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. It has a melting point of 217°C and a pKa of 8.47 at 25°C. This 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. Cyclobenzaprine hydrochloride tablets, USP, intended for oral administration, are available in strengths of 5 mg, 7.5 mg, and 10 mg. Each tablet contains the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, lactose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide. The 5 mg tablet also contains FD&C yellow #6, while both the 5 mg and 10 mg tablets include iron oxide yellow.

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 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 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, USP, for periods longer than two or three weeks is not recommended.

For patients with hepatic impairment or elderly patients, 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 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, use is contraindicated in patients with hyperthyroidism, as it may exacerbate the condition.

Warnings and Precautions

The use of cyclobenzaprine hydrochloride is associated with significant warnings that healthcare professionals must consider 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, has been linked to the development of potentially life-threatening serotonin syndrome. 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, treatment with cyclobenzaprine hydrochloride and any concomitant serotonergic agents must be discontinued immediately, and supportive symptomatic treatment should be initiated. 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 the dosage.

CNS Reactions Cyclobenzaprine is structurally related to tricyclic antidepressants such as amitriptyline and imipramine. In short-term studies involving indications other than muscle spasm associated with acute musculoskeletal conditions, and typically at doses higher than 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 share pharmacological properties with cyclobenzaprine, have been associated with arrhythmias, sinus tachycardia, and prolongation of conduction time, potentially leading to myocardial infarction and stroke.

CNS Depressant Interactions Cyclobenzaprine may potentiate the effects of alcohol, barbiturates, and other central nervous system depressants, necessitating caution when prescribing to patients who consume these substances.

Healthcare professionals are advised to monitor patients closely for any signs of adverse reactions, particularly when cyclobenzaprine hydrochloride is used in combination with other medications that may increase the risk of serotonin syndrome or CNS depression.

Side Effects

Common adverse reactions observed in clinical studies include drowsiness, which occurred in 39% of participants, and dry mouth, reported in 27% of participants. Dizziness was noted in 11% of subjects. In comparison, the incidence of these reactions in a surveillance program was lower, with drowsiness at 16%, dry mouth at 7%, and dizziness at 3%. Other common adverse reactions with an incidence greater than 3% include fatigue (6% for both 5 mg and 10 mg doses) and headache (5% for both doses).

Adverse reactions occurring with an incidence between 1% and 3% 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.

Postmarketing experience has revealed additional adverse reactions occurring at 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, abnormal sensations, 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 where a causal relationship is unknown. 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 reactions 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 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, alteration in EEG patterns, and extrapyramidal symptoms. Respiratory reactions include dyspnea, skin reactions such as photosensitization and alopecia, and urogenital issues like impaired urination, dilatation of the urinary tract, impotence, testicular swelling, gynecomastia, breast enlargement, and galactorrhea.

A serious warning regarding serotonin syndrome is warranted, as this potentially life-threatening condition has been reported when cyclobenzaprine hydrochloride is used in combination with other drugs, including 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 critical manifestations can include cardiac arrest, chest pain, cardiac dysrhythmias, severe hypotension, seizures, and neuroleptic malignant syndrome.

Drug Interactions

Cyclobenzaprine has several notable drug interactions that require careful consideration.

Monoamine Oxidase Inhibitors (MAOIs) Cyclobenzaprine may cause life-threatening interactions when used in conjunction with MAO inhibitors. It is imperative to avoid this combination due to the potential for severe adverse effects.

Serotonergic Drugs Postmarketing reports indicate that the concurrent use 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. Clinicians should exercise caution and closely monitor patients when initiating or increasing doses of cyclobenzaprine in combination with these medications.

Central Nervous System (CNS) Depressants Cyclobenzaprine may potentiate the effects of alcohol, barbiturates, and other CNS depressants. Patients should be advised to avoid or limit the use of these substances while taking cyclobenzaprine to reduce the risk of enhanced sedation and respiratory depression.

Tricyclic Antidepressants and Antihypertensive Agents Tricyclic antidepressants may interfere with the antihypertensive effects of guanethidine and similar compounds. Clinicians should consider monitoring blood pressure and adjusting antihypertensive therapy as necessary when these medications are used concurrently.

Tricyclic Antidepressants and Seizure Risk The use of tricyclic antidepressants may increase the risk of seizures in patients taking tramadol. It is advisable to assess the risk-benefit ratio when prescribing these medications together and to monitor for any signs of seizure activity.

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 times higher than those observed in younger adults. Notably, elderly male subjects exhibited the most significant increase, with mean levels approximately 2.4 times higher, while elderly females showed a lesser increase of about 1.2 times.

Given these pharmacokinetic differences, therapy with cyclobenzaprine hydrochloride in geriatric patients should be initiated at a lower dose of 5 mg, with a gradual titration to achieve the desired therapeutic effect. It is essential to monitor these patients closely, as they 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.

Furthermore, it is advisable to consider less frequent dosing regimens for elderly patients to mitigate potential risks. Cyclobenzaprine should only be prescribed in this population when clearly indicated, ensuring that the benefits outweigh the risks associated with its use.

