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 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. It is supplied as a 10 mg tablet for oral administration. Each 10 mg tablet 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 is 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 has not demonstrated efficacy in the treatment of spasticity associated with cerebral or spinal cord diseases, nor is it indicated for use in children with cerebral palsy.

Dosage and Administration

The recommended dose of cyclobenzaprine hydrochloride for most patients 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 for periods longer than two or three weeks is not recommended. For patients who are hepatically impaired or elderly, 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 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, as this combination has been associated with hyperpyretic crisis, seizures, and fatalities in patients receiving cyclobenzaprine or similar tricyclic antidepressants.

The product is also 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 potential for exacerbating these conditions.

Additionally, use is contraindicated in patients with hyperthyroidism, as it may lead to adverse effects related to thyroid function.

Warnings and Precautions

Cyclobenzaprine is structurally related to tricyclic antidepressants, such as amitriptyline and imipramine. Caution is advised when prescribing cyclobenzaprine, particularly in short-term studies for indications beyond muscle spasm associated with acute musculoskeletal conditions. In these studies, and typically at doses exceeding those recommended for 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, including cyclobenzaprine, have been associated with cardiovascular risks. These include the potential for arrhythmias, sinus tachycardia, and prolongation of conduction time, which may lead to serious outcomes such as myocardial infarction and stroke.

Additionally, cyclobenzaprine hydrochloride may potentiate the effects of alcohol, barbiturates, and other central nervous system depressants. It is imperative to monitor patients for signs of excessive sedation and respiratory depression when these substances are co-administered. Regular assessment of cardiovascular status and central nervous system function is recommended to ensure patient safety during treatment with cyclobenzaprine.

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

In clinical studies, drowsiness was reported in 39% of subjects, while surveillance programs indicated a lower incidence of 16%. Dry mouth was noted in 27% of clinical study participants and 7% in the surveillance program. Dizziness was reported in 11% of clinical study participants, with a lower incidence of 3% in the surveillance program.

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.

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 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 reactions include local weakness (musculoskeletal), sweating (skin), ageusia and tinnitus (special senses), and urinary frequency and/or retention (urogenital).

Rare reactions, for which a causal relationship is unknown, 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 reactions such as inappropriate ADH syndrome, hematologic reactions including purpura, bone marrow depression, leukopenia, eosinophilia, and thrombocytopenia, and metabolic reactions such as elevation and lowering of blood sugar levels, weight gain or loss have also been noted.

Musculoskeletal reactions include myalgia, while nervous system and psychiatric reactions may involve decreased or increased libido, abnormal gait, delusions, aggressive behavior, paranoia, peripheral neuropathy, Bell's palsy, alteration in EEG patterns, and extrapyramidal symptoms. Respiratory reactions such as dyspnea, skin reactions including photosensitization and alopecia, and urogenital reactions such as impaired urination, dilatation of the urinary tract, impotence, testicular swelling, gynecomastia, breast enlargement, and galactorrhea have also been reported.

In cases of overdosage, common effects include drowsiness and tachycardia, while less frequent manifestations may involve tremor, agitation, coma, ataxia, hypertension, slurred speech, confusion, dizziness, nausea, vomiting, and hallucinations. Rare but critical manifestations can include cardiac arrest, chest pain, cardiac dysrhythmias, severe hypotension, seizures, and neuroleptic malignant syndrome.

Drug Interactions

Cyclobenzaprine hydrochloride is associated with significant drug interactions that may lead to serious clinical consequences.

Monoamine Oxidase Inhibitors (MAOIs) Cyclobenzaprine hydrochloride may cause life-threatening interactions when administered concurrently with MAO inhibitors. It is advised that cyclobenzaprine should not be used in combination with MAOIs due to the risk of severe adverse effects.

Central Nervous System (CNS) Depressants The use of cyclobenzaprine hydrochloride may enhance the effects of alcohol, barbiturates, and other CNS depressants. Caution is recommended when these substances are used together, and monitoring for increased sedation and respiratory depression is advised.

Tricyclic Antidepressants (TCAs) Tricyclic antidepressants may interfere with the antihypertensive effects of guanethidine and similar agents. Clinicians should consider monitoring blood pressure and adjusting the dosage of antihypertensive medications as necessary.

Additionally, tricyclic antidepressants may increase the risk of seizures in patients taking tramadol. It is recommended that healthcare providers assess the risk of seizure activity and consider alternative therapies or close monitoring in patients receiving both medications.

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 mean levels 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.

Cyclobenzaprine should only be prescribed to elderly patients when clearly indicated, and healthcare providers should be aware that the frequency and severity of adverse events associated with its use may be heightened in this population, regardless of concomitant medications. Careful assessment and monitoring are essential to ensure the safety and efficacy of treatment in geriatric patients.

