Cyclobenzaprine hydrochloride

Description

Cyclobenzaprine hydrochloride is a white, crystalline tricyclic amine salt with the empirical formula C20H21N•HCl and a molecular weight of 311.9 g/mol. It exhibits a melting point of 217º C and has a pKa of 8.47 at 25º 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 HCl is designated as 3-(5H-dibenzo a,d cyclohepten-5-ylidene)-N,N-dimethyl-1-propanamine hydrochloride. Cyclobenzaprine HCl Tablets are formulated for oral administration and are available in strengths of 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, titanium dioxide, and iron oxide yellow. The 5 mg strength also contains FD&C yellow #6.

Uses and Indications

Cyclobenzaprine HCl tablets 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 HCl 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 HCl tablets are not indicated for the treatment of spasticity associated with cerebral or spinal cord disease, nor are they effective in children with cerebral palsy.

Dosage and Administration

The recommended dose of Cyclobenzaprine HCl 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 HCl tablets for periods exceeding two to three weeks is not recommended. For patients who are elderly or have hepatic impairment, 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 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

Cyclobenzaprine is structurally related to tricyclic antidepressants, such as amitriptyline and imipramine. In short-term studies conducted for indications beyond muscle spasm associated with acute musculoskeletal conditions, and typically at doses exceeding those recommended for skeletal muscle spasm, serious central nervous system reactions similar to those observed with tricyclic antidepressants have been reported.

Healthcare professionals should be aware that tricyclic antidepressants are associated with the risk of arrhythmias, sinus tachycardia, and prolongation of conduction time, which may lead to severe cardiovascular events, including myocardial infarction and stroke.

Additionally, Cyclobenzaprine HCl may potentiate the effects of alcohol, barbiturates, and other central nervous system depressants, necessitating caution in patients who consume these substances concurrently.

Due to its atropine-like properties, Cyclobenzaprine HCl should be administered with caution in patients with a history of urinary retention, angle-closure glaucoma, or increased intraocular pressure. It is also important to consider the potential interactions with anticholinergic medications in these patients. Regular monitoring of relevant parameters is advised to ensure patient safety and mitigate risks associated with these conditions.

Side Effects

Patients receiving treatment may experience a range of adverse reactions. The most common adverse reactions, occurring in more than 3% of participants, include drowsiness (29% at 5 mg, 38% at 10 mg, compared to 10% in the placebo group), dry mouth (21% at 5 mg, 32% 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 dosages, with 8% in the placebo group).

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

Additional adverse reactions reported from postmarketing experience or occurring in less than 1% of patients encompass a variety of systems. Notably, body-related reactions include syncope and malaise. Cardiovascular effects may involve tachycardia, arrhythmia, vasodilatation, palpitations, and hypotension. Digestive system reactions can include vomiting, anorexia, gastrointestinal pain, gastritis, thirst, flatulence, edema of the tongue, abnormal liver function, and rare instances of hepatitis, jaundice, and cholestasis. Hypersensitivity reactions may manifest as anaphylaxis, angioedema, pruritus, facial edema, urticaria, and rash.

Musculoskeletal adverse reactions include local weakness, while nervous system and psychiatric effects may present as 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 may involve sweating, and special senses may be affected by ageusia and tinnitus. Urogenital reactions can include urinary frequency and/or retention.

There are also rare reports of adverse reactions with an unknown causal relationship. These include chest pain and edema in the body as a whole; hypertension, myocardial infarction, heart block, and stroke in the cardiovascular system; paralytic ileus, tongue discoloration, stomatitis, and parotid swelling in the digestive system; inappropriate ADH syndrome in the endocrine system; purpura, bone marrow depression, leukopenia, eosinophilia, and thrombocytopenia in the hematologic and lymphatic systems; and fluctuations in blood sugar levels, as well as weight gain or loss in metabolic, nutritional, and immune responses. Musculoskeletal complaints may include myalgia, while nervous system and psychiatric issues can 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, skin reactions can involve photosensitization and alopecia, and urogenital issues may present as impaired urination, dilatation of the urinary tract, impotence, testicular swelling, gynecomastia, breast enlargement, and galactorrhea.

