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. Cyclobenzaprine Hydrochloride Tablets, USP are formulated for oral administration, supplied as 10 mg tablets. Each tablet contains the following inactive ingredients: croscarmellose sodium, FD&C Yellow #6, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, and titanium dioxide. Additionally, the 10 mg tablets include D&C Yellow #10 and polysorbate.

Uses and Indications

Cyclobenzaprine hydrochloride 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 effect is characterized by the alleviation of muscle spasm and its associated signs and symptoms, including pain, tenderness, limitation of motion, and restrictions in activities of daily living.

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

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

It is important to note that the use of cyclobenzaprine hydrochloride tablets for periods longer than two to 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. This is due to the potential for hyperpyretic crisis, seizures, and fatalities associated with the combination of cyclobenzaprine (or structurally similar tricyclic antidepressants) and MAO inhibitors.

The product is contraindicated in patients in the acute recovery phase of myocardial infarction, as well as those with arrhythmias, heart block or conduction disturbances, or congestive heart failure, due to the risk of exacerbating these conditions.

Additionally, the use of this product is contraindicated in patients with hyperthyroidism, as it may worsen the condition.

Warnings and Precautions

The use of Cyclobenzaprine Hydrochloride necessitates careful consideration of potential risks and precautions to ensure patient safety.

Serotonin Syndrome The concomitant use of Cyclobenzaprine Hydrochloride with other serotonergic agents, including selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), tramadol, bupropion, meperidine, verapamil, or monoamine oxidase (MAO) inhibitors, may lead to the development of serotonin syndrome, a potentially life-threatening condition. Symptoms of serotonin syndrome can manifest as mental status changes (e.g., confusion, agitation, hallucinations), autonomic instability (e.g., diaphoresis, tachycardia, labile blood pressure, hyperthermia), neuromuscular abnormalities (e.g., tremor, ataxia, hyperreflexia, clonus, muscle rigidity), and gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). In the event of these symptoms, treatment with Cyclobenzaprine Hydrochloride and any concomitant serotonergic agents should be discontinued immediately, and supportive symptomatic treatment should be initiated. If the clinical situation necessitates the use of Cyclobenzaprine Hydrochloride alongside other serotonergic drugs, careful observation is advised, particularly during the initiation of treatment or when increasing the dose.

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

Cardiovascular Risks Tricyclic antidepressants, including Cyclobenzaprine, have been associated with arrhythmias, sinus tachycardia, and prolongation of conduction time, which may lead to serious cardiovascular events such as myocardial infarction and stroke.

CNS Depressant Interactions Cyclobenzaprine may potentiate the effects of alcohol, barbiturates, and other central nervous system depressants. Caution is advised when prescribing Cyclobenzaprine to patients who are consuming these substances.

General Precautions Due to its atropine-like properties, Cyclobenzaprine Hydrochloride should be administered with caution in patients with a history of urinary retention, angle-closure glaucoma, or increased intraocular pressure, as well as in those who are taking anticholinergic medications.

Healthcare professionals are encouraged to monitor patients closely for any adverse effects and to consider the aforementioned warnings and precautions when prescribing Cyclobenzaprine Hydrochloride.

Side Effects

Common adverse reactions observed in clinical trials include drowsiness, which occurred in 29% of patients receiving 5 mg and 38% of those receiving 10 mg, compared to 10% in the placebo group. Dry mouth was reported by 21% of patients on 5 mg and 32% on 10 mg, while only 7% of placebo participants experienced this effect. Fatigue and headache were also noted, with both occurring in 6% of patients on either dosage, and 5% of patients on both dosages reporting headaches, compared to 3% and 8% in the placebo group, respectively.

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

Less frequent adverse reactions, occurring in less than 1% of patients, encompassed a range of serious and non-serious effects. These included syncope and malaise as general reactions, tachycardia, arrhythmia, vasodilatation, palpitations, and hypotension in the cardiovascular system. Digestive issues such as vomiting, anorexia, gastrointestinal pain, gastritis, thirst, flatulence, and edema of the tongue were also reported, along with rare instances of abnormal liver function, hepatitis, jaundice, and cholestasis. Hypersensitivity reactions included anaphylaxis, angioedema, pruritus, facial edema, urticaria, and rash.

Nervous system and psychiatric adverse reactions were notable, with reports of seizures, ataxia, vertigo, dysarthria, tremors, hypertonia, convulsions, muscle twitching, disorientation, insomnia, depressed mood, anxiety, agitation, psychosis, abnormal thinking and dreaming, hallucinations, excitement, paresthesia, diplopia, and serotonin syndrome. Other less frequent reactions included sweating, ageusia, tinnitus, urinary frequency and/or retention, and local weakness.

