Cyclobenzaprine hydrochloride

Description

Cyclobenzaprine hydrochloride, USP is a white to off-white crystalline powder with the molecular 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, alcohol, and methanol; sparingly soluble in isopropanol; slightly soluble in chloroform and methylene chloride; and insoluble in hydrocarbons. When aqueous solutions are made alkaline, the free base separates. Chemically, cyclobenzaprine HCl is designated as 3-(5H-dibenzoa,dcyclohepten-5-ylidene)-N,N-dimethyl-1-propanamine hydrochloride. Cyclobenzaprine hydrochloride tablets, USP are formulated for oral administration and are supplied as 7.5 mg tablets. Each tablet contains inactive ingredients including corn starch, hydroxypropyl cellulose, hypromellose, lactose monohydrate, magnesium stearate, polyethylene glycol, pregelatinized starch, talc, and titanium dioxide.

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 two to three 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, specific therapy for extended periods is seldom warranted.

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

Dosage and Administration

The recommended dose of cyclobenzaprine hydrochloride tablets for most patients is 5 mg administered three times a day. Based on individual patient response, the dosage 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 hydrochloride tablets for periods longer than two to 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 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, conduction disturbances, or congestive heart failure, due to the risk of exacerbating these conditions.

Patients with hyperthyroidism should not use this product, as it may worsen their 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 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 Considerations Tricyclic antidepressants, which are closely related to cyclobenzaprine, have been associated with arrhythmias, sinus tachycardia, and prolongation of conduction time, potentially leading to myocardial infarction and stroke. Therefore, caution is warranted when prescribing cyclobenzaprine hydrochloride, particularly in patients with pre-existing cardiovascular conditions.

CNS Depressant Interaction Cyclobenzaprine hydrochloride may potentiate the effects of alcohol, barbiturates, and other central nervous system depressants. Healthcare professionals should advise patients to avoid the concomitant use of these substances to mitigate the risk of enhanced sedation and respiratory depression.

Precautions 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, as well as in those receiving anticholinergic medications.

In summary, healthcare professionals must remain vigilant regarding the potential for serious adverse effects associated with cyclobenzaprine hydrochloride, particularly in the context of drug interactions and specific patient populations. Regular monitoring and patient education are essential components of safe prescribing practices.

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 reported 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.

Less frequent adverse reactions, occurring in less than 1% of patients, encompass a variety of systems. Notable reactions 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 may include anaphylaxis, angioedema, pruritus, facial edema, urticaria, and rash.

Nervous system and psychiatric reactions may involve seizures, ataxia, vertigo, dysarthria, tremors, hypertonia, convulsions, muscle twitching, disorientation, insomnia, depressed mood, abnormal sensations, anxiety, agitation, psychosis, abnormal thinking and dreaming, hallucinations, excitement, paresthesia, diplopia, and serotonin syndrome. Other less frequent reactions include sweating (skin), ageusia and tinnitus (special senses), and urinary frequency and/or retention (urogenital).

Additional adverse reactions with an unknown causal relationship 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 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 and lowering of blood sugar levels, weight gain or loss, and myalgia (musculoskeletal). Psychiatric reactions may include decreased or increased libido, abnormal gait, delusions, aggressive behavior, paranoia, peripheral neuropathy, Bell’s palsy, alteration in EEG patterns, and extrapyramidal symptoms. Respiratory reactions may include dyspnea, while skin reactions may involve photosensitization and alopecia. Urogenital reactions can include impaired urination, dilatation of the urinary tract, impotence, testicular swelling, gynecomastia, breast enlargement, and galactorrhea.

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

Drug Interactions

Cyclobenzaprine has several significant drug interactions that warrant 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 Postmarketing 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, especially during the initiation of treatment or when increasing dosages.

