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 hydrochloride tablets, USP are formulated for oral administration and are available in strengths of 5 mg, 7.5 mg, and 10 mg. Each tablet contains inactive ingredients including colloidal silicon dioxide, croscarmellose sodium, lactose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide. The 5 mg tablet also contains FD&C yellow #6, while both the 5 mg and 10 mg tablets include iron oxide yellow.

Uses and Indications

Cyclobenzaprine hydrochloride tablets, USP are indicated as an adjunct to rest and physical therapy for the relief of muscle spasm associated with acute, painful musculoskeletal conditions. The therapeutic effects are characterized by the alleviation of muscle spasm and its associated signs and symptoms, including pain, tenderness, limitation of motion, and restrictions in activities of daily living.

This medication is intended for short-term use, specifically for periods not exceeding two to three weeks. There is insufficient evidence to support the effectiveness of cyclobenzaprine hydrochloride for prolonged use, as muscle spasms related to acute, painful musculoskeletal conditions are typically of short duration. Therefore, specific therapy for extended periods is seldom warranted.

Cyclobenzaprine hydrochloride tablets have not demonstrated efficacy in treating spasticity associated with cerebral or spinal cord diseases, nor are they indicated for use in children with cerebral palsy.

Dosage and Administration

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

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

For patients with hepatic impairment or elderly patients, consideration should be given to less frequent dosing 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, the use of this product is contraindicated in patients with hyperthyroidism, as it may worsen the condition.

Warnings and Precautions

The use of cyclobenzaprine hydrochloride carries significant warnings that healthcare professionals must be aware of to ensure patient safety.

Serotonin Syndrome Risk The concomitant use of cyclobenzaprine hydrochloride with other serotonergic agents, including selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), tramadol, bupropion, meperidine, verapamil, or monoamine oxidase (MAO) inhibitors, has been 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 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.

CNS Reactions and Cardiac Risks 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 potentially induce arrhythmias, sinus tachycardia, and prolongation of conduction time, which may lead to serious cardiovascular events such as myocardial infarction and stroke.

CNS Depressant Interactions Cyclobenzaprine may potentiate the effects of alcohol, barbiturates, and other central nervous system depressants, necessitating caution when prescribing this medication in conjunction with these substances.

Healthcare professionals are advised to monitor patients closely for any signs of adverse reactions and to educate them on the importance of reporting any unusual symptoms promptly.

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, 38% at 10 mg, compared to 10% for placebo), dry mouth (21% at 5 mg, 32% at 10 mg, versus 7% for placebo), fatigue (6% for both 5 mg and 10 mg, 3% for placebo), and headache (5% for both dosages, 8% for placebo).

Adverse reactions occurring with an incidence of 1% to 3% include abdominal pain, acid regurgitation, constipation, diarrhea, dizziness, nausea, irritability, decreased mental acuity, nervousness, upper respiratory infection, pharyngitis, fatigue/tiredness, asthenia, dyspepsia, unpleasant taste, blurred vision, and confusion.

Serious adverse reactions have also been reported. These include syncope and malaise under the body as a whole category, 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, abnormal liver function, and rare instances of hepatitis, jaundice, and cholestasis. Hypersensitivity reactions can manifest as anaphylaxis, angioedema, pruritus, facial edema, urticaria, and rash.

Nervous system and psychiatric adverse reactions are notable, including 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. Additional reactions may include local weakness in the musculoskeletal system, sweating in the skin category, and ageusia or tinnitus in the special senses.

Certain adverse reactions have an unknown causal relationship with the medication. These include chest pain and edema under the body as a whole, hypertension, myocardial infarction, heart block, and stroke in the cardiovascular category. Digestive issues such as paralytic ileus, tongue discoloration, stomatitis, and parotid swelling, as well as inappropriate ADH syndrome in the endocrine system, have also been noted. Hematic and lymphatic reactions may include purpura, bone marrow depression, leukopenia, eosinophilia, and thrombocytopenia. Metabolic, nutritional, and immune reactions can involve fluctuations in blood sugar levels and weight changes. Musculoskeletal complaints may include myalgia, while nervous system and psychiatric effects can encompass libido changes, abnormal gait, delusions, aggressive behavior, paranoia, peripheral neuropathy, Bell's palsy, alterations in EEG patterns, and extrapyramidal symptoms. Respiratory issues such as dyspnea, skin reactions like photosensitization and alopecia, and urogenital effects including impaired urination, urinary tract dilatation, impotence, testicular swelling, gynecomastia, breast enlargement, and galactorrhea have also been reported.