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 before prescribing this medication to nursing women.

Renal Impairment

Patients with renal impairment have not been specifically addressed in the available prescribing information. There are no dosage adjustments, special monitoring requirements, or safety considerations outlined for individuals with reduced kidney function. Healthcare professionals should exercise caution and consider the lack of data when prescribing to this patient population.

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. 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.

Signs and Symptoms of Toxicity

Symptoms of cyclobenzaprine overdose can manifest rapidly, necessitating immediate hospital monitoring. The acute oral LD50 for cyclobenzaprine hydrochloride is approximately 338 mg/kg in mice and 425 mg/kg in rats. The most prevalent effects observed in overdose cases include drowsiness and tachycardia. Other less common symptoms may include tremor, agitation, coma, ataxia, hypertension, slurred speech, confusion, dizziness, nausea, vomiting, and hallucinations. Critical manifestations, though rare, can include 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 toxicity.

Management Procedures

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, it is crucial to obtain an electrocardiogram (ECG) and initiate cardiac monitoring immediately. The patient's airway should be protected, an intravenous line established, and gastric decontamination initiated. 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 cyclobenzaprine.

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, along 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, and procainamide) are generally contraindicated.

In cases of 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; therefore, it is strongly recommended that healthcare professionals 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 shown no evidence of impaired fertility or teratogenic effects associated with cyclobenzaprine hydrochloride. However, there are no adequate and well-controlled studies in pregnant women. Due to the limitations of animal reproduction studies in predicting human responses, the use of this drug during pregnancy should be considered only when clearly necessary.

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 exhibit mutagenic activity in male mice at dose levels 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. In higher dose groups, these microscopic changes were noted as early as 26 weeks, and even earlier in rats that died prior to this time. In contrast, at lower doses, these changes were not observed until after 26 weeks.

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

Pharmacological studies in animals indicated that the effects of cyclobenzaprine are similar to those of structurally related tricyclic antidepressants, demonstrating reserpine antagonism, norepinephrine potentiation, significant peripheral and central anticholinergic effects, and sedation. Furthermore, 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.

Reactions categorized under Body as a Whole include syncope and malaise. Cardiovascular events reported 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 include anaphylaxis, angioedema, pruritus, facial edema, urticaria, and rash. Musculoskeletal reactions consist of local weakness. Nervous system and psychiatric events reported 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-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 under Body as a Whole; hypertension, myocardial infarction, heart block, and stroke under Cardiovascular; paralytic ileus, tongue discoloration, stomatitis, and parotid swelling under Digestive; inappropriate ADH syndrome under Endocrine; purpura, bone marrow depression, leukopenia, eosinophilia, and thrombocytopenia under Hematic and Lymphatic; elevation and lowering of blood sugar levels, as well as weight gain or loss under Metabolic, Nutritional and Immune; and myalgia under Musculoskeletal.

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 both 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 hydrochloride should be initiated at a dose of 5 mg, with careful titration to higher doses as needed.

Healthcare providers should also exercise caution when prescribing cyclobenzaprine hydrochloride to patients with mild hepatic impairment, starting with a 5 mg dose and titrating slowly. Due to insufficient data regarding its safety in patients with moderate to severe hepatic insufficiency, the use of cyclobenzaprine hydrochloride in these individuals 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 be instructed to report any signs of allergic reactions, such as rash, itching, or swelling.

Additionally, patients should be counseled to take cyclobenzaprine hydrochloride only for short periods, typically up to two or three weeks, as there is inadequate evidence supporting its effectiveness for prolonged use. It is crucial to advise patients against the concomitant use of cyclobenzaprine hydrochloride with monoamine oxidase (MAO) inhibitors due to the risk of serious interactions. Lastly, patients should be made aware that cyclobenzaprine may enhance the effects of alcohol, barbiturates, and other CNS depressants.

Storage and Handling

The product is supplied in a tight, light-resistant container as defined by the United States Pharmacopeia (USP). It must be stored 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).

When dispensing, the contents should be provided with a child-resistant closure to ensure safety. It is imperative to keep this product, along with 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 dosing for most patients is 5 mg 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. Patient counseling should emphasize that cyclobenzaprine, particularly in conjunction with alcohol or other CNS depressants, may impair the ability to perform hazardous tasks, such as driving. In elderly patients, the initial dose should be 5 mg, with careful titration due to an increased risk of adverse events.

Postmarketing experience has revealed adverse reactions occurring in less than 1% of patients, including syncope, tachycardia, gastrointestinal disturbances, hypersensitivity reactions, and various nervous system effects such as seizures and disorientation. Other reported effects include local weakness, urinary issues, and sensory disturbances.

FDA Insert (PDF)

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

View full prescribing information (PDF)