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 has 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. Chemically, it is designated as 3-(5H–dibenzoa,dcyclohepten-5-ylidene)-N,N-dimethyl-1-propanamine hydrochloride.

Cyclobenzaprine HCl is available in two strengths for oral administration: 5 mg and 10 mg tablets. The 5 mg tablets contain the following inactive ingredients: lactose monohydrate, microcrystalline cellulose, pregelatinized starch, colloidal silicon dioxide, magnesium stearate, and opadry beige (which includes hypromellose 6cP, titanium dioxide, PEG 400, iron oxide yellow, and iron oxide red). The 10 mg tablets contain lactose monohydrate, microcrystalline cellulose, pregelatinized starch, colloidal silicon dioxide, magnesium stearate, and opadry yellow (which includes hypromellose 3cp, hypromellose 6cp, titanium dioxide, PEG 400, iron oxide yellow, and polysorbate 80).

Uses and Indications

Cyclobenzaprine HCl 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 only 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 HCl is not indicated for the treatment of spasticity associated with cerebral or spinal cord diseases, nor is it effective in pediatric patients with cerebral palsy.

Dosage and Administration

The recommended dose of cyclobenzaprine HCl 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 HCl tablets USP for periods longer than two or 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 concurrent administration of cyclobenzaprine or structurally similar tricyclic antidepressants.

The product is contraindicated in patients in the acute recovery phase of myocardial infarction, as well as those with arrhythmias, heart block or conduction disturbances, or congestive heart failure, due to the risk of exacerbating these conditions.

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

Warnings and Precautions

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

Serotonin Syndrome Risk The concomitant use of Cyclobenzaprine HCl 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 associated with the development of potentially life-threatening serotonin syndrome. The use of Cyclobenzaprine HCl in conjunction with MAO inhibitors is contraindicated. Symptoms of serotonin syndrome may manifest as mental status changes (e.g., confusion, agitation, hallucinations), autonomic instability (e.g., diaphoresis, tachycardia, labile blood pressure, hyperthermia), neuromuscular abnormalities (e.g., tremor, ataxia, hyperreflexia, clonus, muscle rigidity), and gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Should these symptoms occur, immediate discontinuation of Cyclobenzaprine HCl and any concomitant serotonergic agents is imperative, along with the initiation of supportive symptomatic treatment. If the clinical decision is made to continue treatment with Cyclobenzaprine HCl alongside other serotonergic drugs, careful observation is essential, particularly during the initiation of therapy or when increasing doses.

CNS Reactions Cyclobenzaprine HCl 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 Considerations Tricyclic antidepressants, which share a pharmacological profile with Cyclobenzaprine HCl, 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 HCl, particularly in patients with pre-existing cardiovascular conditions.

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

Precautions in Specific Populations Due to its atropine-like properties, Cyclobenzaprine HCl 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 HCl, 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 receiving treatment may experience a range of adverse reactions. The most common adverse reactions, occurring in more than 3% of participants, include drowsiness (29% at 5 mg, 38% at 10 mg, and 10% with placebo), dry mouth (21% at 5 mg, 32% at 10 mg, and 7% with placebo), fatigue (6% at both 5 mg and 10 mg, and 3% with placebo), and headache (5% at both 5 mg and 10 mg, and 8% with placebo).

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 infection, pharyngitis, fatigue/tiredness, asthenia, dyspepsia, unpleasant taste, blurred vision, and confusion.

Serious adverse reactions have also been reported. These include syncope and malaise as general reactions, as well as cardiovascular events such as tachycardia, arrhythmia, vasodilatation, palpitation, and hypotension. Digestive system reactions may include vomiting, anorexia, gastrointestinal pain, gastritis, thirst, flatulence, edema of the tongue, and abnormal liver function, with rare reports of hepatitis, jaundice, and cholestasis. Hypersensitivity reactions can manifest as anaphylaxis, angioedema, pruritus, facial edema, urticaria, and rash. Musculoskeletal reactions may include local weakness.

Nervous system and psychiatric adverse reactions are notable and may 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, and diplopia. Skin reactions may involve sweating, while special senses may be affected by ageusia and tinnitus. Urogenital reactions can include urinary frequency and/or retention.

