Cyclobenzaprine hydrochloride

Description

Cyclobenzaprine hydrochloride, USP is a white, crystalline tricyclic amine salt with the molecular formula C20H21N • HCl and a molecular weight of 311.9. It has a melting point of 217ºC and a pKa of 8.47 at 25ºC. The compound is freely soluble in water and alcohol, sparingly soluble in isopropanol, and insoluble in hydrocarbon solvents. Chemically, it is designated as 3-(5H-dibenzoa,dcyclohepten-5-ylidene)-N,N-dimethyl-1-propanamine hydrochloride. Cyclobenzaprine hydrochloride is supplied as 5 mg or 10 mg tablets for oral administration. Each tablet contains the following inactive ingredients: croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate, polyethylene glycol, pregelatinized starch (maize), and titanium dioxide. The 5 mg tablet also contains D&C yellow #10 aluminum lake and FD&C yellow #6 aluminum lake, while the 10 mg tablet contains yellow iron oxide.

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 should be utilized for short durations, specifically up to two or three weeks, as there is insufficient evidence to support its effectiveness for prolonged use. Muscle spasms related to acute, painful musculoskeletal conditions are typically of short duration, and specific therapy for extended periods is rarely necessary.

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

Dosage and Administration

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

It is important to note that the use of cyclobenzaprine hydrochloride tablets for periods longer than two to three weeks is not recommended. For patients who are hepatically impaired or elderly, 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 concurrent administration of 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, conduction disturbances, or congestive heart failure, due to the risk of exacerbating these conditions.

Additionally, use is contraindicated in patients with hyperthyroidism, as it may worsen the condition.

Warnings and Precautions

The use of cyclobenzaprine hydrochloride carries significant warnings and precautions that healthcare professionals must consider to ensure patient safety.

Warnings

The concomitant use of cyclobenzaprine hydrochloride with certain medications can lead to the development of serotonin syndrome, a potentially life-threatening condition. This risk is particularly heightened when cyclobenzaprine is used alongside selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), tramadol, bupropion, meperidine, verapamil, or monoamine oxidase inhibitors (MAOIs). It is crucial to note that the use of cyclobenzaprine hydrochloride in conjunction with MAO inhibitors is contraindicated.

Symptoms of serotonin syndrome may manifest as mental status changes, including confusion, agitation, and hallucinations; autonomic instability, such as diaphoresis, tachycardia, labile blood pressure, and hyperthermia; neuromuscular abnormalities, including tremor, ataxia, hyperreflexia, clonus, and muscle rigidity; and gastrointestinal symptoms like nausea, vomiting, and diarrhea. Should any of these symptoms occur, treatment with cyclobenzaprine hydrochloride and any concomitant serotonergic agents must be discontinued immediately, and supportive symptomatic treatment should be initiated.

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. Additionally, tricyclic antidepressants are known to cause arrhythmias, sinus tachycardia, and prolongation of conduction time, which can lead to myocardial infarction and stroke.

Furthermore, cyclobenzaprine hydrochloride may potentiate the effects of alcohol, barbiturates, and other central nervous system depressants, necessitating caution in patients who consume these substances.

General Precautions

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 taking anticholinergic medications.

In patients with hepatic impairment, the plasma concentration of cyclobenzaprine may be elevated, increasing susceptibility to the sedative effects of the drug. For patients with mild hepatic impairment, it is recommended to initiate treatment with a 5 mg dose and to titrate slowly. The use of cyclobenzaprine hydrochloride is not advised in patients with moderate to severe hepatic insufficiency due to insufficient data regarding safety in this population.

Healthcare professionals should remain vigilant regarding these warnings and precautions to mitigate risks associated with cyclobenzaprine hydrochloride therapy.

Side Effects

Patients receiving cyclobenzaprine hydrochloride 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% in the placebo group), dry mouth (21% at 5 mg, 32% at 10 mg, versus 7% in the placebo group), fatigue (6% at both 5 mg and 10 mg, 3% in the placebo group), and headache (5% at both dosages, 8% in the placebo group).

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 infections, 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 such as anaphylaxis, angioedema, pruritus, facial edema, urticaria, and rash have also been reported.

