Cyclobenzaprine hydrochloride

Description

Cyclobenzaprine hydrochloride is a white, crystalline tricyclic amine salt with the chemical formula C20H21N•HCl and a molecular weight of 311.85. 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 HCl is designated as 3-(5-H-dibenzoa,dcyclohepten-5-ylidene)-N,N-dimethyl-1-propanamine hydrochloride.

Each tablet for oral administration contains 10 mg of cyclobenzaprine hydrochloride, USP. The formulation includes the following inactive ingredients: anhydrous lactose, carnauba wax, corn starch, crospovidone, hypromellose, magnesium stearate, pregelatinized starch, polyethylene glycol, polysorbate 80, titanium dioxide, D and C Yellow No. 10 aluminum lake, FD and C Blue No. 2 aluminum lake, and FD and C Yellow No. 6 aluminum lake.

Uses and Indications

Cyclobenzaprine HCl 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 drug should be utilized only 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 HCl has not demonstrated efficacy in treating 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 HCl Tablets USP 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 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.

Healthcare professionals should monitor patient response and adjust the dosage accordingly, while adhering to the recommended duration of therapy.

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 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 potential cardiovascular complications.

Additionally, the use of this product is 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. In short-term studies conducted for indications other than muscle spasm associated with acute musculoskeletal conditions, particularly at doses exceeding those typically 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. Therefore, caution is advised when prescribing cyclobenzaprine, particularly in patients with pre-existing cardiovascular conditions.

Additionally, cyclobenzaprine may potentiate the effects of alcohol, barbiturates, and other central nervous system depressants. This interaction necessitates careful consideration of concurrent medications and patient history to mitigate the risk of excessive sedation and respiratory depression.

Due to its atropine-like properties, cyclobenzaprine should be administered with caution in patients who have a history of urinary retention, angle-closure glaucoma, or increased intraocular pressure. It is also important to consider the use of anticholinergic medications in these patients, as they may exacerbate the aforementioned conditions.

No specific laboratory tests are recommended for monitoring during the use of cyclobenzaprine; however, healthcare providers should remain vigilant for any adverse effects and assess the patient's overall health status regularly.

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 reported 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.

In addition to these, postmarketing experience has revealed additional adverse reactions occurring in less than 1% of patients. These include syncope and malaise (body as a whole), tachycardia, arrhythmia, vasodilatation, palpitation, and hypotension (cardiovascular), as well as vomiting, anorexia, gastrointestinal pain, gastritis, thirst, flatulence, edema of the tongue, abnormal liver function, and rare reports of hepatitis, jaundice, and cholestasis (digestive). Hypersensitivity reactions such as anaphylaxis, angioedema, pruritus, facial edema, urticaria, and rash have also been noted. Musculoskeletal reactions may include local weakness, while nervous system and psychiatric effects can manifest as 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 sweating (skin), ageusia and tinnitus (special senses), and urinary frequency and/or retention (urogenital).

Certain adverse reactions have been reported rarely, with an unknown causal relationship. These include chest pain and edema (body as a whole), hypertension, myocardial infarction, heart block, and stroke (cardiovascular), as well as paralytic ileus, tongue discoloration, stomatitis, and parotid swelling (digestive). Endocrine effects such as inappropriate ADH syndrome, hematologic issues like purpura, bone marrow depression, leukopenia, eosinophilia, and thrombocytopenia, as well as metabolic changes including elevation and lowering of blood sugar levels and weight gain or loss, have also been documented. Musculoskeletal complaints may involve myalgia, while nervous system and psychiatric effects can include decreased or increased libido, 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, dilatation of the urinary tract, impotence, testicular swelling, gynecomastia, breast enlargement, and galactorrhea have also been reported.

Drug Interactions

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

Monoamine Oxidase Inhibitors (MAOIs) Cyclobenzaprine 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 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 (TCAs) Tricyclic antidepressants may interfere with the antihypertensive effects of guanethidine and similar agents. Patients receiving both TCAs and guanethidine should be monitored for blood pressure changes, and dosage adjustments may be necessary to maintain therapeutic efficacy.