Certain adverse reactions have an unknown causal relationship, including chest pain, edema, hypertension, myocardial infarction, heart block, and stroke. Digestive issues such as paralytic ileus, tongue discoloration, stomatitis, and parotid swelling have also been reported. Endocrine effects include inappropriate ADH syndrome, while hematologic and lymphatic reactions encompass purpura, bone marrow depression, leukopenia, eosinophilia, and thrombocytopenia. Metabolic changes such as elevation and lowering of blood sugar levels, as well as weight gain or loss, have been noted. Musculoskeletal complaints include myalgia, and various nervous system and psychiatric effects such as decreased or increased libido, abnormal gait, delusions, aggressive behavior, paranoia, peripheral neuropathy, Bell's palsy, alterations in EEG patterns, and extrapyramidal symptoms have been documented. Respiratory issues like dyspnea, skin reactions including photosensitization and alopecia, and urogenital effects such as impaired urination, dilatation of the urinary tract, impotence, testicular swelling, gynecomastia, breast enlargement, and galactorrhea have also been reported.

A serious warning regarding serotonin syndrome is noted, particularly when Cyclobenzaprine Hydrochloride is used in combination with other medications such as SSRIs, SNRIs, TCAs, tramadol, bupropion, meperidine, verapamil, or MAO inhibitors. Symptoms may include mental status changes, autonomic instability, neuromuscular abnormalities, and gastrointestinal symptoms.

In cases of overdose, the most common effects include drowsiness and tachycardia, with less frequent manifestations such as tremor, agitation, coma, ataxia, hypertension, slurred speech, confusion, dizziness, nausea, vomiting, and hallucinations. Rare but critical manifestations may include cardiac arrest, chest pain, cardiac dysrhythmias, severe hypotension, seizures, and neuroleptic malignant syndrome. Changes in the electrocardiogram, particularly in QRS axis or width, are significant indicators of cyclobenzaprine toxicity, and other symptoms listed under adverse reactions may also occur.

Drug Interactions

Cyclobenzaprine has several significant drug interactions that warrant careful consideration.

Monoamine Oxidase Inhibitors (MAOIs) Cyclobenzaprine may cause life-threatening interactions when used in conjunction with MAO inhibitors. The combination should be avoided due to the potential for severe adverse effects.

Serotonergic Drugs Postmarketing reports indicate that the concurrent use of Cyclobenzaprine Hydrochloride with other serotonergic agents, such as selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), tramadol, bupropion, meperidine, verapamil, or MAO inhibitors, can lead to serotonin syndrome. If the combination of Cyclobenzaprine Hydrochloride and other serotonergic drugs is deemed necessary, careful monitoring is recommended, especially during the initiation of treatment or when increasing dosages.

CNS Depressants Cyclobenzaprine may enhance the effects of alcohol, barbiturates, and other central nervous system (CNS) depressants. Caution is advised when these substances are used concurrently, and dosage adjustments may be necessary to mitigate the risk of excessive sedation.

Tricyclic Antidepressants (TCAs) TCAs may interfere with the antihypertensive effects of guanethidine and similar medications. Additionally, the use of TCAs in patients taking tramadol may increase the risk of seizures. Monitoring and potential dosage adjustments should be considered in these scenarios to ensure patient safety.

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 exhibit increased plasma concentrations of cyclobenzaprine, which necessitates careful consideration when prescribing this medication. Due to this heightened concentration, geriatric patients are at an elevated risk for central nervous system (CNS) adverse events, including hallucinations and confusion. Additionally, there is a potential for cardiac events in this population, which may lead to falls or other serious complications.

It is important to recognize that elderly patients may also be susceptible to drug-drug and drug-disease interactions, further complicating their treatment regimen. Therefore, cyclobenzaprine should be prescribed to geriatric patients only when clearly indicated.

When initiating treatment in elderly patients, it is recommended to start with a lower dose of 5 mg and to titrate the dosage slowly upward, monitoring for any adverse effects or complications throughout the treatment process. Careful monitoring and dose adjustments are essential to ensure the safety and efficacy of cyclobenzaprine in this vulnerable population.

Pregnancy

The safety of cyclobenzaprine during pregnancy has not been established. Cyclobenzaprine is contraindicated in pregnancy due to potential risks to the fetus. Women who are pregnant or planning to become pregnant should avoid using cyclobenzaprine. No specific dosage modifications are provided for use during pregnancy.

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 not been specifically addressed in the available data regarding dosage adjustments, special monitoring, or safety considerations. Therefore, healthcare professionals should exercise caution when prescribing this medication to individuals with reduced kidney function, as the lack of information necessitates careful clinical judgment and monitoring.

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

Although rare, cyclobenzaprine hydrochloride overdose can lead to fatalities, particularly in cases involving multiple drug ingestion, including alcohol. The management of such overdoses is complex and subject to change; therefore, it is imperative for healthcare professionals to contact a poison control center for the most current treatment information.

