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. It is freely soluble in water, alcohol, and methanol; sparingly soluble in isopropanol; slightly soluble in chloroform and methylene chloride; and insoluble in n-hexane. Chemically, it is designated as 3-(5H-dibenzoa,dcyclohepten-5-ylidene)-N,N-dimethyl-1-propanamine hydrochloride.

Cyclobenzaprine hydrochloride 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 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 2 to 3 weeks. There is insufficient evidence to support the effectiveness of cyclobenzaprine hydrochloride for prolonged use, as muscle spasms related to acute, painful musculoskeletal conditions typically resolve within a short duration. Therefore, extended therapy is seldom warranted.

Cyclobenzaprine hydrochloride tablets have not demonstrated efficacy in treating spasticity associated with cerebral or spinal cord diseases, nor are they indicated for use in children with cerebral palsy.

Dosage and Administration

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

It is important to note that the use of cyclobenzaprine hydrochloride tablets for periods longer than 2 or 3 weeks is not recommended. For patients who are elderly or have hepatic impairment, 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 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 risks.

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 potential risks and the implementation of appropriate monitoring strategies.

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

Central Nervous System Effects Cyclobenzaprine hydrochloride shares structural similarities with 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.

Cardiovascular Risks Tricyclic antidepressants, which are closely related to cyclobenzaprine, have been associated with cardiovascular complications, including arrhythmias, sinus tachycardia, and prolongation of conduction time, which may lead to myocardial infarction and stroke.

CNS Depressant Interactions Cyclobenzaprine hydrochloride may potentiate the effects of alcohol, barbiturates, and other central nervous system depressants. Healthcare professionals should exercise caution when prescribing cyclobenzaprine to patients who are concurrently using these substances, as the risk of enhanced sedation and respiratory depression may be increased.

Monitoring parameters should include regular assessment of mental status, cardiovascular function, and any signs of serotonin syndrome, particularly in patients receiving concomitant serotonergic medications.

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

In clinical studies, additional common adverse reactions were reported, including drowsiness (39%) and dry mouth (27%), while surveillance programs noted drowsiness (16%) and dry mouth (7%). Dizziness was reported in 11% of clinical studies and 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, pharyngitis, fatigue/tiredness, asthenia, dyspepsia, unpleasant taste, blurred vision, and confusion.

Postmarketing experiences have identified additional adverse reactions with an incidence of less than 1%. 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 reported reactions include sweating (skin), ageusia and tinnitus (special senses), and urinary frequency and/or retention (urogenital).

Certain adverse reactions have been reported with an unknown causal relationship, including 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 reactions such as inappropriate ADH syndrome, hematologic reactions including purpura, bone marrow depression, leukopenia, eosinophilia, and thrombocytopenia, and metabolic changes such as elevation and lowering of blood sugar levels, weight gain or loss have also been noted. Musculoskeletal reactions include myalgia, while nervous system and psychiatric reactions encompass decreased or increased libido, abnormal gait, delusions, aggressive behavior, paranoia, peripheral neuropathy, Bell's palsy, alterations in EEG patterns, and extrapyramidal symptoms. Respiratory reactions include dyspnea, while skin reactions may involve photosensitization and alopecia. Urogenital reactions include impaired urination, dilatation of the urinary tract, impotence, testicular swelling, gynecomastia, breast enlargement, and galactorrhea.

Patients should be aware of the potential for serotonin syndrome, a potentially life-threatening condition that may occur when cyclobenzaprine hydrochloride is used in combination with other medications such as SSRIs, SNRIs, TCAs, tramadol, bupropion, meperidine, verapamil, or MAO inhibitors. Symptoms may include mental status changes, autonomic instability, neuromuscular abnormalities, and gastrointestinal symptoms.

In cases of overdose, common effects may include drowsiness and tachycardia, while less frequent manifestations can involve tremor, agitation, coma, ataxia, hypertension, slurred speech, confusion, dizziness, nausea, vomiting, and hallucinations. Rare but potentially critical manifestations may 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) Cyclobenzaprine may produce life-threatening interactions when administered concurrently with MAO inhibitors. It is essential to monitor patients closely for any adverse effects 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 of these substances. Clinicians should consider dosage adjustments and closely monitor patients for increased sedation and respiratory depression.

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 elevate the risk of seizures. It is advisable to monitor blood pressure and assess seizure risk in patients receiving these combinations.