Additionally, tricyclic antidepressants can increase the risk of seizures in patients taking tramadol. It is recommended that healthcare providers assess the seizure threshold in patients receiving this combination and consider alternative therapies if necessary.

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 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 than their younger counterparts, while elderly females showed a lesser increase of about 1.2 times.

Given these pharmacokinetic differences, therapy with cyclobenzaprine 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 essential 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 potential for drug-drug and drug-disease interactions is heightened in the elderly population. Therefore, cyclobenzaprine should only be prescribed if clearly indicated, and consideration should be given to less frequent dosing regimens to minimize the risk of adverse effects.

Pregnancy

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 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. Healthcare professionals are advised to weigh the potential benefits against the 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 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 may not have specific dosage adjustments, special monitoring, or safety considerations outlined in the prescribing information. Therefore, healthcare professionals should exercise caution when prescribing to patients with reduced kidney function, as the lack of detailed guidance necessitates careful clinical judgment and individualized patient assessment. Regular monitoring of renal function is advisable to ensure patient safety and therapeutic efficacy.

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 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 overdosage, although rare, fatalities may occur. It is important to note that multiple drug ingestion, including alcohol, is frequently associated with deliberate cyclobenzaprine overdose.

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. Immediate hospital monitoring is essential, as signs and symptoms of toxicity can develop rapidly following an overdose. The acute oral LD50 of cyclobenzaprine is approximately 338 mg/kg in mice and 425 mg/kg in rats.

Signs and Symptoms The most prevalent effects observed in cyclobenzaprine overdose include drowsiness and tachycardia. Other less common symptoms may manifest as tremor, agitation, coma, ataxia, hypertension, slurred speech, confusion, dizziness, nausea, vomiting, and hallucinations. Critical manifestations, although 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 cyclobenzaprine toxicity.

Initial Interventions To mitigate the risk of severe manifestations, it is crucial to obtain an electrocardiogram (ECG) and initiate cardiac monitoring without delay. Protecting the patient's airway, establishing an intravenous line, and commencing gastric decontamination are vital steps. 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 is contraindicated.

Monitoring and Further Management Continuous observation with cardiac monitoring is necessary to detect signs of central nervous system (CNS) or respiratory depression, hypotension, cardiac dysrhythmias or conduction blocks, and seizures. 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 ≥ 0.1 seconds may indicate the severity of the overdose. For patients exhibiting dysrhythmias and/or QRS widening, serum alkalinization to a pH of 7.45 to 7.55 should be initiated using intravenous sodium bicarbonate and hyperventilation as necessary. A pH greater than 7.6 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 that have not responded to other treatments, and only after consultation with a poison control center.

Nonclinical Toxicology

Cyclobenzaprine has been evaluated for its nonclinical toxicology profile through various studies.

In terms of teratogenic effects, no specific information has been provided regarding any teratogenic potential associated with cyclobenzaprine.

Regarding non-teratogenic effects, cyclobenzaprine did not influence the onset, incidence, or distribution of neoplasia in an 81-week study conducted in mice or in a 105-week study in rats. Additionally, at oral doses up to 10 times the human dose, cyclobenzaprine did not adversely affect the reproductive performance or fertility of both male and female rats. Furthermore, cyclobenzaprine did not exhibit mutagenic activity in male mice at dose levels up to 20 times the human dose.

In a long-term study involving rats treated with cyclobenzaprine for up to 67 weeks at doses ranging from approximately 5 to 40 times the maximum recommended human dose, observations included pale and occasionally enlarged livers. There was also a dose-related occurrence of hepatocyte vacuolation with lipidosis. In the higher dose groups, this microscopic change was noted after 26 weeks, and in some cases, even earlier in rats that died prior to the 26-week mark. In contrast, at lower doses, these changes were not observed until after 26 weeks of treatment.

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.

Body as a Whole: Reports include syncope and malaise.