Nervous system and psychiatric 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 less frequent reactions involve 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 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 may involve decreased or increased libido, abnormal gait, delusions, aggressive behavior, paranoia, peripheral neuropathy, Bell’s palsy, alteration in EEG patterns, and extrapyramidal symptoms. Respiratory reactions such as dyspnea, skin reactions including photosensitization and alopecia, and urogenital issues like impaired urination, dilatation of the urinary tract, impotence, testicular swelling, gynecomastia, breast enlargement, and galactorrhea have also been reported.

A serious warning associated with cyclobenzaprine is the potential development of serotonin syndrome, particularly when used in combination with other medications such as selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), tramadol, bupropion, meperidine, verapamil, or MAO inhibitors. Symptoms of serotonin syndrome 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, the most common effects observed are drowsiness and tachycardia, with less frequent manifestations including tremor, agitation, coma, ataxia, hypertension, slurred speech, confusion, dizziness, nausea, vomiting, and hallucinations. Rare but critical manifestations of overdose may include cardiac arrest, chest pain, cardiac dysrhythmias, severe hypotension, seizures, and neuroleptic malignant syndrome. Clinically significant changes in the electrocardiogram, particularly in QRS axis or width, are indicators of cyclobenzaprine toxicity.

Drug Interactions

Cyclobenzaprine has the potential to cause life-threatening interactions when administered concurrently with monoamine oxidase (MAO) inhibitors. It is essential to exercise careful observation when cyclobenzaprine is used alongside other serotonergic medications due to the increased risk of serotonin syndrome.

Additionally, cyclobenzaprine hydrochloride may potentiate the effects of alcohol, barbiturates, and other central nervous system (CNS) depressants. Clinicians should consider monitoring patients for enhanced sedation and respiratory depression when these substances are co-administered.

Tricyclic antidepressants can interfere with the antihypertensive effects of guanethidine and similar agents, necessitating close monitoring of blood pressure in patients receiving this combination. Furthermore, tricyclic antidepressants may increase the risk of seizures in patients taking tramadol, warranting caution and potential dosage adjustments for those on both medications.

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 may exhibit increased plasma concentrations of cyclobenzaprine, which necessitates careful consideration when prescribing this medication. Due to this heightened concentration, geriatric patients are at an elevated risk for central nervous system (CNS) adverse events, including hallucinations and confusion. Additionally, there is a potential for cardiac events in this population, which may lead to falls or other serious complications.

It is important to recognize that elderly patients may also be susceptible to drug-drug and drug-disease interactions, further complicating their treatment regimen. 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 of cyclobenzaprine hydrochloride. The dosage should be titrated slowly upward, taking into account the patient's response and any potential adverse effects. Close monitoring is advised to ensure safety and efficacy in this vulnerable population.

Pregnancy

Pregnancy Category B. Reproduction studies have been conducted in rats, mice, and rabbits at doses up to 20 times the human dose, demonstrating no evidence of impaired fertility or harm to the fetus associated with cyclobenzaprine hydrochloride. 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 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

In cases of cyclobenzaprine hydrochloride overdosage, although rare, fatalities may occur. It is important to note that multiple drug ingestion, including alcohol, is frequently associated with deliberate overdose. Therefore, healthcare professionals should be vigilant in monitoring patients who present with signs of toxicity, as these symptoms can develop rapidly.

Signs and Symptoms of Overdosage

The most common effects observed in cyclobenzaprine overdose include drowsiness and tachycardia. Other less frequent manifestations may include tremor, agitation, coma, ataxia, hypertension, slurred speech, confusion, dizziness, nausea, vomiting, and hallucinations. Rare but critical symptoms can involve 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.

Recommended Actions and Management Procedures

Immediate hospital monitoring is essential upon suspicion of overdose. Initial management should include obtaining an electrocardiogram (ECG) and initiating cardiac monitoring to protect against potentially critical manifestations. It is crucial to secure the patient's airway, establish an intravenous line, and commence gastric decontamination, which should involve large volume gastric lavage followed by activated charcoal. If the patient is unconscious, airway protection must be prioritized before performing lavage, and emesis is contraindicated.

Observation should include continuous cardiac monitoring and assessment for signs of central nervous system (CNS) or respiratory depression, hypotension, cardiac dysrhythmias, conduction blocks, and seizures. 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.