Packaging & NDC

The table below lists all NDC Code configurations of Cyclobenzaprine Hydrochloride, the U.S. brand-name prescription product. Columns show Packaging, Formulation Type, and Active Ingredient Strength.

Pediatric Use

The safety and effectiveness of cyclobenzaprine 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, with pharmacokinetic studies indicating that mean steady-state AUC values in individuals aged 65 years and older are approximately 1.7-fold higher than those observed in younger adults. Notably, elderly male subjects exhibited the most significant increase, with plasma concentrations approximately 2.4-fold higher than their younger counterparts, while elderly females showed a lesser increase of about 1.2-fold.

Due to these pharmacokinetic differences, elderly patients may be at a heightened risk for central nervous system (CNS) adverse events, including hallucinations and confusion, as well as cardiac events that could lead to falls or other complications. Therefore, cyclobenzaprine should be prescribed to geriatric patients only when clearly indicated.

When initiating treatment in elderly patients, it is recommended to start with a lower dose of 5 mg and to titrate slowly upward, taking into account the patient's response and tolerance. Additionally, less frequent dosing should be considered to mitigate the risk of adverse effects and drug interactions, including potential drug-drug and drug-disease interactions that may be more prevalent in this population. Careful monitoring of these patients is essential to ensure safety and efficacy.

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 any possible 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 relation to the use of this medication. Consequently, there are no established dosage adjustments, special monitoring requirements, or precautions for individuals with compromised liver function. It is recommended that healthcare providers exercise caution when prescribing this medication to patients with hepatic impairment, given the lack of data on its safety and efficacy in this population. Regular monitoring of liver function may be prudent in these cases, although specific parameters are not defined in the available information.

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.

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, and seizures. Critical manifestations, albeit rare, can include cardiac arrest, chest pain, cardiac dysrhythmias, severe hypotension, and neuroleptic malignant syndrome. Clinicians should be vigilant for changes in the electrocardiogram, especially alterations in the QRS axis or width, as these are significant indicators of toxicity.

Management Procedures

All patients suspected of cyclobenzaprine overdose should undergo gastrointestinal decontamination. This includes performing a large volume gastric lavage followed by the administration of activated charcoal. In cases where consciousness is impaired, securing the airway is imperative prior to lavage, and emesis is contraindicated.

A maximal limb-lead QRS duration of ≥ 0.10 seconds may indicate the severity of the overdose, and serum alkalinization should be initiated for patients exhibiting dysrhythmias. For those experiencing central nervous system (CNS) depression, early intubation is recommended due to the risk of sudden deterioration. Seizures should be managed with benzodiazepines or other anticonvulsants if benzodiazepines prove ineffective.

It is strongly advised that healthcare professionals contact the local poison control center for tailored treatment recommendations, particularly in pediatric cases of overdose.

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.

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.

In a long-term study 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 occasionally enlarged livers, along with dose-related hepatocyte vacuolation and lipidosis. In the higher dose groups, these microscopic changes were noted after 26 weeks and even earlier in rats that died prior to the 26-week mark.

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 such as syncope and malaise have been noted. Cardiovascular events include tachycardia, arrhythmia, vasodilatation, palpitation, and hypotension. Digestive system reactions consist of vomiting, anorexia, diarrhea, gastrointestinal pain, gastritis, thirst, flatulence, edema of the tongue, and abnormal liver function, with rare reports of hepatitis, jaundice, and cholestasis.

Hypersensitivity reactions reported include anaphylaxis, angioedema, pruritus, facial edema, urticaria, and rash. Musculoskeletal reactions have included local weakness.

Nervous system and psychiatric events encompass 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 events reported are 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:

In the Body as a Whole category, chest pain and edema have been noted. Cardiovascular reactions include hypertension, myocardial infarction, heart block, and stroke. Digestive system 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 have included myalgia.

Nervous system and psychiatric 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 consist of photosensitization and alopecia. Urogenital events 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 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 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, with a gradual titration to higher doses as appropriate.

Patients should also be cautioned about the potential risk of serotonin syndrome when cyclobenzaprine is used alongside 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 tight, light-resistant container that complies with the standards set forth by the United States Pharmacopeia (USP) and features a child-resistant closure. It is essential to store the product at a temperature range of 20°C to 25°C (68°F to 77°F), in accordance with USP Controlled Room Temperature guidelines. Proper adherence to these storage conditions is crucial to maintain the integrity and efficacy of the product.

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 Medcore LLC. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)