Cyclobenzaprine hydrochloride

Description

Cyclobenzaprine hydrochloride, USP is a white, crystalline tricyclic amine salt with the empirical formula C20H21N·HCl and a molecular weight of 311.9 g/mol. It exhibits 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: croscarmellose sodium, D&C Yellow #10 aluminum lake, FD&C Blue #2 aluminum lake, FD&C Yellow #6 aluminum lake, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, silicon dioxide, 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 are typically of short duration. Therefore, specific therapy for extended periods is seldom warranted.

Cyclobenzaprine hydrochloride tablets, USP 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 dose of cyclobenzaprine hydrochloride tablets, USP for most patients 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.

It is important to note that the use of cyclobenzaprine hydrochloride tablets, USP for periods longer than two or three weeks is not recommended. Additionally, less frequent dosing should be considered for patients who are hepatically impaired or elderly 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 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, as this combination has been associated with hyperpyretic crisis, seizures, and fatalities in patients receiving cyclobenzaprine or similar tricyclic antidepressants.

The product is contraindicated in the acute recovery phase of myocardial infarction, as well as in patients with arrhythmias, heart block, conduction disturbances, or congestive heart failure, due to potential cardiovascular complications.

Additionally, the use of this product is 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 monitoring requirements 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, may lead to the development of serotonin syndrome, a potentially life-threatening condition. The use of Cyclobenzaprine Hydrochloride with MAO inhibitors is contraindicated. Symptoms of serotonin syndrome may manifest as mental status changes (e.g., confusion, agitation, hallucinations), autonomic instability (e.g., diaphoresis, tachycardia, labile blood pressure, hyperthermia), neuromuscular abnormalities (e.g., tremor, ataxia, hyperreflexia, clonus, muscle rigidity), and gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Should these symptoms occur, 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 doses.

Central Nervous System Effects 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.

Cardiovascular Risks Tricyclic antidepressants are known to be associated with arrhythmias, sinus tachycardia, and prolongation of conduction time, which may lead to serious cardiovascular events such as myocardial infarction and stroke. Cyclobenzaprine Hydrochloride may potentiate the effects of alcohol, barbiturates, and other central nervous system depressants, necessitating caution in patients who consume these substances.

Healthcare professionals are advised to monitor patients closely for any signs of adverse reactions, particularly in those receiving concomitant medications that may interact with Cyclobenzaprine Hydrochloride.

Side Effects

Patients receiving treatment may experience a range of adverse reactions. The most common adverse reactions, occurring in more than 3% of participants, include drowsiness (29% at 5 mg, 38% at 10 mg, compared to 10% for placebo), dry mouth (21% at 5 mg, 32% at 10 mg, versus 7% for placebo), fatigue (6% at both 5 mg and 10 mg, 3% for placebo), and headache (5% at both dosages, 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 infections, pharyngitis, fatigue/tiredness, asthenia, dyspepsia, unpleasant taste, blurred vision, 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 reactions include local weakness (musculoskeletal), sweating (skin), ageusia and tinnitus (special senses), and urinary frequency and/or retention (urogenital).

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

The development of serotonin syndrome, a potentially life-threatening condition, has been reported in patients using Cyclobenzaprine Hydrochloride in combination with other medications 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 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 include cardiac arrest, chest pain, cardiac dysrhythmias, severe hypotension, seizures, and neuroleptic malignant syndrome.

Drug Interactions

Cyclobenzaprine has several significant drug interactions that warrant careful consideration during treatment.

Monoamine Oxidase Inhibitors (MAOIs) Cyclobenzaprine is contraindicated in patients taking MAO inhibitors due to the potential for life-threatening interactions.

Serotonergic Drugs Postmarketing reports indicate that the concomitant use of Cyclobenzaprine Hydrochloride with 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 combination of Cyclobenzaprine Hydrochloride and other serotonergic drugs is deemed necessary, careful monitoring is recommended, especially during the initiation of therapy 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 conjunction with 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 (≥65 years old) exhibit significantly altered pharmacokinetics when administered cyclobenzaprine hydrochloride. In a pharmacokinetic study, mean steady-state area under the curve (AUC) values for cyclobenzaprine were approximately 1.7 times higher in elderly individuals compared to younger adults. Notably, elderly male subjects demonstrated the highest observed mean increase, approximately 2.4 times that of younger adults, while elderly females showed a lesser increase of about 1.2 times.

Due to the increased plasma concentration of cyclobenzaprine in this population, therapy should be initiated at a lower dose of 5 mg, with careful and gradual titration to achieve the desired therapeutic effect. It is essential to consider less frequent dosing intervals for elderly patients to mitigate the risk of adverse effects.

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. Additionally, the potential for drug-drug and drug-disease interactions is heightened in this demographic. Therefore, cyclobenzaprine hydrochloride should be prescribed to elderly patients only when clearly indicated, with close monitoring for any adverse effects throughout the course of treatment.

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 before prescribing this medication to 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

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, which complicates management. Therefore, it is strongly advised that healthcare professionals contact a poison control center for the most current treatment information.

Signs and Symptoms of Overdosage

Toxicity symptoms can develop rapidly following an overdose, necessitating immediate hospital monitoring. The most frequently observed effects include drowsiness and tachycardia. Other less common manifestations may include tremor, agitation, coma, ataxia, hypertension, slurred speech, confusion, dizziness, nausea, vomiting, and hallucinations. Critical symptoms, although 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.

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 prior to lavage is essential, and emesis is contraindicated.

