Cyclobenzaprine hydrochloride

Description

Cyclobenzaprine hydrochloride, USP is a tricyclic amine salt presented as a white to off-white, odourless, crystalline powder. Its molecular formula is C20H21N • HCl, and it has a molecular weight of 311.9. The compound has a melting point of 217°C and a pKa of 8.47 at 25°C. Cyclobenzaprine hydrochloride is freely soluble in water, alcohol, and methanol; it is 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 tablets, USP are available in strengths of 5 mg, 7.5 mg, and 10 mg for oral administration. Each tablet contains cyclobenzaprine hydrochloride along with inactive ingredients, which include crospovidone, hypromellose, lactose anhydrous, macrogol, magnesium stearate, polysorbate 80, pregelatinized starch, silicified microcrystalline cellulose, and titanium dioxide. The 5 mg and 10 mg tablets also contain D&C Yellow #10 Aluminum Lake and FD&C Yellow #6 Sunset Yellow FCF Aluminum Lake, while the 5 mg tablets additionally contain FD&C Blue #2/INDIGO Carmine 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 benefits 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 2 to 3 weeks, as there is insufficient evidence to support the effectiveness of prolonged treatment. Muscle spasms related to acute, painful musculoskeletal conditions are typically of short duration, and extended therapy is rarely justified.

Cyclobenzaprine hydrochloride tablets are not indicated for the treatment of spasticity associated with cerebral or spinal cord disease, nor are they effective in pediatric patients with cerebral palsy.

Dosage and Administration

The recommended dose of cyclobenzaprine hydrochloride tablets for most patients is 5 mg administered three times a day. Based on individual patient response, the dosage may be increased to 10 mg three times a day.

It is important to note that the use of cyclobenzaprine hydrochloride tablets for periods longer than 2 to 3 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 the product.

Concomitant use with monoamine oxidase (MAO) inhibitors or within 14 days of their discontinuation is contraindicated due to the risk of hyperpyretic crisis, seizures, and fatalities associated with 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 or conduction disturbances, or congestive heart failure, due to potential cardiovascular complications.

Use is also contraindicated in patients with hyperthyroidism, as it may exacerbate the condition.

Warnings and Precautions

The use of cyclobenzaprine hydrochloride necessitates careful consideration of several critical warnings and precautions to ensure patient safety.

Serotonin Syndrome 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. The use of cyclobenzaprine hydrochloride in conjunction with MAO inhibitors is contraindicated. Clinicians should be vigilant for symptoms indicative of serotonin syndrome, which 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). Should these symptoms arise, immediate discontinuation of cyclobenzaprine hydrochloride and any concomitant serotonergic agents is warranted, along with the initiation of supportive symptomatic treatment. If the clinical decision is made to continue treatment with cyclobenzaprine hydrochloride alongside other serotonergic medications, careful observation is essential, particularly during the initiation of therapy or when adjusting dosages.

CNS Reactions 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 central nervous system reactions similar to those observed with tricyclic antidepressants have been reported. Healthcare professionals should monitor patients for any adverse CNS effects during treatment.

Arrhythmias Tricyclic antidepressants, including cyclobenzaprine, have been linked to the occurrence of arrhythmias, sinus tachycardia, and prolongation of conduction time, which may lead to serious cardiovascular events such as myocardial infarction and stroke. Clinicians should assess the cardiovascular status of patients prior to initiating treatment and monitor for any signs of arrhythmia throughout the course of therapy.

CNS Depressants Cyclobenzaprine hydrochloride may potentiate the effects of alcohol, barbiturates, and other central nervous system depressants. Caution is advised when prescribing cyclobenzaprine to patients who are concurrently using these substances, as the risk of enhanced CNS depression may increase. Monitoring for signs of excessive sedation or respiratory depression is recommended in these cases.

Side Effects

Patients may experience a range of adverse reactions while using the medication. Common adverse reactions, occurring in more than 3% of participants, include drowsiness (29% at 5 mg, 38% at 10 mg, compared to 10% for placebo), dry mouth (21% at 5 mg, 32% at 10 mg, 7% for placebo), fatigue (6% at both 5 mg and 10 mg, 3% for placebo), and headache (5% at both 5 mg and 10 mg, 8% for placebo).

