demonstrated effects of cyclobenzaprine that are similar to those of structurally related tricyclic antidepressants, including reserpine antagonism, norepinephrine potentiation, and significant peripheral and central anticholinergic effects, as well as sedation. Cyclobenzaprine was also 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 category, 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 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 hydrochloride under circumstances where a causal relationship could not be established, or reported for other tricyclic drugs, and are listed to serve as alerting information to physicians. 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.

In the Hematic and Lymphatic category, reactions such as purpura, bone marrow depression, leukopenia, eosinophilia, and thrombocytopenia have been reported. Metabolic, Nutritional, and Immune reactions include elevation and lowering of blood sugar levels, as well as weight gain or loss. Musculoskeletal reactions also include myalgia. Nervous System and Psychiatric reactions reported are 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. Lastly, 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 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.

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 available in various package configurations, identified by their respective National Drug Code (NDC) numbers. Specific storage instructions, handling details, and disposal information are not provided. Therefore, it is recommended that healthcare professionals adhere to standard storage practices for pharmaceutical products.

Additional Clinical Information

Laboratory tests related to cyclobenzaprine hydrochloride have not been specified. 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.

Patient counseling is essential, particularly regarding the potential impairment of mental and physical abilities when cyclobenzaprine hydrochloride is used in conjunction with alcohol or other CNS depressants. Patients should also be informed about the risk of serotonin syndrome when cyclobenzaprine is taken with certain 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.

In a post-marketing surveillance program involving 7,607 patients with acute musculoskeletal disorders, including 297 patients treated with cyclobenzaprine hydrochloride 10 mg for 30 days or longer, the overall effectiveness was consistent with findings from double-blind controlled studies, while the incidence of adverse effects was lower.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Cyclobenzaprine Hydrochloride as submitted by Unichem Pharmaceuticals (USA) , Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)