To mitigate the risk of severe manifestations, it is crucial to obtain an electrocardiogram (ECG) and initiate cardiac monitoring immediately. The patient's airway should be protected, an intravenous line established, and gastric decontamination initiated. Continuous observation for signs of central nervous system (CNS) or respiratory depression, hypotension, cardiac dysrhythmias, conduction blocks, and seizures is necessary. Extended monitoring is warranted if any signs of toxicity arise during this period. It is important to note that monitoring plasma drug levels should not dictate patient management, and dialysis is likely ineffective due to the low plasma concentrations of cyclobenzaprine.

A maximal limb-lead QRS duration of ≥0.10 seconds may indicate the severity of the overdose. For patients exhibiting dysrhythmias or QRS widening, serum alkalinization to a pH of 7.45 to 7.55 should be initiated using intravenous sodium bicarbonate, with hyperventilation as needed. A pH greater than 7.60 or a pCO2 less than 20 mmHg is considered undesirable. Dysrhythmias that do not respond to sodium bicarbonate therapy or hyperventilation may be treated with lidocaine, bretylium, or phenytoin, while Type 1A and 1C antiarrhythmics (e.g., quinidine, disopyramide, procainamide) are generally contraindicated.

In cases of CNS depression, early intubation is recommended due to the risk of sudden deterioration. Seizures should be managed with benzodiazepines, or if ineffective, other anticonvulsants such as phenobarbital or phenytoin. The use of physostigmine is not recommended except for life-threatening symptoms unresponsive to other treatments, and only after consultation with a poison control center.

Given that overdosage is often intentional, there is a risk that patients may attempt suicide by other means during the recovery phase, making psychiatric referral a consideration. The management principles for both child and adult overdosages are similar, and it is strongly recommended that healthcare professionals consult the local poison control center for specific pediatric treatment guidance.

Nonclinical Toxicology

Reproduction studies conducted in rats, mice, and rabbits at doses up to 20 times the human dose have classified cyclobenzaprine hydrochloride as Pregnancy Category B, indicating no evidence of impaired fertility or teratogenic effects on the fetus. Additionally, 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. Furthermore, cyclobenzaprine did not demonstrate mutagenic activity in male mice at dose levels of up to 20 times the human dose.

In nonclinical 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, observations included pale and sometimes enlarged livers, along with dose-related hepatocyte vacuolation with 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 this time. At lower doses, these changes were not observed until after 26 weeks. Importantly, 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 pharmacology and toxicology studies indicate that cyclobenzaprine effectively reduces or abolishes skeletal muscle hyperactivity across several animal models. It has been determined 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 brain stem levels, although its action on spinal cord levels may also contribute to its overall skeletal muscle relaxant activity. Evidence suggests that the net effect of cyclobenzaprine is a reduction of tonic somatic motor activity, influencing both gamma (γ) and alpha (α) motor systems. Pharmacological studies in animals have shown 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. Additionally, cyclobenzaprine was associated with a slight to moderate increase in heart rate in animal studies.

Postmarketing Experience

Postmarketing experience has identified several adverse reactions reported voluntarily or through surveillance programs, with an incidence of less than 1% of patients in clinical trials involving 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 encompass 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 effects consist of local weakness. The Nervous System and Psychiatric category includes 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-related reactions include sweating, while special senses may experience ageusia and tinnitus. Urogenital effects reported are urinary frequency and/or retention.

Additionally, other reactions have been reported rarely for cyclobenzaprine hydrochloride, where a causal relationship could not be established, or have been noted for other tricyclic drugs. These include chest pain and edema in the Body as a Whole category; hypertension, myocardial infarction, heart block, and stroke in the Cardiovascular category; and paralytic ileus, tongue discoloration, stomatitis, and parotid swelling in the Digestive category. Endocrine reactions include inappropriate ADH syndrome, while Hematic and Lymphatic reactions consist of purpura, bone marrow depression, leukopenia, eosinophilia, and thrombocytopenia.

Metabolic, Nutritional, and Immune reactions may involve elevation and lowering of blood sugar levels, as well as weight gain or loss. Musculoskeletal reactions include myalgia. The Nervous System and Psychiatric category also reports 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, while skin reactions may involve photosensitization and alopecia. Urogenital effects 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 container that is not intended for household use. It must be dispensed with a child-resistant closure, as required, and stored in a tight, light-resistant container in accordance with USP guidelines.

Storage conditions require the product to be maintained at a temperature range of 20° to 25°C (68° to 77°F), with permissible excursions between 15° to 30°C (59° to 86°F) as defined by USP Controlled Room Temperature.

It is essential to keep this and all medications out of the reach of children.

Additional Clinical Information

Laboratory tests specific to cyclobenzaprine hydrochloride have not been detailed. 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.

Cyclobenzaprine hydrochloride is administered orally. Patients should be counseled on the potential impairment of mental and physical abilities when using this medication, particularly in conjunction with alcohol or other CNS depressants, which may affect tasks such as driving or operating machinery. Additionally, there is a risk of serotonin syndrome when cyclobenzaprine is used with certain medications, including SSRIs, SNRIs, TCAs, tramadol, bupropion, meperidine, verapamil, or MAO inhibitors. Patients should be informed of the signs and symptoms of serotonin syndrome and advised to seek immediate medical attention if they occur.

A post-marketing surveillance program involving 7,607 patients with acute musculoskeletal disorders indicated that the effectiveness of cyclobenzaprine hydrochloride was consistent with findings from controlled studies, while the overall incidence of adverse effects was lower.

FDA Insert (PDF)

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

View full prescribing information (PDF)