Cyclobenzaprine hydrochloride

Description

Cyclobenzaprine hydrochloride, USP is a white, crystalline tricyclic amine salt with the chemical formula C20H21N•HCl and a molecular weight of 311.85. It has a melting point of 217°C and a pKa of 8.47 at 25°C. 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. Each tablet for oral administration contains 10 mg of cyclobenzaprine hydrochloride, USP, along with the following inactive ingredients: anhydrous lactose, carnauba wax, corn starch, crospovidone, hypromellose, magnesium stearate, pregelatinized corn starch, polyethylene glycol, polysorbate 80, titanium dioxide, D&C Yellow #10 aluminum lake, FD&C Blue #2 aluminum lake, and FD&C Yellow #6 aluminum lake.

Uses and Indications

Cyclobenzaprine Hydrochloride Tablets USP are indicated as an adjunct to rest and physical therapy for the relief of muscle spasm associated with acute, painful musculoskeletal conditions. The therapeutic benefit is 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 diseases, nor are they effective in pediatric patients 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 for periods exceeding two to three weeks is not recommended.

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 the acute recovery phase of myocardial infarction, as well as in patients with arrhythmias, heart block, 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 necessitates careful consideration of potential risks associated with its administration, particularly concerning serotonin syndrome and interactions with other medications.

Serotonin Syndrome Risk 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 serotonin syndrome, a potentially life-threatening condition. 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. If the clinical situation necessitates the concurrent use of cyclobenzaprine hydrochloride with other serotonergic drugs, careful observation is essential, particularly during the initiation of treatment or when increasing doses.

CNS Reactions and Cardiac Risks 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. Therefore, caution is advised when prescribing cyclobenzaprine hydrochloride, particularly in patients with pre-existing cardiovascular conditions.

Caution in Specific Populations Due to its atropine-like properties, cyclobenzaprine hydrochloride should be administered with caution in patients who have a history of urinary retention, angle-closure glaucoma, or increased intraocular pressure. This caution extends to patients who are concurrently taking anticholinergic medications, as the risk of adverse effects may be heightened.

CNS Depressant Interactions Cyclobenzaprine hydrochloride may potentiate the effects of alcohol, barbiturates, and other central nervous system depressants. Healthcare professionals should advise patients regarding the potential for increased sedation and impairment when these substances are used in conjunction with cyclobenzaprine hydrochloride.

In summary, the safe use of cyclobenzaprine hydrochloride requires vigilant monitoring for signs of serotonin syndrome, awareness of potential CNS and cardiac risks, and careful consideration of patient history regarding urinary and ocular conditions.

Side Effects

Common adverse reactions observed in clinical trials, occurring in more than 3% of patients, include drowsiness (29% at 5 mg, 38% at 10 mg, and 10% for placebo), dry mouth (21% at 5 mg, 32% 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 encompass a range of symptoms, including 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), 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 noted. Musculoskeletal reactions include local weakness, while nervous system and psychiatric effects may involve 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 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 include inappropriate ADH syndrome, while hematologic and lymphatic reactions can involve 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 present as decreased or increased libido, abnormal gait, delusions, aggressive behavior, paranoia, peripheral neuropathy, Bell’s palsy, alteration in EEG patterns, and extrapyramidal symptoms. Respiratory symptoms 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 warning regarding serotonin syndrome is pertinent, as the development of this potentially life-threatening condition has been reported with cyclobenzaprine hydrochloride when 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/or 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) Cyclobenzaprine hydrochloride may cause life-threatening interactions when used in conjunction with MAO inhibitors. It is advised that this combination be avoided.

Serotonergic Drugs Postmarketing reports indicate that the concurrent use 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, can lead to serotonin syndrome. If the combination of cyclobenzaprine hydrochloride and other serotonergic 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 medications. Additionally, the use of TCAs in patients taking tramadol may increase the risk of seizures. Monitoring for these effects is recommended when these medications are used together.

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, 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 than their younger counterparts, while elderly females showed a lesser increase of about 1.2 times.

Due to these pharmacokinetic differences, 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. Additionally, there is an increased potential for drug-drug and drug-disease interactions in this population.

When initiating therapy with cyclobenzaprine hydrochloride in geriatric patients, it is recommended to start with a lower dose of 5 mg and to titrate slowly upward as needed. Furthermore, therapy should be approached with caution and only if clearly indicated. Consideration should also be given to less frequent dosing regimens to mitigate the risk of adverse effects in elderly patients. Regular monitoring for any adverse reactions is advised to ensure patient safety.

Pregnancy

Pregnancy Category B indicates that reproduction studies conducted in rats, mice, and rabbits at doses up to 20 times the human dose have shown no evidence of impaired fertility or harm to the fetus due to cyclobenzaprine 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 outlined for individuals with compromised liver function. It is recommended that healthcare providers exercise caution when prescribing this medication to patients with hepatic impairment, given the lack of data on its safety and efficacy in this population. Regular monitoring of liver function may be prudent in these cases, although specific parameters are not defined in the available information.

