Cyclobenzaprine hydrochloride

Description

Cyclobenzaprine hydrochloride, USP is a white to off-white, odorless, crystalline powder with the molecular formula C20H21N•HCl and a molecular weight of 311.85. It has a melting point between 215°C to 219°C and a pKa of 8.47. The compound is freely soluble in water, alcohol, and methanol; sparingly soluble in isopropanol; slightly soluble in chloroform and methylene chloride; and insoluble in n-Hexane. Chemically, it is designated as 3-(5H-Dibenzoa,d cyclohepten-5-ylidene)-N,N-dimethyl-1-propanamine hydrochloride.

Cyclobenzaprine hydrochloride is available in tablet form for oral administration, with strengths of 5 mg, 7.5 mg, and 10 mg. The 5 mg tablets contain inactive ingredients including colloidal silicon dioxide, croscarmellose sodium, hypromellose, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, talc, titanium dioxide, and triacetin. The 7.5 mg tablets include the same inactive ingredients as the 5 mg tablets, with the addition of yellow iron oxide. The 10 mg tablets contain colloidal silicon dioxide, croscarmellose sodium, FD&C Blue No. 2 Aluminium Lake, hypromellose, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, talc, titanium dioxide, triacetin, and 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 benefits 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 rarely 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 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 exceeding two to three weeks is not recommended. Additionally, 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 the product.

Concomitant use with monoamine oxidase (MAO) inhibitors or within 14 days of their discontinuation is contraindicated due to the risk of hyperpyretic crisis, seizures, and fatalities associated with cyclobenzaprine or structurally similar tricyclic antidepressants.

The product should not be used in the acute recovery phase of myocardial infarction, or in patients with arrhythmias, heart block, conduction disturbances, or congestive heart failure, as these conditions may exacerbate cardiovascular risks.

Additionally, the product is contraindicated in patients with hyperthyroidism.

Warnings and Precautions

The use of cyclobenzaprine hydrochloride necessitates careful consideration of potential risks associated with its administration, particularly concerning serotonin syndrome and interactions with other medications.

Serotonin Syndrome Risk The concomitant use of cyclobenzaprine hydrochloride with 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 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, immediate discontinuation of cyclobenzaprine hydrochloride 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 hydrochloride alongside other serotonergic drugs, careful observation is essential, particularly during the initiation of therapy or when increasing dosages.

CNS Reactions and Tricyclic Antidepressant Association Cyclobenzaprine hydrochloride shares structural similarities with tricyclic antidepressants such as amitriptyline and imipramine. In short-term studies involving indications other than muscle spasm associated with acute musculoskeletal conditions, and typically at doses exceeding those recommended for muscle spasm, serious central nervous system reactions akin to those observed with tricyclic antidepressants have been reported.

Cardiovascular Considerations Tricyclic antidepressants, with which cyclobenzaprine is closely related, have been associated with cardiovascular risks, including arrhythmias, sinus tachycardia, and prolongation of conduction time, which may lead to myocardial infarction and stroke.

CNS Depressant Interactions Cyclobenzaprine hydrochloride may potentiate the effects of alcohol, barbiturates, and other central nervous system depressants. Caution is advised when prescribing cyclobenzaprine hydrochloride to patients who are concurrently using these substances, as the risk of enhanced sedation and respiratory depression may be increased.

Healthcare professionals are encouraged to monitor patients closely for any signs of adverse reactions and to conduct appropriate laboratory tests as necessary to ensure safe use of 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, 39% at 10 mg, and 10% in the placebo group), dry mouth (21% at 5 mg, 27% at 10 mg, and 7% in the placebo group), fatigue (6% at both 5 mg and 10 mg, and 3% in the placebo group), and headache (5% at both 5 mg and 10 mg, and 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.

Serious adverse reactions have also been noted. 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 involve 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.