A significant warning associated with cyclobenzaprine is the risk of serotonin syndrome, which can occur when the drug is used in combination with other medications such as SSRIs, SNRIs, 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. Less frequent manifestations may include tremor, agitation, coma, ataxia, hypertension, slurred speech, confusion, dizziness, nausea, vomiting, and hallucinations. Rare but potentially critical manifestations of overdose include cardiac arrest, chest pain, cardiac dysrhythmias, severe hypotension, seizures, and neuroleptic malignant syndrome.

Drug Interactions

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

When administered concurrently with monoamine oxidase (MAO) inhibitors, cyclobenzaprine may lead to life-threatening interactions. It is crucial to monitor patients closely for signs of serotonin syndrome when cyclobenzaprine is used alongside other serotonergic agents.

Additionally, cyclobenzaprine has the potential to enhance the effects of alcohol, barbiturates, and other central nervous system (CNS) depressants. Caution is advised when prescribing these combinations, and dosage adjustments may be necessary to mitigate the risk of excessive sedation.

Tricyclic antidepressants also present notable interactions. They may inhibit the antihypertensive effects of guanethidine and similar compounds, necessitating careful blood pressure monitoring and possible dosage adjustments of antihypertensive medications. Furthermore, tricyclic antidepressants can increase the risk of seizures in patients taking tramadol, which requires vigilance in monitoring for seizure activity and potential dose modifications of tramadol.

No additional drug interactions or laboratory test interactions have been identified.

Packaging & NDC

The table below lists all NDC Code configurations of Cyclobenzaprine Hydrochloride, the U.S. brand-name prescription product. Columns show Packaging, Formulation Type, and Active Ingredient Strength.

Pediatric Use

Safety and effectiveness of cyclobenzaprine in pediatric patients below 15 years of age have not been established. Therefore, caution is advised when considering the use of this medication in this age group.

Geriatric Use

Elderly patients, defined as those aged 65 years and older, may experience increased plasma concentrations of cyclobenzaprine. A pharmacokinetic study demonstrated that mean steady-state area under the curve (AUC) values for cyclobenzaprine in this population were approximately 1.7 times higher than those observed in younger adults. Notably, elderly male subjects exhibited the most significant increase, with AUC values approximately 2.4 times higher, while elderly females showed a lesser increase of about 1.2 times.

Due to these pharmacokinetic differences, therapy with cyclobenzaprine hydrochloride in geriatric patients should be initiated at a lower dose of 5 mg, with careful and gradual titration to achieve the desired therapeutic effect. It is crucial to monitor these patients closely, as they may be at an elevated risk for central nervous system (CNS) adverse events, including hallucinations and confusion, as well as cardiac events that could lead to falls or other complications.

Cyclobenzaprine should only be prescribed to elderly patients when clearly indicated, given the increased frequency and severity of adverse events associated with its use in this demographic, whether or not they are taking concomitant medications. Caution is advised when considering cyclobenzaprine therapy in geriatric patients, and ongoing assessment of safety and efficacy is essential.

Pregnancy

Pregnancy Category B indicates that reproduction studies conducted in rats, mice, and rabbits at doses up to 20 times the human dose have shown no evidence of impaired fertility or harm to the fetus due to cyclobenzaprine. However, there are no adequate and well-controlled studies in pregnant women.

Due to the limitations of animal reproduction studies in predicting human response, cyclobenzaprine should be used during pregnancy only if clearly needed. Healthcare professionals are advised to weigh the potential benefits against any possible risks when considering the use of this medication in pregnant patients.

Lactation

It is not known whether this drug is excreted in human milk. Due to the structural similarity of cyclobenzaprine to tricyclic antidepressants, some of which are known to be excreted in human milk, caution should be exercised when administering cyclobenzaprine hydrochloride to lactating mothers. The potential effects on breastfed infants have not been established, and healthcare professionals should consider the risks and benefits of treatment in nursing women.

Renal Impairment

There is no specific information regarding renal impairment, dosage adjustments, special monitoring, or safety considerations for patients with reduced kidney function. Healthcare professionals should exercise caution and consider individual patient factors when treating patients with renal impairment, as the absence of detailed guidance necessitates careful clinical judgment.