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 infection, pharyngitis, fatigue/tiredness, asthenia, dyspepsia, unpleasant taste, blurred vision, and confusion.

Additional adverse reactions reported include syncope and malaise (body as a whole); tachycardia, arrhythmia, vasodilatation, palpitation, and hypotension (cardiovascular); vomiting, anorexia, gastrointestinal pain, gastritis, thirst, flatulence, edema of the tongue, abnormal liver function, and rare reports of hepatitis, jaundice, and cholestasis (digestive); and hypersensitivity reactions such as anaphylaxis, angioedema, pruritus, facial edema, urticaria, and rash. Musculoskeletal reactions may include local weakness, while nervous system and psychiatric effects can encompass 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. Skin-related reactions may involve sweating, and special senses may be affected by ageusia and tinnitus. Urogenital adverse reactions include urinary frequency and/or retention.

Certain adverse reactions have an unknown causal relationship with the medication. These include chest pain and edema (body as a whole); hypertension, myocardial infarction, heart block, and stroke (cardiovascular); paralytic ileus, tongue discoloration, stomatitis, and parotid swelling (digestive); inappropriate ADH syndrome (endocrine); purpura, bone marrow depression, leukopenia, eosinophilia, and thrombocytopenia (hematic and lymphatic); fluctuations in blood sugar levels, weight gain or loss (metabolic, nutritional, and immune); myalgia (musculoskeletal); decreased or increased libido, abnormal gait, delusions, aggressive behavior, paranoia, peripheral neuropathy, Bell's palsy, alteration in EEG patterns, and extrapyramidal symptoms (nervous system and psychiatric); dyspnea (respiratory); photosensitization and alopecia (skin); and impaired urination, dilatation of the urinary tract, impotence, testicular swelling, gynecomastia, breast enlargement, and galactorrhea (urogenital).

A serious warning regarding serotonin syndrome is noted, as the development of this potentially life-threatening condition has been reported when the medication is used in combination with other drugs, such as selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), tramadol, bupropion, meperidine, verapamil, or MAO inhibitors. Symptoms may include mental status changes (e.g., confusion, agitation, hallucinations), autonomic instability (e.g., diaphoresis, tachycardia, labile blood pressure, hyperthermia), neuromuscular abnormalities (e.g., tremor, ataxia, hyperreflexia, clonus, muscle rigidity), and gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).

In cases of overdose, common effects include drowsiness and tachycardia, while less frequent manifestations may involve tremor, agitation, coma, ataxia, hypertension, slurred speech, confusion, dizziness, nausea, vomiting, and hallucinations. Rare but potentially critical manifestations can include cardiac arrest, chest pain, cardiac dysrhythmias, severe hypotension, seizures, and neuroleptic malignant syndrome.

Drug Interactions

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

Monoamine Oxidase Inhibitors (MAOIs) and Serotonergic Drugs Cyclobenzaprine may lead to life-threatening interactions when administered concurrently with MAO inhibitors. It is essential to monitor patients closely for signs of serotonin syndrome when cyclobenzaprine is used alongside other serotonergic medications.

Central Nervous System (CNS) Depressants The concomitant use of cyclobenzaprine with alcohol, barbiturates, and other CNS depressants may enhance the sedative effects. Caution is advised, and dosage adjustments may be necessary to mitigate the risk of excessive sedation.

Tricyclic Antidepressants (TCAs) Tricyclic antidepressants may interfere with the antihypertensive effects of guanethidine and similar agents. Additionally, the use of TCAs in patients taking tramadol may increase the risk of seizures. Monitoring and potential dosage adjustments should be considered in these scenarios 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 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-fold higher than those observed in younger adults. Notably, elderly male subjects exhibited the most significant increase, with mean levels approximately 2.4-fold higher, while elderly females showed a lesser increase of about 1.2-fold.

Given these pharmacokinetic findings, it is recommended that therapy with cyclobenzaprine in geriatric patients be initiated at a lower dose of 5 mg, with a gradual titration to achieve the desired therapeutic effect. Additionally, 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. There is also an increased potential for drug-drug and drug-disease interactions in this population.

Therefore, cyclobenzaprine should be prescribed to elderly patients only when clearly indicated, and consideration should be given to less frequent dosing to mitigate risks associated with higher plasma concentrations and increased sensitivity to adverse effects. 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. 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 should be used during pregnancy only if clearly needed. Healthcare professionals are advised to weigh the potential benefits against the risks when considering the use of this medication in pregnant patients.