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. Additional reactions may involve local weakness in the musculoskeletal system, sweating in the skin, ageusia and tinnitus in the special senses, and urinary frequency and/or retention in the urogenital system.

Certain adverse reactions have been reported where a causal relationship is unknown. These include chest pain and edema as general reactions, hypertension, myocardial infarction, heart block, and stroke in the cardiovascular system. Digestive system reactions may include paralytic ileus, tongue discoloration, stomatitis, and parotid swelling. Endocrine reactions such as inappropriate ADH syndrome, hematologic reactions including purpura, bone marrow depression, leukopenia, eosinophilia, and thrombocytopenia, as well as metabolic and nutritional changes like elevation and lowering of blood sugar levels, and weight gain or loss have also been noted. Musculoskeletal reactions may involve myalgia, while nervous system and psychiatric reactions can include decreased or increased libido, abnormal gait, delusions, aggressive behavior, paranoia, peripheral neuropathy, Bell's palsy, alteration in EEG patterns, and extrapyramidal symptoms. Respiratory reactions may present as dyspnea, while skin reactions can include photosensitization and alopecia. Urogenital reactions may involve impaired urination, dilatation of the urinary tract, impotence, testicular swelling, gynecomastia, breast enlargement, and galactorrhea.

It is important to note that the development of a potentially life-threatening serotonin syndrome has been reported with cyclobenzaprine hydrochloride when used in combination with other drugs. Symptoms may include mental status changes, autonomic instability, neuromuscular abnormalities, and gastrointestinal symptoms.

Drug Interactions

Cyclobenzaprine hydrochloride is associated with several significant drug interactions that warrant careful consideration.

Interactions with MAO Inhibitors and Serotonergic Drugs Cyclobenzaprine hydrochloride may lead to life-threatening interactions when administered concurrently with monoamine oxidase inhibitors (MAOIs). It is essential to monitor patients closely when cyclobenzaprine is used in conjunction with serotonergic agents, including selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), tramadol, bupropion, meperidine, or verapamil.

CNS Depressants The use of cyclobenzaprine hydrochloride may potentiate the effects of alcohol, barbiturates, and other central nervous system (CNS) depressants. Caution is advised, and dosage adjustments may be necessary to mitigate the risk of excessive sedation or respiratory depression.

Interactions with Tricyclic Antidepressants Tricyclic antidepressants may interfere with the antihypertensive effects of guanethidine and similar compounds. Additionally, these antidepressants can increase the risk of seizures in patients taking tramadol. Monitoring for blood pressure changes and seizure activity is recommended when these medications are used together.

No information regarding drug and laboratory test interactions has been provided.

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 experience increased plasma concentrations of cyclobenzaprine, with pharmacokinetic studies indicating that mean steady-state AUC values in individuals aged 65 years and older are approximately 1.7 times higher than those observed in younger adults. Notably, elderly male subjects exhibited the most significant increase, with levels approximately 2.4 times higher, while elderly females showed a lesser increase of about 1.2 times.

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

In light of these considerations, it is recommended that therapy with cyclobenzaprine hydrochloride in geriatric patients be initiated at a lower dose of 5 mg, with careful and gradual titration as needed. The frequency and severity of adverse events associated with cyclobenzaprine use, whether alone or in conjunction with other medications, are increased in elderly patients. Therefore, cyclobenzaprine should be prescribed only when clearly indicated in this demographic, with close monitoring for adverse effects.

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 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 of these patients.

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 considered as part of standard clinical practice.

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 of cyclobenzaprine. 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, should be closely monitored as indicators of toxicity.

Management Procedures

Immediate hospital monitoring is essential upon suspicion of overdose. An electrocardiogram (ECG) should be obtained, and cardiac monitoring should be initiated to protect against potentially critical manifestations. The patient's airway must be secured, and an intravenous line established. Gastrointestinal decontamination is crucial and should include large volume gastric lavage followed by activated charcoal. If the patient is unconscious, airway protection is paramount prior to performing lavage, and emesis is contraindicated.

