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. When aqueous solutions are made alkaline, the free base separates.

Chemically, cyclobenzaprine hydrochloride is designated as 3-(5H–dibenzoa,dcyclohepten-5-ylidene)-N,N-dimethyl-1-propanamine hydrochloride. The drug is supplied as a 10 mg tablet for oral administration. Each cyclobenzaprine hydrochloride tablet, USP, 10 mg contains the following inactive ingredients: croscarmellose sodium, D&C Yellow #10 aluminum lake, FD&C Blue #2 aluminum lake, FD&C Yellow #6 aluminum lake, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, silicon dioxide, talc, and titanium dioxide.

Uses and Indications

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

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

Cyclobenzaprine hydrochloride 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 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 who are hepatically impaired or elderly, 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 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 complications.

Use is also contraindicated in patients with hyperthyroidism, as it may exacerbate the condition.

Warnings and Precautions

Cyclobenzaprine is structurally related to tricyclic antidepressants, such as amitriptyline and imipramine. Caution is advised when prescribing cyclobenzaprine, particularly in patients with a history of cardiovascular disorders, as serious central nervous system reactions similar to those observed with tricyclic antidepressants have been reported in short-term studies involving doses higher than those typically recommended for muscle spasm associated with acute musculoskeletal conditions. Healthcare professionals should be vigilant for these potential adverse effects (refer to the WARNINGS and ADVERSE REACTIONS sections for further details).

Tricyclic antidepressants, including cyclobenzaprine, have been associated with significant cardiovascular risks, including arrhythmias, sinus tachycardia, and prolongation of conduction time, which may lead to myocardial infarction and stroke. Therefore, it is imperative to monitor patients for any signs of cardiovascular instability during treatment.

Additionally, cyclobenzaprine hydrochloride may potentiate the effects of alcohol, barbiturates, and other central nervous system depressants. Healthcare providers should advise patients to avoid the concurrent use of these substances to mitigate the risk of enhanced sedation and respiratory depression. Regular assessment of the patient's overall medication regimen and potential interactions is recommended to ensure safe use of cyclobenzaprine.

Side Effects

Patients receiving treatment may experience a range of adverse reactions, which can be categorized by frequency and seriousness.

Common adverse reactions, occurring in more than 3% of patients, 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 with an incidence of 1% to 3% include abdominal pain, acid regurgitation, constipation, diarrhea, dizziness, nausea, irritability, decreased mental acuity, nervousness, upper respiratory infections, pharyngitis, fatigue or tiredness, asthenia, dyspepsia, unpleasant taste, blurred vision, and confusion.

Less frequent adverse reactions, occurring in less than 1% of patients, encompass a variety of systems. Notable reactions include syncope and malaise (body as a whole), tachycardia, arrhythmia, vasodilatation, palpitation, and hypotension (cardiovascular), as well as vomiting, anorexia, gastrointestinal pain, gastritis, thirst, flatulence, edema of the tongue, abnormal liver function, and rare reports of hepatitis, jaundice, and cholestasis (digestive). Hypersensitivity reactions may manifest as anaphylaxis, angioedema, pruritus, facial edema, urticaria, and rash.

Nervous system and psychiatric 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, and diplopia. Other less frequent reactions involve local weakness (musculoskeletal), sweating (skin), ageusia and tinnitus (special senses), and urinary frequency and/or retention (urogenital).

Additional adverse reactions of clinical significance 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-related reactions may include inappropriate ADH syndrome. Hematic and lymphatic reactions can involve purpura, bone marrow depression, leukopenia, eosinophilia, and thrombocytopenia.

Metabolic, nutritional, and immune reactions may present as elevation or lowering of blood sugar levels, as well as weight gain or loss. Musculoskeletal reactions can include myalgia. Nervous system and psychiatric reactions may also involve decreased or increased libido, abnormal gait, delusions, aggressive behavior, paranoia, peripheral neuropathy, Bell's palsy, alterations in EEG patterns, and extrapyramidal symptoms. Respiratory reactions may include dyspnea, while skin reactions can manifest as photosensitization and alopecia. Urogenital reactions may involve impaired urination, dilatation of the urinary tract, impotence, testicular swelling, gynecomastia, breast enlargement, and galactorrhea.

Healthcare professionals should monitor patients for these adverse reactions and manage them appropriately.

Drug Interactions

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

Monoamine Oxidase Inhibitors (MAOIs) Cyclobenzaprine hydrochloride may lead to life-threatening interactions when administered concurrently with MAO inhibitors. It is advised that the use of cyclobenzaprine be avoided in patients receiving MAOIs or that a minimum of 14 days be allowed between the discontinuation of an MAOI and the initiation of cyclobenzaprine therapy.