Lactation

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

Renal Impairment

There is no specific information available regarding dosage adjustments, special monitoring, or safety considerations for patients with renal impairment. Healthcare professionals should exercise caution when prescribing to patients with reduced kidney function, as the absence of detailed guidance necessitates careful clinical judgment. Regular monitoring of renal function may be advisable in this patient population.

Hepatic Impairment

Patients with hepatic impairment have not been specifically studied in clinical trials for this medication. Consequently, there is no available information regarding 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 warranted based on clinical judgment.

Overdosage

In cases of cyclobenzaprine overdosage, although rare, fatalities may occur, particularly when multiple substances, including alcohol, are ingested deliberately. The onset of toxicity symptoms can be rapid, necessitating immediate hospital monitoring.

The acute oral LD50 of cyclobenzaprine has been established at approximately 338 mg/kg in mice and 425 mg/kg in rats. The most frequently observed effects of 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. 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 the QRS axis or width, serve as important indicators of cyclobenzaprine toxicity. A maximal limb-lead QRS duration of ≥ 0.10 seconds may suggest a severe overdose, warranting immediate intervention.

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

In cases where CNS depression is evident, early intubation is recommended due to the risk of sudden deterioration. Seizures should be managed with benzodiazepines or other anticonvulsants. Additionally, for patients exhibiting dysrhythmias and/or QRS widening, serum alkalinization with intravenous sodium bicarbonate should be initiated.

It is strongly advised that healthcare professionals contact a poison control center for the most current information regarding overdose management and treatment protocols.

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. 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 should be used during pregnancy only if clearly needed.

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

In long-term studies involving rats treated with cyclobenzaprine for up to 67 weeks at doses ranging from approximately 5 to 40 times the maximum recommended human dose, observations included pale and sometimes enlarged livers, along with dose-related hepatocyte vacuolation and lipidosis. These microscopic changes were noted in higher dose groups after 26 weeks and even earlier in rats that died prior to this time frame. Furthermore, 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.

Animal studies have demonstrated that cyclobenzaprine effectively reduces or abolishes skeletal muscle hyperactivity across various models. It has been established that cyclobenzaprine does not act at the neuromuscular junction or directly on skeletal muscle. Instead, it primarily exerts its effects within the central nervous system, particularly at the brain stem level, although its action on the spinal cord may also contribute to its overall skeletal muscle relaxant activity. Pharmacological studies in animals have revealed similarities between the effects of cyclobenzaprine and those of structurally related tricyclic antidepressants, including reserpine antagonism, norepinephrine potentiation, potent peripheral and central anticholinergic effects, and sedation. Cyclobenzaprine has also been 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 noted include anaphylaxis, angioedema, pruritus, facial edema, urticaria, and rash. Musculoskeletal reactions include local weakness. In the Nervous System and Psychiatric categories, 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 include urinary frequency and/or retention.

Additionally, other reactions have been reported rarely for cyclobenzaprine 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 noted are myalgia. In the Nervous System and Psychiatric categories, 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 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, particularly when used in conjunction with alcohol or other central nervous system (CNS) depressants, may impair their mental and 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 emphasize the need for a gradual titration to higher doses.

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, instructing 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, compliant with USP standards, and equipped with a child-resistant closure. It should be stored at a temperature range of 20°C to 25°C (68°F to 77°F), in accordance with USP Controlled Room Temperature guidelines.

Additional Clinical Information

Patients using cyclobenzaprine should be aware that the medication may impair mental and physical abilities, particularly when combined with alcohol or other central nervous system (CNS) depressants, which can affect tasks such as operating machinery or driving. In elderly patients, the incidence and severity of adverse events may be heightened; therefore, it is recommended that treatment begins with a 5 mg dose, which should be titrated slowly.

Clinicians should inform patients about the potential risk of serotonin syndrome when cyclobenzaprine is used alongside other medications, including SSRIs, SNRIs, TCAs, tramadol, bupropion, meperidine, verapamil, or MAO inhibitors. Patients should be educated on the signs and symptoms of serotonin syndrome and advised to seek immediate medical attention if they experience any related symptoms.

FDA Insert (PDF)

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

View full prescribing information (PDF)