Rare adverse reactions, for which a causal relationship is unknown, include chest pain and edema as general reactions, hypertension, myocardial infarction, heart block, and stroke in the cardiovascular category. Digestive reactions may involve paralytic ileus, tongue discoloration, stomatitis, and parotid swelling. Endocrine reactions can include inappropriate ADH syndrome. Hematic and lymphatic reactions may present as 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 may include myalgia, while nervous system and psychiatric reactions can manifest as 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, and skin reactions can involve photosensitization and alopecia. Urogenital reactions may include impaired urination, dilatation of the urinary tract, impotence, testicular swelling, gynecomastia, breast enlargement, and galactorrhea.

A significant warning regarding serotonin syndrome is noted, as the development of this potentially life-threatening condition has been reported with Cyclobenzaprine HCl when used 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 HCl is associated with significant drug interactions that warrant careful consideration.

Monoamine Oxidase Inhibitors (MAOIs) and Serotonergic Drugs Cyclobenzaprine HCl may lead to life-threatening interactions when administered concurrently with MAO inhibitors. It is essential to monitor patients closely for signs of serotonin syndrome when cyclobenzaprine is used alongside other serotonergic medications.

CNS Depressants The concomitant use of cyclobenzaprine HCl with alcohol, barbiturates, and other central nervous system (CNS) depressants may enhance the sedative effects of these substances. Caution is advised, 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 agents. Clinicians should consider monitoring blood pressure and adjusting antihypertensive therapy as needed. Additionally, tricyclic antidepressants can increase the risk of seizures in patients taking tramadol, necessitating careful patient evaluation and potential dosage modifications for either medication.

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, defined as those aged 65 years and older, may experience increased plasma concentrations of cyclobenzaprine compared to younger adults. Specifically, mean steady-state area under the curve (AUC) values in this population are approximately 1.7 times higher than those observed in younger individuals. Notably, elderly male subjects exhibit the most significant increase, with plasma concentrations approximately 2.4 times higher than their younger counterparts, while elderly females show a lesser increase of about 1.2 times.

Due to these elevated plasma levels, elderly patients may be at a greater risk for central nervous system (CNS) adverse events, including hallucinations and confusion. Additionally, there is an increased risk of cardiac events that may lead to falls or other complications, as well as potential drug-drug and drug-disease interactions.

Given these considerations, therapy with cyclobenzaprine HCl in geriatric patients should be approached with caution. It is recommended that treatment be initiated at a lower dose of 5 mg, with careful and gradual titration as needed. Cyclobenzaprine HCl should only be prescribed to elderly patients when clearly indicated, and healthcare providers should closely monitor for the frequency and severity of adverse events, which tend to be heightened in this demographic.

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 HCl. 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 HCl 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 HCl 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

In cases of cyclobenzaprine HCl overdosage, although rare, fatalities may occur. It is important to note that multiple drug ingestion, including alcohol, is frequently associated with deliberate cyclobenzaprine overdose.

Signs and Symptoms Toxicity symptoms can manifest rapidly following an overdose, necessitating immediate hospital monitoring. The most prevalent effects include drowsiness and tachycardia. Other less common symptoms may involve tremor, agitation, coma, ataxia, hypertension, slurred speech, confusion, dizziness, nausea, vomiting, and hallucinations. Critical manifestations, 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 QRS axis or width, serve as important indicators of cyclobenzaprine toxicity.

Management Procedures Upon suspicion of an overdose, it is imperative to obtain an electrocardiogram (ECG) and initiate cardiac monitoring to safeguard against potentially critical manifestations. The patient's airway should be protected, an intravenous line established, and gastric decontamination initiated. 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's consciousness is impaired, securing the airway prior to lavage is essential, and emesis is contraindicated.

Observation should include cardiac monitoring and vigilance for signs of central nervous system (CNS) or respiratory depression, hypotension, cardiac dysrhythmias or 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 of no benefit due to the low plasma concentrations of the drug.