CNS Depressants Cyclobenzaprine hydrochloride may potentiate the effects of alcohol, barbiturates, and other central nervous system (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 Tricyclic antidepressants may interfere with the antihypertensive effects of guanethidine and similar medications. Additionally, the use of tricyclic antidepressants 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

In a pharmacokinetic study involving elderly individuals aged 65 years and older, it was observed that the mean steady-state area under the curve (AUC) values for cyclobenzaprine were approximately 1.7 times higher than those recorded in younger adult populations. Notably, elderly male subjects exhibited the most significant increase, with AUC values approximately 2.4 times higher, while elderly females demonstrated a lesser increase of about 1.2 times.

Given these findings, it is recommended that therapy with cyclobenzaprine hydrochloride in geriatric patients be initiated at a lower dose of 5 mg. Furthermore, careful titration of the dosage should be conducted, allowing for a gradual upward adjustment to ensure safety and efficacy in this population. Monitoring for potential adverse effects is advised, considering the altered pharmacokinetics observed in elderly patients.

Pregnancy

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 associated with cyclobenzaprine hydrochloride. The drug is classified as Pregnancy Category B. However, there are no adequate and well-controlled studies in pregnant women. Due to the limitations of animal reproduction studies in predicting human response, cyclobenzaprine hydrochloride should be used during pregnancy only if clearly needed. Healthcare professionals are advised to weigh the potential benefits against any possible risks when considering this medication for pregnant patients.

Lactation

It is not known whether this drug is excreted in human milk. Due to the structural similarity of cyclobenzaprine to tricyclic antidepressants, some of which are known to be excreted in human milk, caution should be exercised when administering cyclobenzaprine hydrochloride tablets 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 data regarding dosage adjustments, special monitoring, or safety considerations. Therefore, healthcare professionals should exercise caution when prescribing this medication to patients with reduced kidney function, as the lack of information necessitates careful clinical judgment and monitoring.

Hepatic Impairment

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

Overdosage

Although rare, cyclobenzaprine hydrochloride overdosage can lead to fatalities. It is important to note that multiple drug ingestion, including alcohol, is frequently observed in cases of deliberate overdose. Due to the complexity and evolving nature of overdose management, it is strongly advised that healthcare professionals contact a poison control center for the most current treatment information.

Signs and Symptoms

Toxicity symptoms may manifest rapidly following an overdose, necessitating immediate hospital monitoring. The most common effects include drowsiness and tachycardia. Other less frequent symptoms may encompass 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, should be closely monitored.

Management Procedures

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 is imperative prior to lavage, and emesis is contraindicated.

Cardiac monitoring should be initiated immediately, and an ECG should be obtained to assess the severity of the overdose, with a maximal limb-lead QRS duration of ≥ 0.10 seconds serving as a critical indicator. For patients exhibiting dysrhythmias or QRS widening, serum alkalinization to a pH of 7.45 to 7.55 using intravenous sodium bicarbonate, along with hyperventilation as needed, should be implemented. It is important to avoid a pH > 7.60 or a pCO2 < 20 mmHg.

In cases where dysrhythmias do not respond to sodium bicarbonate therapy or hyperventilation, alternative treatments such as lidocaine, bretylium, or phenytoin may be effective. However, Type 1A and 1C antiarrhythmics (e.g., quinidine, disopyramide, and procainamide) are generally contraindicated.

For patients exhibiting CNS depression, early intubation is recommended due to the risk of sudden deterioration. Seizures should be managed with benzodiazepines, and if these are ineffective, other anticonvulsants such as phenobarbital or phenytoin may be utilized. The use of physostigmine is not recommended except in life-threatening situations unresponsive to other therapies, and only after consultation with a poison control center.

Additional Considerations

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 recommended that physicians consult the local poison control center for specific pediatric treatment guidelines. Monitoring of plasma drug levels should not dictate patient management, and dialysis is likely ineffective due to the low plasma concentrations of cyclobenzaprine. Continuous observation for signs of CNS or respiratory depression, hypotension, cardiac dysrhythmias, conduction blocks, and seizures is essential, with extended monitoring required if any signs of toxicity arise.

Nonclinical Toxicology

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

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, indicating no evidence of carcinogenic potential.

Reproductive performance and fertility were not adversely affected in male or female rats administered oral doses of cyclobenzaprine up to 10 times the human dose.

