Cyclobenzaprine hydrochloride

Description

Cyclobenzaprine hydrochloride is a white, crystalline tricyclic amine salt with the empirical formula C20H21N•HCl and a molecular weight of 311.9 g/mol. 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. It is supplied in tablet form for oral administration, available in dosages of 5 mg and 10 mg. The tablets contain the following inactive ingredients: colloidal silicon dioxide, corn starch, hypromellose, lactose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, and propylene glycol.

Uses and Indications

Cyclobenzaprine hydrochloride 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 should be utilized only for short durations, specifically up to two or three weeks, as there is insufficient evidence supporting its effectiveness for prolonged use. Muscle spasms related to acute, painful musculoskeletal conditions are typically of short duration, and specific therapy for extended periods is rarely necessary.

Cyclobenzaprine hydrochloride is not indicated for the treatment of spasticity associated with cerebral or spinal cord diseases, nor is it effective in pediatric patients with cerebral palsy.

Dosage and Administration

The recommended dose of cyclobenzaprine hydrochloride 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 for periods longer than two or three weeks is not recommended. For patients who are elderly or have hepatic impairment, less frequent dosing should be considered to ensure safety and efficacy.

Contraindications

Use of this product is contraindicated in the following situations:

Patients with hypersensitivity to any component of this product should not use it due to the risk of severe allergic reactions.

Concomitant use with monoamine oxidase (MAO) inhibitors or within 14 days of their discontinuation is contraindicated. This is due to the potential for hyperpyretic crisis, seizures, and fatalities associated with the combination of cyclobenzaprine (or structurally similar tricyclic antidepressants) and MAO inhibitors.

The product is contraindicated in patients in the acute recovery phase of myocardial infarction, as well as those with arrhythmias, heart block or conduction disturbances, or congestive heart failure, due to the risk of exacerbating these conditions.

Additionally, 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 and precautions 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, may lead to the development of serotonin syndrome, a potentially life-threatening condition. Symptoms of serotonin syndrome can 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). In the event of these reactions, treatment with cyclobenzaprine hydrochloride and any concomitant serotonergic agents should be discontinued immediately, and supportive symptomatic treatment should be initiated. If the clinical situation necessitates the use of cyclobenzaprine hydrochloride alongside other serotonergic drugs, careful observation is advised, particularly during the initiation of treatment 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 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.

Caution in Specific Populations 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. This caution extends to patients who are concurrently taking anticholinergic medications.

CNS Depressant Interaction Cyclobenzaprine hydrochloride may potentiate the effects of alcohol, barbiturates, and other central nervous system depressants, necessitating careful monitoring of patients who are using these substances concurrently.

In summary, healthcare professionals should remain vigilant regarding the potential for serious adverse effects associated with cyclobenzaprine hydrochloride, particularly in the context of drug interactions and specific patient histories.

Side Effects

Patients receiving treatment with 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% 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, 3% in the placebo group), and headache (5% at both dosages, 8% in the placebo group).

In clinical studies, drowsiness was reported in 39% of subjects, while surveillance programs indicated a lower incidence of 16%. Similarly, dry mouth was noted in 27% of clinical study participants, with only 7% reported in surveillance. Dizziness was observed in 11% of clinical study participants, compared to 3% in surveillance programs.

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, and pharyngitis.

Less frequent adverse reactions may include fatigue, asthenia, nausea, constipation, dyspepsia, unpleasant taste, blurred vision, headache, nervousness, 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 reported.

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 common reactions include sweating (skin) and ageusia or tinnitus (special senses). Urogenital effects such as urinary frequency and/or retention have also been noted.

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 such as inappropriate ADH syndrome, hematologic issues like purpura, bone marrow depression, leukopenia, eosinophilia, and thrombocytopenia, and metabolic changes including fluctuations in blood sugar levels and weight changes have also been documented. Musculoskeletal complaints such as myalgia, nervous system and psychiatric effects like libido changes, abnormal gait, delusions, aggressive behavior, paranoia, peripheral neuropathy, Bell's palsy, alterations in EEG patterns, and extrapyramidal symptoms have been reported. Respiratory issues such as dyspnea, skin reactions like photosensitization and alopecia, and urogenital concerns including impaired urination, urinary tract dilatation, impotence, testicular swelling, gynecomastia, breast enlargement, and galactorrhea have also been noted.