For patients exhibiting dysrhythmias and/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. In cases of CNS depression, early intubation is recommended due to the risk of abrupt deterioration. Seizures should be managed with benzodiazepines, or if ineffective, alternative anticonvulsants such as phenobarbital or phenytoin may be utilized.

Physostigmine is not advised except for the treatment of life-threatening symptoms unresponsive to other therapies, and only after consultation with a poison control center. Given that overdosage is often intentional, there is a risk of patients attempting suicide by other means during the recovery phase; thus, a psychiatric referral may be appropriate.

The management principles for both child and adult overdosages are similar. It is strongly recommended that physicians contact the local poison control center for specific pediatric treatment guidance.

Nonclinical Toxicology

In studies evaluating the nonclinical toxicology of cyclobenzaprine, no relevant information regarding teratogenic effects was provided. However, non-teratogenic effects were observed in reproductive performance and fertility assessments. Specifically, 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.

In long-term studies involving rats treated with cyclobenzaprine HCl for up to 67 weeks at doses ranging from approximately 5 to 40 times the maximum recommended human dose, notable findings included pale and occasionally enlarged livers, along with dose-related hepatocyte vacuolation and lipidosis. In the higher dose groups, these microscopic changes were evident after 26 weeks, and in some cases, even earlier in rats that died prior to the 26-week mark. Conversely, at lower doses, these changes were not observed until after 26 weeks of treatment.

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

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:

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. Skin: Sweating. Special Senses: Ageusia; tinnitus. Urogenital: Urinary frequency and/or retention.

Additionally, other reactions have been reported rarely for cyclobenzaprine HCl under circumstances where a causal relationship could not be established or reported for other tricyclic drugs, and are included for alerting information to physicians:

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

Patients should be cautioned about the risk of serotonin syndrome associated with the concomitant use of Cyclobenzaprine Hydrochloride and other medications, including selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), tramadol, bupropion, meperidine, verapamil, or MAO inhibitors. Healthcare providers should advise patients to be aware of the signs and symptoms of serotonin syndrome, such as confusion, rapid heart rate, and severe muscle rigidity, and instruct them to seek medical care immediately if they experience these symptoms.

It is important to inform patients that Cyclobenzaprine HCl, 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. Providers should emphasize the need for caution in these situations.

In elderly patients, the frequency and severity of adverse events associated with the use of Cyclobenzaprine may be increased, whether or not other medications are being taken concurrently. Therefore, healthcare providers should recommend initiating treatment with a 5 mg dose for elderly patients and advise a slow upward titration based on individual tolerance and response.

Patients should also be cautioned about the potential for drowsiness and advised not to drive or operate heavy machinery until they are aware of how Cyclobenzaprine affects them. Additionally, it is essential to inform patients that Cyclobenzaprine is not recommended for use in children under 15 years of age, as safety and effectiveness in this population have not been established.

Finally, healthcare providers should advise patients to use Cyclobenzaprine HCl only for short periods, typically up to two or three weeks, since adequate evidence supporting effectiveness for prolonged use is lacking.

Storage and Handling

The product is supplied in accordance with the National Drug Code (NDC) specifications. It should be stored at a temperature range of 20° to 25°C (68° to 77°F), in compliance with USP Controlled Room Temperature guidelines. Proper storage conditions are essential to maintain the integrity and efficacy of the product.

Additional Clinical Information

Patients using cyclobenzaprine HCl should be aware that the medication may impair mental and physical abilities, particularly when combined with alcohol or other central nervous system (CNS) depressants, which can affect tasks such as operating machinery or driving. In elderly patients, the incidence and severity of adverse events may be heightened; therefore, it is recommended that treatment begins with a 5 mg dose, which should be titrated slowly.

Clinicians should counsel patients on the risk of serotonin syndrome when cyclobenzaprine is used alongside other medications, including selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), tramadol, bupropion, meperidine, verapamil, or monoamine oxidase inhibitors (MAOIs). Patients should be informed about the signs and symptoms of serotonin syndrome and advised to seek immediate medical attention if they experience any related symptoms.

FDA Insert (PDF)

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

View full prescribing information (PDF)