Cardiovascular: Adverse events such as tachycardia, arrhythmia, vasodilatation, palpitation, and hypotension have been noted.

Digestive: Reactions include vomiting, anorexia, diarrhea, gastrointestinal pain, gastritis, thirst, flatulence, edema of the tongue, and abnormal liver function, with rare cases of hepatitis, jaundice, and cholestasis.

Hypersensitivity: Instances of anaphylaxis, angioedema, pruritus, facial edema, urticaria, and rash have been documented.

Musculoskeletal: Local weakness has been reported.

Nervous System and Psychiatric: Adverse 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: Increased sweating has been observed.

Special Senses: Reports of ageusia and tinnitus have been noted.

Urogenital: Urinary frequency and/or retention have been reported.

Additionally, other reactions have been reported rarely for cyclobenzaprine, where a causal relationship could not be established, or have been associated with other tricyclic drugs. These include:

Body as a Whole: Chest pain and edema.

Cardiovascular: Hypertension, myocardial infarction, heart block, and stroke.

Digestive: Paralytic ileus, tongue discoloration, stomatitis, and parotid swelling.

Endocrine: Inappropriate ADH syndrome.

Hematic and Lymphatic: Purpura, bone marrow depression, leukopenia, eosinophilia, and thrombocytopenia.

Metabolic, Nutritional and Immune: Elevation and lowering of blood sugar levels, as well as weight gain or loss.

Musculoskeletal: Myalgia has been reported.

Nervous System and Psychiatric: Decreased or increased libido, abnormal gait, delusions, aggressive behavior, paranoia, peripheral neuropathy, Bell’s palsy, alteration in EEG patterns, and extrapyramidal symptoms have been noted.

Respiratory: Instances of dyspnea have been documented.

Skin: Reports of photosensitization and alopecia have been made.

Urogenital: Impaired urination, dilatation of the urinary tract, impotence, testicular swelling, gynecomastia, breast enlargement, and galactorrhea have been observed.

Patient Counseling

Healthcare providers should advise patients that cyclobenzaprine, particularly when used in conjunction with alcohol or other central nervous system (CNS) depressants, may impair their mental and physical abilities necessary for performing hazardous tasks, including 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 cyclobenzaprine, whether or not they are taking other medications. For this population, cyclobenzaprine should be initiated at a 5 mg dose, 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 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, cyclobenzaprine is not recommended for these patients.

Patients should be made aware of the potential for drowsiness and should be advised against driving or operating heavy machinery until they understand how cyclobenzaprine affects them. It is also crucial to recommend that patients avoid alcohol and other CNS depressants while taking this medication.

Furthermore, patients should be informed that cyclobenzaprine is not recommended for use beyond two to three weeks. They should be encouraged to report any signs of allergic reactions, such as rash, itching, or swelling, to their healthcare provider promptly.

Storage and Handling

The product is supplied in a well-closed container that meets the specifications outlined in the United States Pharmacopeia (USP), featuring a child-resistant closure as required. It is essential to store the product at a temperature range of 20° to 25°C (68° to 77°F), in accordance with USP Controlled Room Temperature guidelines.

Healthcare professionals are reminded to keep this product, along with all medications, out of the reach of children to ensure safety.

Additional Clinical Information

No additional information is available regarding laboratory tests or the route, method, and frequency of administration for cyclobenzaprine.

Clinicians should be aware that while cyclobenzaprine has not been reported to cause withdrawal symptoms, abrupt cessation after prolonged use may lead to nausea, headache, and malaise, which are not indicative of addiction. Patient counseling should emphasize that cyclobenzaprine, particularly when combined with alcohol or other CNS depressants, may impair mental and physical abilities necessary for performing hazardous tasks, such as operating machinery or driving. In elderly patients, the risk of adverse events is heightened, and treatment should begin with a 5 mg dose, titrated slowly. Additionally, postmarketing experience indicates that the overall incidence of adverse reactions in the surveillance program was lower than that observed in controlled clinical studies.

FDA Insert (PDF)

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

View full prescribing information (PDF)