Drug Interactions

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

Monoamine Oxidase Inhibitors (MAOIs) Cyclobenzaprine HCl may lead to life-threatening interactions when administered concurrently with MAO inhibitors. It is advised that cyclobenzaprine should not be used in patients receiving MAOIs or within 14 days of discontinuing such treatment due to the risk of severe adverse effects.

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

Tricyclic Antidepressants Tricyclic antidepressants may interfere with the antihypertensive effects of guanethidine and similar agents. It is recommended that blood pressure be monitored in patients taking both tricyclic antidepressants and guanethidine to ensure adequate management of blood pressure.

Additionally, tricyclic antidepressants may increase the risk of seizures in patients who are also taking tramadol. Caution is advised, and healthcare providers should evaluate the risk-to-benefit ratio when prescribing these medications together, considering potential seizure history and monitoring for seizure activity.

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

The safety and effectiveness of Cyclobenzaprine HCl 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, exhibit increased plasma concentrations of cyclobenzaprine. A pharmacokinetic study demonstrated that the 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 experienced the most significant increase, with mean levels approximately 2.4 times higher, while elderly females showed a lesser increase of about 1.2 times.

Given these pharmacokinetic findings, it is recommended that therapy with Cyclobenzaprine HCl in geriatric patients be initiated at a lower dose of 5 mg, with careful and gradual titration to achieve the desired therapeutic effect.

Additionally, elderly patients 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. There is also a heightened potential for drug-drug and drug-disease interactions in this population. Therefore, cyclobenzaprine should be prescribed to elderly patients only when clearly indicated, and close monitoring for adverse effects is advised throughout the course of treatment.

Pregnancy

Reproduction studies have been conducted in rats, mice, and rabbits at doses up to 20 times the human dose of Cyclobenzaprine HCl, revealing no evidence of impaired fertility or harm to the fetus. Cyclobenzaprine is classified as Pregnancy Category B. However, there are no adequate and well-controlled studies in pregnant women. Due to the limitations of animal reproduction studies in predicting human response, Cyclobenzaprine HCl should be used during pregnancy only if clearly needed. Healthcare professionals are advised to weigh the potential benefits against any possible risks when considering this medication for pregnant patients.

Lactation

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

Renal Impairment

There is no specific information available regarding renal impairment, including dosage adjustments, special monitoring, or safety considerations for patients with reduced kidney function. Healthcare professionals should exercise caution and consider individual patient factors when prescribing to 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 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 prudent in these cases, although specific parameters are not defined in the available information.

Overdosage

In the absence of specific information regarding overdosage, healthcare professionals are advised to exercise caution and adhere to general principles of management in cases of suspected overdose.

It is essential to monitor the patient closely for any potential symptoms that may arise from an overdose. Symptoms can vary widely depending on the substance involved and the individual patient's response.

In the event of an overdose, immediate medical attention should be sought. Healthcare providers should implement supportive care measures, which may include maintaining airway patency, providing supplemental oxygen, and monitoring vital signs.

If available, specific antidotes or treatments should be administered as indicated based on the clinical scenario and the substance involved. Continuous assessment and supportive care are critical in managing the patient's condition effectively.

Healthcare professionals are encouraged to consult local poison control centers or toxicology experts for guidance on the management of overdose cases, ensuring that appropriate interventions are undertaken promptly.

Nonclinical Toxicology

In rats treated with Cyclobenzaprine HCl for up to 67 weeks at doses 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 of treatment.

Cyclobenzaprine did not affect the onset, incidence, or distribution of neoplasia in an 81-week study conducted in mice or in a 105-week study in rats, indicating no evidence of carcinogenic potential.

Reproductive performance and fertility were not adversely affected in male or female rats at oral doses of up to 10 times the human dose, suggesting that Cyclobenzaprine does not impair fertility.

Additionally, Cyclobenzaprine did not demonstrate mutagenic activity in male mice at dose levels of up to 20 times the human dose, indicating a lack of mutagenic potential.