Central Nervous System (CNS) Depressants The concomitant use of cyclobenzaprine hydrochloride with alcohol, barbiturates, and other CNS depressants may enhance the sedative effects of these agents. Clinicians should monitor patients closely for increased sedation and consider dosage adjustments of cyclobenzaprine or the CNS depressants as necessary.

Tricyclic Antidepressants Tricyclic antidepressants may interfere with the antihypertensive effects of guanethidine and similar compounds. It is recommended that blood pressure be monitored in patients taking both tricyclic antidepressants and guanethidine, and dosage adjustments may be required based on the patient's response.

Additionally, tricyclic antidepressants can increase the risk of seizures in patients who are also taking tramadol. Caution is advised, and healthcare providers should evaluate the risk-benefit ratio when prescribing these medications together. Monitoring for seizure activity is recommended in such cases.

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, necessitating careful consideration when prescribing this medication. In a pharmacokinetic study involving individuals aged 65 years and older, the mean steady-state area under the curve (AUC) values for cyclobenzaprine were found to be 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.

Given these pharmacokinetic differences, therapy with cyclobenzaprine hydrochloride in geriatric patients should be initiated at a lower dose of 5 mg, with a 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.

Furthermore, the frequency and severity of adverse events associated with cyclobenzaprine use, whether alone or in conjunction with other medications, tend to be higher in elderly patients. Therefore, cyclobenzaprine hydrochloride should only be prescribed to geriatric patients when clearly indicated, ensuring that the benefits outweigh the potential risks.

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 no specific information regarding dosage adjustments, special monitoring, or safety considerations provided in the text. Therefore, healthcare professionals should exercise caution and consider individual patient factors when prescribing to this population. Regular assessment of renal function may be warranted to ensure safe and effective use of the medication in patients with reduced kidney function.

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 cyclobenzaprine overdose.

Signs and Symptoms of Toxicity Symptoms of toxicity can manifest rapidly following an overdose, necessitating immediate hospital monitoring. The acute oral LD50 of cyclobenzaprine hydrochloride is approximately 338 mg/kg in mice and 425 mg/kg in rats. The most prevalent effects observed in cases of overdose include drowsiness and tachycardia. Other less common symptoms may include tremor, agitation, coma, ataxia, hypertension, slurred speech, confusion, dizziness, nausea, vomiting, and hallucinations. Rare but critical manifestations can involve 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 Recommendations Due to the complexity and evolving nature of overdose management, it is strongly advised that healthcare professionals contact a poison control center for the most current treatment information. All patients suspected of cyclobenzaprine overdose should undergo gastrointestinal decontamination, which includes large volume gastric lavage followed by the administration of activated charcoal. In cases where consciousness is impaired, securing the airway prior to lavage is essential, and emesis is contraindicated.

To mitigate the risk of severe manifestations, an electrocardiogram (ECG) should be obtained, and cardiac monitoring should be initiated immediately. It is crucial to protect the patient's airway, establish an intravenous line, and commence gastric decontamination. Continuous observation 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 monitoring period, extended observation is warranted. 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 the drug.

A maximal limb-lead QRS duration of ≥0.10 seconds may indicate the severity of the overdose. For patients exhibiting dysrhythmias or QRS widening, serum alkalinization to a pH of 7.45 to 7.55 should be initiated using intravenous sodium bicarbonate, with hyperventilation as needed. A pH greater than 7.60 or a pCO2 less than 20 mmHg is considered undesirable. Dysrhythmias that do not respond to sodium bicarbonate therapy or hyperventilation may be treated with lidocaine, bretylium, or phenytoin, while Type 1A and 1C antiarrhythmics (e.g., quinidine, disopyramide, procainamide) are generally contraindicated.

In patients exhibiting CNS depression, early intubation is recommended due to the risk of sudden deterioration. Seizures should be managed with benzodiazepines, or if these are ineffective, alternative anticonvulsants such as phenobarbital or phenytoin may be utilized. The use of physostigmine is not recommended except for life-threatening symptoms unresponsive to other treatments, and only after consultation with a poison control center.

Given that overdosage is often intentional, there is a risk that patients may attempt suicide by other means during the recovery phase, making psychiatric referral a consideration. The management principles for both child and adult overdosages are similar; however, it is strongly recommended that physicians consult the local poison control center for specific pediatric treatment guidance.

Nonclinical Toxicology

Reproduction studies conducted in rats, mice, and rabbits at doses up to 20 times the human dose have classified cyclobenzaprine hydrochloride as Pregnancy Category B, indicating no evidence of impaired fertility or teratogenic effects on the fetus. Additionally, 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. Furthermore, cyclobenzaprine did not demonstrate mutagenic activity in male mice at dose levels of up to 20 times the human dose.