A serious warning regarding the potential development of serotonin syndrome has been issued, particularly when cyclobenzaprine hydrochloride is used in combination with other medications. Symptoms of this potentially life-threatening condition may include changes in mental status, autonomic instability, neuromuscular abnormalities, and gastrointestinal symptoms.

Drug Interactions

Cyclobenzaprine has several notable drug interactions that require 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 Post-marketing 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, 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 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 experience increased plasma concentrations of cyclobenzaprine, which necessitates careful consideration when prescribing this medication. Due to this heightened concentration, geriatric patients are at an elevated risk for central nervous system (CNS) adverse events, including hallucinations and confusion. Additionally, there is a concern for cardiac events in this population, which may lead to falls or other serious complications.

Given these risks, cyclobenzaprine should be prescribed to elderly patients only when clearly indicated. When initiating treatment, it is recommended that cyclobenzaprine hydrochloride be started at a lower dose of 5 mg. Dosage should be titrated slowly to monitor for any adverse effects and to ensure patient safety.

Healthcare providers should remain vigilant for potential drug-drug and drug-disease interactions that may be more pronounced in geriatric patients, further underscoring the importance of careful monitoring and assessment throughout the treatment process.

Pregnancy

Reproduction studies have been conducted in rats, mice, and rabbits at doses up to 20 times the human dose of cyclobenzaprine hydrochloride, revealing no evidence of impaired fertility or harm to the fetus. 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

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 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

In cases of cyclobenzaprine hydrochloride overdosage, although rare, fatalities may occur. It is important to note that deliberate overdose often involves the ingestion of multiple substances, including alcohol.

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

Signs and Symptoms The most frequently observed effects of cyclobenzaprine overdose include drowsiness and tachycardia. Other less common symptoms may manifest as tremor, agitation, coma, ataxia, hypertension, slurred speech, confusion, dizziness, nausea, vomiting, and hallucinations.

Healthcare providers should be vigilant for rare but critical manifestations, which 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, are important indicators of cyclobenzaprine toxicity.

Toxicity Thresholds The acute oral LD50 of cyclobenzaprine hydrochloride has been established at approximately 338 mg/kg in mice and 425 mg/kg in rats.

In addition to the aforementioned symptoms, other potential effects of overdosage may align with those listed under ADVERSE REACTIONS. Prompt recognition and intervention are critical in managing cyclobenzaprine overdose effectively.

Nonclinical Toxicology

In studies evaluating the nonclinical toxicology of cyclobenzaprine, no relevant information regarding teratogenic effects was provided. However, non-teratogenic effects were observed in reproductive performance and fertility assessments. At oral doses of up to 10 times the human dose, cyclobenzaprine did not adversely affect the reproductive performance or fertility of male or female rats.

In long-term studies 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, notable findings included pale, sometimes enlarged livers, along with dose-related hepatocyte vacuolation and lipidosis. In the higher dose groups, these microscopic changes were observed as early as 26 weeks, and even earlier in rats that died prior to this time. At lower doses, these changes were not evident until after 26 weeks of treatment.

Furthermore, 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.

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, 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 noted. 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 included for 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, 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, 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 supplied in a tight, light-resistant container to ensure its integrity and efficacy. 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 quality of the product throughout its shelf life.

Additional Clinical Information

Laboratory tests specific to cyclobenzaprine hydrochloride have not been detailed. 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. The recommended dosing for most patients is 5 mg three times a day, with the possibility of increasing to 10 mg three times a day based on individual response. Prolonged use beyond two to three weeks is not advised.

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. Additionally, there is a risk of serotonin syndrome when cyclobenzaprine hydrochloride is combined 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 experience these symptoms. A post-marketing surveillance program involving 7,607 patients indicated that the effectiveness of cyclobenzaprine hydrochloride 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 Mutual Pharmaceutical. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)