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,dcyclohepten-5-ylidene)-N,N-dimethyl-1-propanamine hydrochloride.

Cyclobenzaprine hydrochloride is available in tablet form for oral administration in three strengths: 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, typically not exceeding two to three weeks, as there is insufficient evidence to support its effectiveness for prolonged treatment. Muscle spasms related to acute, painful musculoskeletal conditions are generally of limited duration, and specific therapy beyond this timeframe 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 initial dose of cyclobenzaprine hydrochloride tablets, USP is 5 mg administered three times a day. Based on individual patient response, the dose may be increased to 10 mg three times a day.

It is important to note that the use of cyclobenzaprine hydrochloride tablets, USP for periods longer than two or three weeks is not recommended.

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.

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

Use is also 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 monitoring is essential, particularly during the initiation of therapy or when adjusting dosages.

CNS Reactions and Tricyclic Antidepressant Similarities 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, which are closely related to cyclobenzaprine, have been associated with cardiovascular effects, including arrhythmias, sinus tachycardia, and prolongation of conduction time, which may lead to serious outcomes such as 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 urged to monitor patients closely for any adverse effects and to consider these warnings and precautions when prescribing cyclobenzaprine hydrochloride.

Side Effects

Patients receiving treatment with 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 and 39% at 10 mg), dry mouth (21% at 5 mg and 27% at 10 mg), fatigue (6% at both dosages), and headache (5% at both dosages).

Adverse reactions reported in 1% to 3% of patients encompass a variety of symptoms, including 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.

In addition to these, postmarketing experience has revealed additional adverse reactions occurring in less than 1% of patients. These include syncope and malaise (body as a whole), tachycardia, arrhythmia, vasodilatation, palpitation, and hypotension (cardiovascular), as well as vomiting, anorexia, gastrointestinal pain, gastritis, thirst, flatulence, edema of the tongue, abnormal liver function, and rare reports of hepatitis, jaundice, and cholestasis (digestive). Hypersensitivity reactions such as anaphylaxis, angioedema, pruritus, facial edema, urticaria, and rash have also been reported.

Nervous system and psychiatric adverse reactions include seizures, ataxia, vertigo, dysarthria, tremors, hypertonia, convulsions, muscle twitching, disorientation, insomnia, depressed mood, anxiety, agitation, psychosis, abnormal thinking and dreaming, hallucinations, excitement, paresthesia, diplopia, and serotonin syndrome. Other reactions include local weakness (musculoskeletal), sweating (skin), ageusia and tinnitus (special senses), and urinary frequency and/or retention (urogenital).

Certain adverse reactions have been reported rarely, with an unknown causal relationship. These include chest pain and edema (body as a whole), hypertension, myocardial infarction, heart block, and stroke (cardiovascular), as well as paralytic ileus, tongue discoloration, stomatitis, and parotid swelling (digestive). Endocrine effects such as inappropriate ADH syndrome, hematologic issues like purpura and bone marrow depression, and metabolic changes including fluctuations in blood sugar levels and weight changes have also been noted. Musculoskeletal complaints such as myalgia, various nervous system and psychiatric symptoms, respiratory issues like dyspnea, skin reactions including photosensitization and alopecia, and urogenital effects such as impaired urination and gynecomastia have been reported.

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

Drug Interactions

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

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

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

Tricyclic Antidepressants (TCAs) Tricyclic antidepressants may interfere with the antihypertensive effects of guanethidine and similar agents. Clinicians should be aware of this interaction and consider monitoring blood pressure in patients receiving both medications. Additionally, the concomitant use of TCAs and tramadol may increase the risk of seizures; therefore, careful patient assessment and monitoring are recommended when these drugs are prescribed together.

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, therapy with cyclobenzaprine hydrochloride 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. Furthermore, cyclobenzaprine hydrochloride should only be prescribed if clearly indicated for elderly patients, and less frequent dosing should be considered to mitigate the risk of adverse events, which tend to be more frequent and severe in this demographic. Regular monitoring for adverse effects is advised to ensure patient safety.

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

There is no specific information available regarding dosage adjustments, special monitoring, or safety considerations for patients with renal impairment. Healthcare professionals should exercise caution when prescribing to patients with reduced kidney function, as the absence of detailed guidance necessitates careful clinical judgment. Regular monitoring of renal function may be advisable in these patients to ensure safety and efficacy.

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

Overdosage with cyclobenzaprine hydrochloride, although rare, can lead to severe outcomes, including death. It is critical for healthcare professionals to recognize the signs and symptoms of toxicity, which may develop rapidly following an overdose. Immediate hospital monitoring is essential.

Clinical Manifestations

The most common effects observed in cases of cyclobenzaprine overdose include drowsiness and tachycardia. Other less frequent symptoms may manifest as tremor, agitation, coma, ataxia, hypertension, slurred speech, confusion, dizziness, nausea, vomiting, and hallucinations. Rarely, patients may experience critical conditions such as cardiac arrest, chest pain, cardiac dysrhythmias, severe hypotension, seizures, and neuroleptic malignant syndrome. Clinically significant changes in the electrocardiogram, particularly alterations in the QRS axis or width, serve as important indicators of cyclobenzaprine toxicity.

Management Procedures

In the event of an overdose, it is imperative to obtain an electrocardiogram (ECG) and initiate cardiac monitoring without delay 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 crucial, 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.

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

Physostigmine is not advised except for the treatment of life-threatening symptoms that do not respond to other therapies, and its use should only occur in close consultation with a poison control center. Additionally, it is important to consider that patients who overdose may have suicidal intentions and could attempt self-harm during the recovery phase.

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. Additionally, cyclobenzaprine did not adversely affect the onset, incidence, or distribution of neoplasia in an 81-week study in mice or a 105-week study in rats. At oral doses of up to 10 times the human dose, cyclobenzaprine did not impact the reproductive performance or fertility of male or female rats. Furthermore, cyclobenzaprine did not demonstrate mutagenic activity in male mice at dose levels of up to 20 times the human dose.

In 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.

Animal studies indicate that cyclobenzaprine effectively reduces or abolishes skeletal muscle hyperactivity across various models. It does not act at the neuromuscular junction or directly on skeletal muscle, but primarily exerts its effects within the central nervous system, particularly at brain stem levels, although its action on spinal cord levels may also contribute to its overall skeletal muscle relaxant activity. Evidence suggests that cyclobenzaprine reduces tonic somatic motor activity, influencing both gamma (γ) and alpha (α) motor systems. Pharmacological studies in animals have demonstrated similarities between the effects of cyclobenzaprine and those of structurally related tricyclic antidepressants, including reserpine antagonism, norepinephrine potentiation, potent peripheral and central anticholinergic effects, and sedation. Additionally, cyclobenzaprine has been associated with 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.

The following adverse reactions have been reported in post-marketing 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; serotonin syndrome. Skin: Sweating. Special Senses: Ageusia; tinnitus. Urogenital: Urinary frequency and/or retention.

Other reactions reported rarely for cyclobenzaprine hydrochloride, under circumstances 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/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 elderly patients, healthcare providers should recommend initiating treatment with a 5 mg dose of cyclobenzaprine hydrochloride and advise 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 plastic bottle containing 90 units. 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 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 CNS depressants. Clinicians should note that elderly patients are at an increased risk for adverse events, and treatment should begin with a 5 mg dose, which can be titrated 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 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)