Overdosage

Although rare, cyclobenzaprine hydrochloride overdose can lead to fatalities, particularly in cases of multiple drug ingestion, including alcohol, which is common in deliberate overdoses. Due to the complexity and evolving nature of overdose management, it is imperative 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. Hospital monitoring is essential as soon as possible. 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. Rare but critical manifestations can involve 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 important indicators of cyclobenzaprine toxicity.

Management Procedures

To mitigate the risk of severe manifestations, it is crucial to obtain an electrocardiogram (ECG) and initiate cardiac monitoring immediately. Protecting the patient's airway, establishing an intravenous line, and commencing gastric decontamination are essential steps. 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 prior to lavage is necessary, and emesis is contraindicated.

Continuous observation with cardiac monitoring is required to detect signs of central nervous system (CNS) or respiratory depression, hypotension, cardiac dysrhythmias, conduction blocks, and seizures. If 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 the drug.

A maximal limb-lead QRS duration of ≥ 0.1 seconds may serve as a key 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, along with hyperventilation as necessary. A pH exceeding 7.6 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, 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 advised except for life-threatening symptoms unresponsive to other treatments, and only after consulting with a poison control center.

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 fetal harm 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 long-term studies involving rats treated with cyclobenzaprine hydrochloride for up to 67 weeks at doses approximately 5 to 40 times the maximum recommended human dose, observations included pale and occasionally enlarged livers, along with dose-related hepatocyte vacuolation and lipidosis. The microscopic changes were noted in higher dose groups after 26 weeks, and in some cases, even earlier in rats that died prior to 26 weeks. At lower doses, these changes were not observed until after 26 weeks.

Cyclobenzaprine did not affect the onset, incidence, or distribution of neoplasia in an 81-week study in mice or in a 105-week study in rats. Additionally, at oral doses of up to 10 times the human dose, cyclobenzaprine did not adversely impact the reproductive performance or fertility of male or female rats. Furthermore, cyclobenzaprine did not demonstrate 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:

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 noted are local weakness. In the Nervous System and Psychiatric category, seizures, ataxia, vertigo, dysarthria, tremors, hypertonia, convulsions, muscle twitching, disorientation, insomnia, depressed mood, abnormal sensations, anxiety, agitation, psychosis, abnormal thinking and dreaming, hallucinations, excitement, paresthesia, diplopia, and serotonin syndrome have been reported. 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 Body as a Whole reactions such as chest pain and edema. Cardiovascular events include hypertension, myocardial infarction, heart block, and stroke. Digestive reactions consist of paralytic ileus, tongue discoloration, stomatitis, and parotid swelling. Endocrine reactions include inappropriate ADH syndrome. Hematic and Lymphatic reactions reported are purpura, bone marrow depression, leukopenia, eosinophilia, and thrombocytopenia.

Metabolic, Nutritional, and Immune reactions include elevation and lowering of blood sugar levels, as well as weight gain or loss. Musculoskeletal reactions noted are myalgia. In the Nervous System and Psychiatric category, decreased or increased libido, abnormal gait, delusions, aggressive behavior, paranoia, peripheral neuropathy, Bell’s palsy, alteration in EEG patterns, and extrapyramidal symptoms have been reported. Respiratory reactions include dyspnea. Skin reactions consist of photosensitization and alopecia. Urogenital reactions reported are impaired urination, dilatation of the urinary tract, impotence, testicular swelling, gynecomastia, breast enlargement, and galactorrhea.

Patient Counseling

Healthcare providers should advise patients that cyclobenzaprine 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, cyclobenzaprine hydrochloride should be initiated at a dose of 5 mg and titrated slowly upward to minimize risks.

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 (MAO) inhibitors.

Healthcare providers should ensure that patients are aware of the signs and symptoms of serotonin syndrome, and instruct them to seek immediate medical attention if they experience any of these symptoms.

Storage and Handling

The product is supplied in a tight, light-resistant container that complies with USP standards and includes a child-resistant closure as required. It should be stored at a temperature range of 20° to 25°C (68° to 77°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

Laboratory tests specific to cyclobenzaprine hydrochloride have not been detailed. Clinicians should be aware that while withdrawal symptoms have not been reported with cyclobenzaprine, abrupt cessation after prolonged use may lead to nausea, headache, and malaise, which are not indicative of addiction.

The recommended dosage for cyclobenzaprine hydrochloride tablets is 5 mg taken three times daily, with the possibility of increasing to 10 mg three times daily based on individual patient response. Prolonged use beyond two to three weeks is not advised. Patients should be counseled on the potential for impaired mental and physical abilities when using cyclobenzaprine, particularly in conjunction with alcohol or other CNS depressants. Additionally, there is a risk of serotonin syndrome when cyclobenzaprine 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 instructed to seek immediate medical attention if they occur.

A post-marketing surveillance program involving 7,607 patients with acute musculoskeletal disorders indicated that the effectiveness of cyclobenzaprine hydrochloride was consistent with findings from controlled studies, with a lower incidence of adverse effects reported.

FDA Insert (PDF)

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

View full prescribing information (PDF)