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 necessary. In cases of CNS depression, early intubation is recommended due to the risk of sudden deterioration. Seizures should be managed with benzodiazepines, and if these are ineffective, alternative anticonvulsants such as phenobarbital or phenytoin may be utilized.

Physostigmine is not advised except for life-threatening symptoms that do not respond to other treatments, and its use should be in close consultation with a poison control center. The management principles for both child and adult overdosages are similar, and it is strongly recommended that physicians contact the local poison control center for specific pediatric treatment guidance.

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 accompanied by 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 the 26-week mark. At lower doses, these changes were not observed until after 26 weeks of treatment.

Cyclobenzaprine did not influence 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 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, suggesting no impairment of fertility.

Additionally, cyclobenzaprine did not exhibit mutagenic activity in male mice at dose levels up to 20 times the human dose, indicating a lack of mutagenic potential.

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.

Body as a Whole: Reports include syncope and malaise.

Cardiovascular: Adverse events such as tachycardia, arrhythmia, vasodilatation, palpitation, and hypotension have been noted.

Digestive: Reactions include vomiting, anorexia, diarrhea, gastrointestinal pain, gastritis, thirst, flatulence, edema of the tongue, and abnormal liver function, with rare cases of hepatitis, jaundice, and cholestasis.

Hypersensitivity: Instances of anaphylaxis, angioedema, pruritus, facial edema, urticaria, and rash have been documented.

Musculoskeletal: Local weakness has been reported.

Nervous System and Psychiatric: A range of neurological and psychiatric events has been observed, including 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: Increased sweating has been reported.

Special Senses: Ageusia and tinnitus have been noted.

Urogenital: Reports of urinary frequency and/or retention have been documented.

Additionally, other reactions have been reported rarely for cyclobenzaprine hydrochloride, where a causal relationship could not be established, or have been associated with other tricyclic drugs. These include:

Body as a Whole: Chest pain and edema.

Cardiovascular: Hypertension, myocardial infarction, heart block, and stroke.

Digestive: Paralytic ileus, tongue discoloration, stomatitis, and parotid swelling.

Endocrine: Inappropriate ADH syndrome.

Hematic and Lymphatic: Purpura, bone marrow depression, leukopenia, eosinophilia, and thrombocytopenia.

Metabolic, Nutritional and Immune: Elevation and lowering of blood sugar levels, as well as weight gain or loss.

Musculoskeletal: Myalgia has been reported.

Nervous System and Psychiatric: Decreased or increased libido, abnormal gait, delusions, aggressive behavior, paranoia, peripheral neuropathy, Bell’s palsy, alteration in EEG patterns, and extrapyramidal symptoms have been noted.

Respiratory: Dyspnea has been reported.

Skin: Instances of photosensitization and alopecia have been documented.

Urogenital: Impaired urination, dilatation of the urinary tract, impotence, testicular swelling, gynecomastia, breast enlargement, and galactorrhea have been observed.

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 the frequency and severity of adverse events associated with cyclobenzaprine may be increased, regardless of whether 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 to minimize potential risks.

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

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

Storage and Handling

The product is available in the following packaging configurations: 12 in 1 plastic bottle, 14 in 1 plastic bottle, and 21 in 1 plastic bottle.

It is recommended to store the product at a temperature range of 20° to 25°C (68° to 77°F). Temporary excursions are permissible between 15° to 30°C (59° to 86°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

Patients receiving cyclobenzaprine hydrochloride should be informed that the medication may impair mental and physical abilities necessary for performing hazardous tasks, including operating machinery or driving, particularly when used in conjunction with alcohol or other central nervous system (CNS) depressants. Clinicians should be aware that elderly patients may experience an increased frequency and severity of adverse events; therefore, it is recommended to initiate treatment with a 5 mg dose and to titrate slowly.

Additionally, patients must be cautioned about the potential risk of serotonin syndrome when cyclobenzaprine is used alongside other medications such as SSRIs, SNRIs, TCAs, tramadol, bupropion, meperidine, verapamil, or MAO inhibitors. They should be educated on the signs and symptoms of serotonin syndrome and advised to seek immediate medical attention if these symptoms occur.

FDA Insert (PDF)

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

View full prescribing information (PDF)