Observation should include cardiac monitoring and vigilance for signs of central nervous system (CNS) or respiratory depression, hypotension, cardiac dysrhythmias, 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.

In cases where dysrhythmias or QRS widening is present, serum alkalinization to a pH of 7.45 to 7.55 using intravenous sodium bicarbonate, along with hyperventilation, should be initiated. For patients exhibiting CNS depression, early intubation is recommended due to the risk of abrupt deterioration. Seizures should be managed with benzodiazepines or other anticonvulsants if benzodiazepines prove ineffective.

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. It is also strongly recommended that physicians contact the local poison control center for specific pediatric treatment protocols in cases of overdose.

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 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, the use of this drug during pregnancy should be considered 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.

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.

Cyclobenzaprine did not influence the onset, incidence, or distribution of neoplasia in an 81-week study 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.

Pharmacological studies in animals indicate that cyclobenzaprine effectively reduces or abolishes skeletal muscle hyperactivity through actions primarily within the central nervous system, particularly at the brain stem level, rather than at the neuromuscular junction or directly on skeletal muscle. The drug's effects are similar to those of structurally related tricyclic antidepressants, demonstrating reserpine antagonism, norepinephrine potentiation, significant peripheral and central anticholinergic effects, and sedation. Cyclobenzaprine was also observed to cause a slight to moderate increase in heart rate in animal models.

Postmarketing Experience

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

The following adverse reactions have been documented in post-marketing experience or occurred in less than 1% of patients during clinical trials with the 10 mg tablet:

Body as a Whole: Syncope; malaise. Cardiovascular: Tachycardia; arrhythmia; vasodilatation; palpitation; hypotension. Digestive: Vomiting; anorexia; diarrhea; gastrointestinal pain; gastritis; thirst; flatulence; edema of the tongue; abnormal liver function; rare reports of hepatitis, jaundice, and cholestasis. Hypersensitivity: Anaphylaxis; angioedema; pruritus; facial edema; urticaria; rash. Musculoskeletal: Local weakness. Nervous System and Psychiatric: Seizures; ataxia; vertigo; dysarthria; tremors; hypertonia; convulsions; muscle twitching; disorientation; insomnia; depressed mood; abnormal sensations; anxiety; agitation; psychosis; abnormal thinking and dreaming; hallucinations; excitement; paresthesia; diplopia; serotonin syndrome. Skin: Sweating. Special Senses: Ageusia; tinnitus. Urogenital: Urinary frequency and/or retention.

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

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

Patient Counseling

Healthcare providers should advise patients that cyclobenzaprine hydrochloride, particularly when used in conjunction with alcohol or other central nervous system (CNS) depressants, may impair their mental and physical abilities necessary for performing hazardous tasks, including operating machinery or driving a motor vehicle.

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

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

It is essential for healthcare providers to inform patients about the signs and symptoms of serotonin syndrome, emphasizing the importance of seeking immediate medical attention if they experience any of these symptoms.

Storage and Handling

The product is supplied in various packaging configurations, including plastic bottles and blister packs. It is essential to store the product at a temperature range of 20° to 25°C (68° to 77°F), in accordance with USP Controlled Room Temperature guidelines. Proper storage conditions must be maintained to ensure the integrity and efficacy of the product.

Additional Clinical Information

Patients receiving cyclobenzaprine hydrochloride should be informed about the potential impairment of mental and physical abilities, particularly when used in conjunction with alcohol or other central nervous system (CNS) depressants. This impairment may affect the performance of hazardous tasks, including operating machinery or driving.

Clinicians should exercise caution when prescribing cyclobenzaprine to elderly patients, as they may experience an increased frequency and severity of adverse events. It is recommended to initiate treatment in this population with a 5 mg dose, titrating slowly as needed. Additionally, patients must be made aware of the 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 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)