Postmarketing Experience

The following adverse reactions have been reported in the postmarketing experience or with an incidence of less than 1% of patients in clinical trials with the 10 mg tablet:

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

Hypersensitivity reactions include anaphylaxis, angioedema, pruritus, facial edema, urticaria, and rash. Musculoskeletal reactions reported are local weakness. In the Nervous System and Psychiatric category, events include seizures, ataxia, vertigo, dysarthria, tremors, hypertonia, convulsions, muscle twitching, disorientation, insomnia, depressed mood, abnormal sensations, anxiety, agitation, psychosis, abnormal thinking and dreaming, hallucinations, excitement, paresthesia, and diplopia. Skin reactions include sweating, while special senses reactions consist of ageusia and tinnitus. Urogenital reactions reported are urinary frequency and/or retention.

Additionally, other reactions have been reported rarely for Cyclobenzaprine HCl under circumstances where a causal relationship could not be established, or reported for other tricyclic drugs. These include chest pain and edema in the Body as a Whole category; hypertension, myocardial infarction, heart block, and stroke in the Cardiovascular category; and paralytic ileus, tongue discoloration, stomatitis, and parotid swelling in the Digestive category. Endocrine reactions include inappropriate ADH syndrome. Hematic and Lymphatic reactions consist of purpura, bone marrow depression, leukopenia, eosinophilia, and thrombocytopenia.

In the Metabolic, Nutritional, and Immune category, reactions include elevation and lowering of blood sugar levels, as well as weight gain or loss. Musculoskeletal reactions reported are myalgia. Nervous System and Psychiatric reactions 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 consist of dyspnea. Skin reactions include photosensitization and alopecia. Urogenital reactions reported are impaired urination, dilatation of the urinary tract, impotence, testicular swelling, gynecomastia, breast enlargement, and galactorrhea.

Patient Counseling

Healthcare providers should advise patients that Cyclobenzaprine HCl, particularly when combined with alcohol or other central nervous system (CNS) depressants, may impair their 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 they may experience an increased frequency and severity of adverse events associated with the use of Cyclobenzaprine, whether or not they are taking other medications. For elderly patients, Cyclobenzaprine HCl should be initiated at a dose of 5 mg, with careful titration to higher doses as needed.

Healthcare providers should also counsel patients with mild hepatic impairment to start with a 5 mg dose of Cyclobenzaprine HCl and to titrate slowly. Due to insufficient data regarding its safety in individuals with moderate to severe hepatic insufficiency, the use of Cyclobenzaprine HCl in these patients is not recommended.

Patients should be made aware of the potential for drowsiness and should be advised to refrain from activities that require mental alertness until they understand how Cyclobenzaprine HCl affects them. Additionally, patients should be instructed to report any signs of allergic reactions, such as rash, itching, or swelling.

It is crucial to emphasize that patients should take Cyclobenzaprine HCl only as prescribed and should not exceed the recommended dose. They should also be informed that Cyclobenzaprine HCl is not intended for long-term use and should only be utilized for short periods, typically up to two or three weeks. Lastly, patients should be advised to avoid the use of monoamine oxidase (MAO) inhibitors while taking Cyclobenzaprine HCl and for 14 days following the discontinuation of MAO inhibitors.

Storage and Handling

The product is supplied in accordance with the National Drug Code (NDC) specifications. It should be stored at a controlled room temperature of 20-25°C (68-77°F), as defined by the United States Pharmacopeia (USP) guidelines. Proper storage conditions are essential to maintain the integrity and efficacy of the product.

Additional Clinical Information

Patients receiving Cyclobenzaprine HCl should be aware that abrupt cessation after prolonged use may lead to withdrawal symptoms such as nausea, headache, and malaise, although these symptoms are not indicative of addiction. The recommended starting dose for most patients is 5 mg taken three times daily, with the possibility of increasing to 10 mg three times daily based on individual response. Prolonged use beyond two to three weeks is not advised.

Clinicians should counsel patients on the potential for impaired mental and physical abilities when Cyclobenzaprine HCl is used, particularly in conjunction with alcohol or other CNS depressants, which may affect tasks such as driving or operating machinery. In elderly patients, the risk of adverse events is heightened; therefore, treatment should begin with a 5 mg dose and be titrated slowly. Post-marketing surveillance involving 7,607 patients indicated that the effectiveness of Cyclobenzaprine HCl aligns with findings from 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 Contract Pharmacy Services-PA. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)