Signs and Symptoms

Toxicity symptoms may manifest rapidly following an overdose of cyclobenzaprine. Hospital monitoring is essential as soon as an overdose is suspected. The acute oral LD50 of cyclobenzaprine hydrochloride is approximately 338 mg/kg in mice and 425 mg/kg in rats. The most frequently observed effects 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, are important indicators of cyclobenzaprine toxicity.

Initial Management

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 is crucial prior to performing lavage, and emesis is contraindicated.

To mitigate the risk of severe manifestations, it is essential 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 the drug.

Advanced Management

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 undesirable. Dysrhythmias that do not respond to sodium bicarbonate therapy or hyperventilation may be treated with lidocaine, bretylium, or phenytoin. It is important to avoid Type 1A and 1C antiarrhythmics, such as quinidine, disopyramide, and procainamide.

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 used. The use of physostigmine is not advised except for life-threatening symptoms that have not responded to other treatments, and only after consulting with a poison control center.

Pediatric Considerations

The management principles for both child and adult overdoses are similar. However, it is strongly recommended that healthcare professionals consult the local poison control center for specific treatment protocols tailored to pediatric patients.

Nonclinical Toxicology

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

At oral doses of up to 10 times the human dose, cyclobenzaprine did not adversely affect the reproductive performance or fertility of male or female rats.

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, pale and sometimes enlarged livers were observed. There was a dose-related hepatocyte vacuolation with lipidosis, with these microscopic changes noted in higher dose groups after 26 weeks and even earlier in rats that died prior to this time. At lower doses, these changes were not observed until after 26 weeks.

Cyclobenzaprine did not affect the onset, incidence, or distribution of neoplasia in an 81-week study in mice or in a 105-week study in rats. Additionally, cyclobenzaprine did not demonstrate mutagenic activity in male mice at dose levels of up to 20 times the human dose.

Postmarketing Experience

Postmarketing experience has revealed additional adverse reactions associated with the use of the 10 mg tablet, reported voluntarily or through surveillance programs, with an incidence of less than 1% in clinical trials.

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 cases of hepatitis, jaundice, and cholestasis noted.

Hypersensitivity reactions include anaphylaxis, angioedema, pruritus, facial edema, urticaria, and rash. Musculoskeletal reactions consist of local weakness. The 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, diplopia, and serotonin syndrome. Skin-related reactions include sweating, while special senses reactions involve ageusia and tinnitus. Urogenital events 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 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

Patients should be cautioned about the risk of serotonin syndrome when using Cyclobenzaprine Hydrochloride in conjunction with other medications, including selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), tramadol, bupropion, meperidine, verapamil, or monoamine oxidase (MAO) inhibitors. It is important for patients to be informed about the signs and symptoms of serotonin syndrome and to seek medical care immediately if they experience any of these symptoms.

Patients should also be made aware that Cyclobenzaprine hydrochloride tablets, particularly when combined with alcohol or other central nervous system (CNS) depressants, may impair their mental and/or physical abilities necessary for performing hazardous tasks, such as operating machinery or driving a motor vehicle.

In elderly patients, the frequency and severity of adverse events associated with the use of Cyclobenzaprine may be increased, whether or not other medications are being taken concurrently. Therefore, it is recommended that Cyclobenzaprine hydrochloride tablets be initiated at a 5 mg dose in this population and titrated slowly upward.

Patients should be cautioned about the potential for drowsiness and advised not to drive or operate heavy machinery until they are aware of how Cyclobenzaprine affects them. Additionally, it should be communicated that Cyclobenzaprine is not recommended for use in children under 15 years of age, as safety and effectiveness have not been established in this age group.

Finally, patients should be advised to inform their healthcare provider if they are pregnant, plan to become pregnant, or are breastfeeding, as it is currently unknown whether Cyclobenzaprine is excreted in human milk.

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). Proper storage conditions are essential to maintain the integrity of the product.

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 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. Patients should be counseled on the potential impairment of mental and physical abilities when using cyclobenzaprine, particularly in conjunction with alcohol or other CNS depressants. Additionally, there is a risk of serotonin syndrome when cyclobenzaprine is used with certain medications, including SSRIs, SNRIs, TCAs, tramadol, bupropion, meperidine, verapamil, or MAO inhibitors. Patients should be informed of the signs and symptoms of serotonin syndrome and instructed to seek immediate medical attention if they occur.

A post-marketing surveillance program involving 7,607 patients with acute musculoskeletal disorders indicated that the effectiveness of cyclobenzaprine was consistent with findings from controlled studies, while the incidence of adverse effects was lower.

FDA Insert (PDF)

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

View full prescribing information (PDF)