Cyclobenzaprine hydrochloride

Description

Cyclobenzaprine hydrochloride is a white, crystalline tricyclic amine salt with a molecular weight of 311.9 g/mol. It is chemically designated as 3-(5-H-dibenzoa,dcyclohepten-5-ylidene)-N,N-dimethyl-1-propanamine hydrochloride, with a structural formula of C20H21N•HCl. The compound has a melting point of 217°C and a pK of 8.47 at 25°C. Cyclobenzaprine hydrochloride 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.

Cyclobenzaprine hydrochloride is available in tablet form for oral administration, with dosages of 5 mg, 7.5 mg, and 10 mg. Each tablet contains inactive ingredients including colloidal silicon dioxide, croscarmellose sodium, dibasic calcium phosphate, hydroxypropyl cellulose, hypromellose, polyethylene glycol, magnesium stearate, microcrystalline cellulose, and titanium dioxide.

Uses and Indications

Cyclobenzaprine HCl is 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. This limitation is based on the lack of adequate evidence supporting the effectiveness of cyclobenzaprine HCl 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 HCl has not demonstrated efficacy in the treatment of spasticity associated with cerebral or spinal cord diseases, nor is it indicated for use in children with cerebral palsy.

Dosage and Administration

The recommended dose of cyclobenzaprine HCl for most patients is 5 mg administered three times a day. Based on individual patient response, the dose may be increased to either 7.5 mg or 10 mg, also taken three times a day.

It is important to note that the use of cyclobenzaprine HCl 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 is associated with several significant warnings and precautions that healthcare professionals must consider to ensure patient safety.

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 linked to the development of potentially life-threatening serotonin syndrome. The use of Cyclobenzaprine Hydrochloride 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, treatment with Cyclobenzaprine Hydrochloride and any concomitant serotonergic agents must be discontinued immediately, and supportive symptomatic treatment should be initiated. If the clinical decision is made to continue treatment with Cyclobenzaprine Hydrochloride alongside other serotonergic drugs, careful observation is essential, particularly during the initiation of therapy or when increasing doses.

CNS Reactions 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 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.

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, as well as in those who are taking anticholinergic medications.

CNS Depressant Interaction Cyclobenzaprine HCl may potentiate the effects of alcohol, barbiturates, and other central nervous system depressants, necessitating careful consideration of concurrent use to avoid excessive sedation or respiratory depression.

Healthcare professionals are advised to remain vigilant regarding these warnings and precautions to mitigate risks associated with Cyclobenzaprine Hydrochloride therapy.

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% in the placebo group), dry mouth (21% at 5 mg, 32% at 10 mg, and 7% in the placebo group), fatigue (6% at both 5 mg and 10 mg, and 3% in the placebo group), and headache (5% at both dosages, with 8% in the placebo group).

Adverse reactions occurring 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.

Postmarketing experience has identified additional adverse reactions occurring in less than 1% of patients. These include syncope and malaise (body as a whole), tachycardia, arrhythmia, vasodilatation, palpitation, and hypotension (cardiovascular). Digestive system reactions may include vomiting, anorexia, diarrhea, gastrointestinal pain, gastritis, thirst, flatulence, edema of the tongue, abnormal liver function, and rare reports of hepatitis, jaundice, and cholestasis. Hypersensitivity reactions such as anaphylaxis, angioedema, pruritus, facial edema, urticaria, and rash have also been reported.

Nervous system and psychiatric adverse reactions include seizures, ataxia, vertigo, dysarthria, tremors, hypertonia, convulsions, muscle twitching, disorientation, insomnia, depressed mood, abnormal sensations, anxiety, agitation, psychosis, abnormal thinking and dreaming, hallucinations, excitement, paresthesia, diplopia, and serotonin syndrome. Musculoskeletal reactions may involve local weakness, while skin reactions can include sweating. Special senses may be affected, leading to ageusia and tinnitus, and urogenital issues such as urinary frequency and/or retention have been noted.

Certain adverse reactions have been reported where a causal relationship is unknown. These include chest pain and edema (body as a whole), hypertension, myocardial infarction, heart block, and stroke (cardiovascular). Digestive issues such as paralytic ileus, tongue discoloration, stomatitis, and parotid swelling have also been observed. Endocrine reactions 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 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 concerns including impaired urination, dilatation of the urinary tract, impotence, testicular swelling, gynecomastia, breast enlargement, and galactorrhea have also been reported.

Drug Interactions

Cyclobenzaprine HCl is associated with several significant drug interactions that warrant careful consideration.