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

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 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 fatal outcomes. It is important to note that multiple drug ingestion, including alcohol, is frequently associated with deliberate cyclobenzaprine overdose.

Signs and Symptoms of Overdosage

Toxicity symptoms may manifest rapidly following an overdose, necessitating immediate hospital monitoring. The acute oral LD50 of cyclobenzaprine is approximately 338 mg/kg in mice and 425 mg/kg in rats. The most prevalent effects observed in cases of overdose include drowsiness and tachycardia. Other less common symptoms may include tremor, agitation, coma, ataxia, hypertension, slurred speech, confusion, dizziness, nausea, vomiting, and hallucinations. Rare but critical manifestations can involve 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, serve as important indicators of cyclobenzaprine toxicity.

Management of Overdosage

Given the complexity and evolving nature of overdose management, it is strongly recommended that healthcare professionals contact a poison control center for the most current treatment information. All patients suspected of cyclobenzaprine overdose should undergo gastrointestinal decontamination, which includes large volume gastric lavage followed by the administration of activated charcoal. In cases where consciousness is impaired, securing the airway prior to lavage is essential, and emesis is contraindicated.

To mitigate the risk of severe manifestations, an electrocardiogram (ECG) should be obtained, and cardiac monitoring should commence immediately. It is crucial to protect the patient's airway, establish an intravenous line, and initiate gastric decontamination. Continuous observation for signs of central nervous system (CNS) or respiratory depression, hypotension, cardiac dysrhythmias, conduction blocks, and seizures is necessary. If any signs of toxicity arise during this monitoring period, extended observation is warranted. 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, along 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, and 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 these are ineffective, alternative anticonvulsants such as phenobarbital or phenytoin may be utilized. The use of physostigmine is not advised except for life-threatening symptoms unresponsive to other treatments, and only after consultation with a poison control center.

Considerations for Recovery

As overdosage is often intentional, there is a risk that patients may attempt suicide by other means during the recovery phase. Therefore, psychiatric referral may be appropriate. The management principles for both child and adult overdosages are similar; however, it is strongly advised that physicians consult the local poison control center for specific pediatric treatment recommendations.

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 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 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.

Pharmacological studies in animals have indicated that the effects of cyclobenzaprine are similar to those of structurally related tricyclic antidepressants. These effects include reserpine antagonism, norepinephrine potentiation, potent peripheral and central anticholinergic effects, and sedation. Cyclobenzaprine was also observed to cause 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 include anaphylaxis, angioedema, pruritus, facial edema, urticaria, and rash. Musculoskeletal reactions noted are local weakness. In the Nervous System and Psychiatric category, seizures, ataxia, vertigo, dysarthria, tremors, hypertonia, convulsions, muscle twitching, disorientation, insomnia, depressed mood, abnormal sensations, anxiety, agitation, psychosis, abnormal thinking and dreaming, hallucinations, excitement, paresthesia, diplopia, and serotonin syndrome have been reported.

Skin reactions include sweating, while special senses reactions consist of ageusia and tinnitus. Urogenital reactions reported are urinary frequency and/or retention.

Additionally, other reactions have been reported rarely for cyclobenzaprine under circumstances where a causal relationship could not be established, or reported 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. Hematic and Lymphatic reactions consist of 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 category, decreased or increased libido, abnormal gait, delusions, aggressive behavior, paranoia, peripheral neuropathy, Bell's palsy, alteration in EEG patterns, and extrapyramidal symptoms have been reported. Respiratory reactions include dyspnea. Skin reactions consist of photosensitization and alopecia. Urogenital reactions reported are impaired urination, dilatation of the urinary tract, impotence, testicular swelling, gynecomastia, breast enlargement, and galactorrhea.

Patient Counseling

Healthcare providers should advise patients that cyclobenzaprine, 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, with a gradual titration to higher doses as appropriate.

Patients should also be cautioned about the potential risk of serotonin syndrome when cyclobenzaprine hydrochloride is used concurrently with other medications, such as selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), tramadol, bupropion, meperidine, verapamil, or monoamine oxidase inhibitors (MAOIs).

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

Storage and Handling

The product is supplied in a tight, light-resistant container, as defined by the United States Pharmacopeia (USP), and is equipped with a child-resistant closure to ensure safety. 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 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.

The recommended dosage for most patients is 5 mg taken three times daily, with the possibility of increasing to 10 mg three times daily based on individual response. Prolonged use beyond two to three weeks is not advised. Patients should be counseled on the potential for impaired mental and physical abilities when cyclobenzaprine is used in conjunction with alcohol or other CNS depressants, particularly regarding tasks such as operating machinery or driving. 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 instructed to seek immediate medical attention if they occur.

A postmarketing surveillance program involving 7,607 patients with acute musculoskeletal disorders indicated that the effectiveness of cyclobenzaprine was consistent with findings from controlled studies, while 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 SOLA Pharmaceuticals, LLC. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)