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 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 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.

Recommended Actions and Management Procedures

Immediate hospital monitoring is essential upon suspicion of overdose. It is recommended that healthcare providers contact a poison control center for the most current treatment information. An electrocardiogram (ECG) should be obtained, and cardiac monitoring should be initiated without delay.

In managing the patient, it is crucial to protect the airway, establish an intravenous line, and commence gastric decontamination. 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 is unconscious, securing the airway prior to lavage is imperative, and emesis should be avoided.

Monitoring for signs of central nervous system (CNS) or respiratory depression, hypotension, cardiac dysrhythmias, conduction blocks, and seizures is necessary. If any signs of toxicity arise during this observation period, extended monitoring is warranted. It is important to note that plasma drug level monitoring 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 using intravenous sodium bicarbonate and hyperventilation should be initiated. If dysrhythmias do not respond to sodium bicarbonate therapy or hyperventilation, alternative treatments such as lidocaine, bretylium, or phenytoin may be considered.

In cases of CNS depression, early intubation is advised due to the risk of sudden deterioration. Seizures should be managed with benzodiazepines or other anticonvulsants if benzodiazepines prove ineffective. The use of physostigmine is not recommended except for life-threatening symptoms that have not responded to other therapies, and only after consulting with a poison control center.

The management principles for both child and adult overdosages are similar; however, it is strongly advised that healthcare professionals consult the local poison control center for specific pediatric treatment recommendations.

Nonclinical Toxicology

Reproduction studies conducted in rats, mice, and rabbits at doses up to 20 times the human dose have shown no evidence of impaired fertility or teratogenic effects associated with cyclobenzaprine. However, there are no adequate and well-controlled studies in pregnant women. Due to the limitations of animal reproduction studies in predicting human response, cyclobenzaprine should be used during pregnancy only if clearly needed.

At oral doses of up to 10 times the human dose, cyclobenzaprine did not adversely affect the reproductive performance or fertility of male or female rats. Additionally, cyclobenzaprine did not demonstrate mutagenic activity in male mice at dose levels of up to 20 times the human dose.

In long-term studies, rats treated with cyclobenzaprine hydrochloride for up to 67 weeks at doses approximately 5 to 40 times the maximum recommended human dose exhibited pale, sometimes enlarged livers, along with dose-related hepatocyte vacuolation and lipidosis. In higher dose groups, these microscopic changes were observed after 26 weeks, and even earlier in rats that died prior to this time. At lower doses, these changes were not evident until after 26 weeks.

Cyclobenzaprine did not affect the onset, incidence, or distribution of neoplasia in an 81-week study in mice or in a 105-week study in rats.

Pharmacological studies in animals have demonstrated that cyclobenzaprine reduces or abolishes skeletal muscle hyperactivity across several models. The effects of cyclobenzaprine are similar to those of structurally related tricyclic antidepressants, including reserpine antagonism, norepinephrine potentiation, potent peripheral and central anticholinergic effects, and sedation. Furthermore, cyclobenzaprine caused a slight to moderate increase in heart rate in animal studies.

Postmarketing Experience

A postmarketing 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 was comparable to that observed in double-blind controlled studies, with a lower overall incidence of adverse effects reported (see ADVERSE REACTIONS).

The following adverse reactions have been documented in postmarketing experience or reported 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.

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

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 SSRIs, SNRIs, 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, 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.

Healthcare providers should also note that the frequency and severity of adverse events associated with cyclobenzaprine use may be increased in elderly patients, whether or not they are taking other medications. For elderly patients, it is recommended that cyclobenzaprine hydrochloride be initiated at a 5 mg dose, with a gradual titration upward as needed.

Patients should 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 should only be used for short periods, typically up to two or three weeks, as there is insufficient evidence to support its effectiveness for longer durations. Finally, patients should be advised to take cyclobenzaprine exactly as prescribed and not to exceed the recommended dose.

Storage and Handling

The product is supplied in a tight, light-resistant container, compliant with USP standards, and equipped with a child-resistant closure. 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.

Additional Clinical Information

Patients using cyclobenzaprine 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. Clinicians should note that elderly patients are at an increased risk for adverse events, and it is recommended to initiate treatment with a 5 mg dose, titrating slowly as needed.

Additionally, patients must be informed about the potential risk of serotonin syndrome when cyclobenzaprine is used alongside other medications, including 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 Doc Rx. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)