Monoamine Oxidase Inhibitors (MAOIs) Cyclobenzaprine HCl may lead to life-threatening interactions when used in conjunction with MAO inhibitors. The combination should be avoided due to the potential for severe adverse effects.

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, has been associated with cases of 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 HCl may potentiate the effects of alcohol, barbiturates, and other CNS depressants. Caution is advised when these substances are used concurrently, as the risk of sedation and respiratory depression may be increased.

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 elevate 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 HCl 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 HCl 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 crucial to monitor these patients closely, as they 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.

Cyclobenzaprine should only be prescribed to elderly patients when clearly indicated, and healthcare providers should be aware that the frequency and severity of adverse events associated with cyclobenzaprine, whether used alone or in conjunction with other medications, tend to be higher in this population. Therefore, careful assessment and ongoing monitoring are essential to ensure the safety and efficacy of treatment in geriatric patients.

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 HCl. 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 HCl 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 HCl 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

In cases of cyclobenzaprine HCl overdosage, although rare, fatalities may occur. It is important to note that deliberate overdose often involves the ingestion of multiple drugs, including alcohol. Due to the complexity and evolving nature of overdose management, healthcare professionals are advised to contact a poison control center for the most current treatment information.

Signs and Symptoms of Toxicity

Symptoms of cyclobenzaprine overdose can develop rapidly, necessitating immediate hospital monitoring. The acute oral LD50 for cyclobenzaprine HCl 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 include cardiac arrest, chest pain, cardiac dysrhythmias, severe hypotension, seizures, and neuroleptic malignant syndrome. Clinically significant changes in the electrocardiogram, particularly alterations in QRS axis or width, serve as important indicators of toxicity.

Management Procedures

To mitigate the risk of severe manifestations, it is essential 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. 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 critical, and emesis is contraindicated.

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

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 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 ineffective, other anticonvulsants such as phenobarbital or phenytoin. The use of physostigmine is not recommended except for life-threatening symptoms unresponsive to other treatments, and only after consultation with 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; however, it is strongly advised that physicians consult the local poison control center for specific pediatric treatment recommendations.

Nonclinical Toxicology

Cyclobenzaprine has been evaluated for its nonclinical toxicology profile, with specific attention to reproductive effects, hepatotoxicity, carcinogenicity, and mutagenicity.

In terms of reproductive 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.

Hepatotoxicity was observed in rats treated with cyclobenzaprine HCl for up to 67 weeks at doses ranging from approximately 5 to 40 times the maximum recommended human dose. Notable findings included pale, sometimes enlarged livers, along with dose-related hepatocyte vacuolation and lipidosis. In higher dose groups, these microscopic changes were evident after 26 weeks, and in some cases, even earlier in rats that died prior to the 26-week mark. At lower doses, these changes were not observed until after 26 weeks of treatment.

Regarding carcinogenicity, cyclobenzaprine did not affect the onset, incidence, or distribution of neoplasia in an 81-week study conducted in mice or in a 105-week study in rats.

Additionally, cyclobenzaprine did not demonstrate mutagenic activity in male mice at dose levels of up to 20 times the human dose.

No information is available regarding teratogenic effects.

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 HCl 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 include myalgia. In the Nervous System and Psychiatric category, additional events 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 reported are photosensitization and alopecia. Urogenital reactions 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 HCl may impair mental and physical abilities necessary for performing hazardous tasks, including operating machinery or driving a motor vehicle, particularly when used in conjunction with alcohol or other central nervous system (CNS) depressants.

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 HCl and advise that the dosage be titrated slowly upward as needed.

Patients should also be cautioned about the risk of serotonin syndrome when cyclobenzaprine 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, instructing them to seek immediate medical attention if they experience any of these symptoms.

Storage and Handling

The product is supplied in a well-closed container equipped with a child-resistant closure. 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

Patients receiving cyclobenzaprine HCl should be aware that abrupt cessation after prolonged use may lead to withdrawal symptoms such as nausea, headache, and malaise, although these are not indicative of addiction. The recommended starting dose is 5 mg taken three times daily, with the possibility of increasing to 7.5 mg or 10 mg three times daily based on individual response. Prolonged use beyond two to three weeks is not advised.

Clinicians should counsel patients on the potential for impaired mental and physical abilities when cyclobenzaprine HCl is used in conjunction with alcohol or other CNS depressants, particularly regarding tasks that require alertness, such as driving or operating machinery. Additionally, there is a risk of serotonin syndrome when cyclobenzaprine HCl 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. Postmarketing data from a surveillance program involving 7,607 patients indicated that the effectiveness of cyclobenzaprine HCl aligns 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 Liberty Pharmaceuticals, Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)