In nonclinical 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. In higher dose groups, these microscopic changes were noted after 26 weeks, and in some cases, even earlier in rats that died prior to 26 weeks. At lower doses, these changes were not observed until after 26 weeks. Importantly, 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 effects of cyclobenzaprine that are similar to those of structurally related tricyclic antidepressants, including reserpine antagonism, norepinephrine potentiation, potent peripheral and central anticholinergic effects, and sedation. Additionally, cyclobenzaprine was associated with a slight to moderate increase in heart rate in animal studies.

Postmarketing Experience

Postmarketing experience has identified several adverse reactions reported voluntarily or through surveillance programs, with an incidence of less than 1% of patients in clinical trials involving the 10 mg tablet.

In the category of Body as a Whole, reactions such as syncope and malaise have been noted. Cardiovascular events include tachycardia, arrhythmia, vasodilatation, palpitation, and hypotension. Digestive system reactions encompass vomiting, anorexia, diarrhea, gastrointestinal pain, gastritis, thirst, flatulence, edema of the tongue, and abnormal liver function, with rare reports of hepatitis, jaundice, and cholestasis.

Hypersensitivity reactions reported include anaphylaxis, angioedema, pruritus, facial edema, urticaria, and rash. Musculoskeletal reactions consist of local weakness. The Nervous System and Psychiatric category includes 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-related reactions include sweating, while special senses reactions involve ageusia and tinnitus. Urogenital reactions reported include urinary frequency and/or retention.

Additionally, other reactions have been reported rarely for cyclobenzaprine hydrochloride, where a causal relationship could not be established, or have been reported for other tricyclic drugs. These include chest pain and edema in the Body as a Whole category; hypertension, myocardial infarction, heart block, and stroke in the Cardiovascular category; paralytic ileus, tongue discoloration, stomatitis, and parotid swelling in the Digestive category; inappropriate ADH syndrome in the Endocrine category; purpura, bone marrow depression, leukopenia, eosinophilia, and thrombocytopenia in the Hematic and Lymphatic category; elevation and lowering of blood sugar levels, as well as weight gain or loss in the Metabolic, Nutritional, and Immune category; and myalgia in the Musculoskeletal category.

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 mental and physical abilities necessary for performing hazardous tasks, such as 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 concomitant medications. For elderly patients, cyclobenzaprine hydrochloride should be initiated at a dose of 5 mg, with careful titration to higher doses as needed.

Healthcare providers should counsel patients with a history of urinary retention, angle-closure glaucoma, or increased intraocular pressure, as well as those taking anticholinergic medications, to use cyclobenzaprine hydrochloride with caution. Additionally, patients with mild hepatic impairment should also start with a 5 mg dose and titrate slowly. Due to insufficient data regarding its safety in individuals with moderate to severe hepatic insufficiency, the use of cyclobenzaprine hydrochloride in these patients is not recommended.

Patients should be informed about the potential for drowsiness and advised to avoid activities that require mental alertness until they understand how cyclobenzaprine affects them. They should also be instructed to report any signs of allergic reactions, such as rash, itching, or swelling.

It is essential to emphasize that patients should take cyclobenzaprine hydrochloride only as prescribed and not exceed the recommended dose. Furthermore, patients should be cautioned against using cyclobenzaprine hydrochloride in combination with monoamine oxidase (MAO) inhibitors or within 14 days of their discontinuation due to the risk of serious interactions.

Storage and Handling

The product is supplied in a tight, light-resistant container, adhering to the specifications outlined in the United States Pharmacopeia (USP). It is essential to dispense the contents with a child-resistant closure, as required.

Storage conditions must be maintained at a temperature range of 20°C to 25°C (68°F to 77°F), with permissible excursions between 15°C and 30°C (59°F to 86°F) in accordance with USP Controlled Room Temperature guidelines.

Healthcare professionals are reminded to keep this and all medications out of the reach of children.

Additional Clinical Information

Laboratory tests specific to cyclobenzaprine hydrochloride have not been detailed. Clinicians should be aware that while withdrawal symptoms have not been reported with cyclobenzaprine, abrupt cessation after prolonged use may lead to nausea, headache, and malaise, which are not indicative of addiction.

The recommended administration for most patients is 5 mg of cyclobenzaprine hydrochloride tablets USP three times daily, with the option to increase to 10 mg three times daily based on individual response. Prolonged use beyond two to three weeks is not advised. Patient counseling should emphasize that cyclobenzaprine may impair mental and physical abilities, particularly when combined with alcohol or other CNS depressants. Elderly patients are at increased risk for adverse events and should start with a 5 mg dose, titrating slowly. Post-marketing experience involving 7,607 patients indicated that the effectiveness of cyclobenzaprine was consistent with controlled studies, with a lower incidence of adverse effects reported.

FDA Insert (PDF)

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

View full prescribing information (PDF)