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

Postmarketing Experience

A postmarketing surveillance program involving 7,607 patients with acute musculoskeletal disorders included 297 patients treated with cyclobenzaprine hydrochloride tablets 10 mg for 30 days or longer. The overall effectiveness of cyclobenzaprine hydrochloride was comparable to that observed in double-blind controlled studies, with a lower overall incidence of adverse effects reported.

The following adverse reactions have been documented in postmarketing experience or occurred with an incidence of less than 1% of patients in clinical trials with the 10 mg tablet:

Body as a Whole: Syncope; malaise. Cardiovascular: Tachycardia; arrhythmia; vasodilatation; palpitation; hypotension. Digestive: Vomiting; anorexia; diarrhea; gastrointestinal pain; gastritis; thirst; flatulence; edema of the tongue; abnormal liver function; rare reports of hepatitis, jaundice, and cholestasis. Hypersensitivity: Anaphylaxis; angioedema; pruritus; facial edema; urticaria; rash. Musculoskeletal: Local weakness. Nervous System and Psychiatric: 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; serotonin syndrome. Skin: Sweating. Special Senses: Ageusia; tinnitus. Urogenital: Urinary frequency and/or retention.

Additionally, other reactions reported rarely for cyclobenzaprine hydrochloride, where a causal relationship could not be established, or reported for other tricyclic drugs, include:

Body as a Whole: Chest pain; edema. Cardiovascular: Hypertension; myocardial infarction; heart block; stroke. Digestive: Paralytic ileus; tongue discoloration; stomatitis; parotid swelling. Endocrine: Inappropriate ADH syndrome. Hematic and Lymphatic: Purpura; bone marrow depression; leukopenia; eosinophilia; thrombocytopenia. Metabolic, Nutritional and Immune: Elevation and lowering of blood sugar levels; weight gain or loss. Musculoskeletal: Myalgia. Nervous System and Psychiatric: Decreased or increased libido; abnormal gait; delusions; aggressive behavior; paranoia; peripheral neuropathy; Bell’s palsy; alteration in EEG patterns; extrapyramidal symptoms. Respiratory: Dyspnea. Skin: Photosensitization; alopecia. Urogenital: Impaired urination; dilatation of urinary tract; impotence; testicular swelling; gynecomastia; breast enlargement; 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 physical abilities necessary for performing hazardous tasks, including operating machinery or driving a motor vehicle.

In elderly patients, it is important to communicate that the frequency and severity of adverse events associated with cyclobenzaprine may be increased, regardless of whether other medications are being taken concurrently. Therefore, healthcare providers should recommend initiating treatment with a 5 mg dose in this population, with a gradual titration to higher doses as appropriate.

Additionally, patients should be cautioned about the potential risk of serotonin syndrome when cyclobenzaprine hydrochloride 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 inhibitors (MAOIs).

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

Storage and Handling

The product is available in plastic bottles containing 15, 30, 60, or 90 tablets. It should be stored at a temperature range of 20 to 25° C (68 to 77° F), in accordance with USP Controlled Room Temperature guidelines. Proper storage conditions are essential to maintain the integrity and efficacy of the product.

Additional Clinical Information

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

For most patients, the recommended dosage of cyclobenzaprine hydrochloride tablets is 5 mg three times daily, with potential increases to 7.5 or 10 mg three times daily based on individual response. Prolonged use beyond two to three weeks is not advised, and dosage adjustments may be necessary for elderly or hepatically impaired patients. Patients should be counseled on the risk of serotonin syndrome when cyclobenzaprine is used with other medications, including SSRIs, SNRIs, and MAO inhibitors, and should be instructed to seek immediate medical attention if symptoms arise. Additionally, the use of cyclobenzaprine, particularly with alcohol or CNS depressants, may impair mental and physical abilities, necessitating caution in activities such as driving. In a postmarketing surveillance program involving 7,607 patients, the effectiveness of cyclobenzaprine was consistent with controlled studies, and the incidence of adverse effects was lower.

FDA Insert (PDF)

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

View full prescribing information (PDF)