Cyclobenzaprine hydrochloride

Description

Cyclobenzaprine hydrochloride, USP is a white to off-white crystalline powder with the molecular 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, alcohol, and methanol; sparingly soluble in isopropanol; slightly soluble in chloroform and methylene chloride; and insoluble in hydrocarbons. 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, with each tablet containing 7.5 mg of the active ingredient. The tablets also include the following inactive ingredients: corn starch, hydroxypropyl cellulose, hypromellose, lactose monohydrate, magnesium stearate, polyethylene glycol, pregelatinized starch, talc, and titanium dioxide.

Uses and Indications

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

This medication 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 typically resolve within a short duration. Therefore, specific therapy for extended periods is seldom warranted.

Cyclobenzaprine hydrochloride tablets, USP have not demonstrated efficacy in treating spasticity associated with cerebral or spinal cord diseases, nor are they indicated for use 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 either 7.5 mg or 10 mg, also taken three times a day.

It is important to note that the use of cyclobenzaprine hydrochloride tablets for durations exceeding two to three weeks is not recommended. Additionally, for patients who are elderly or have hepatic impairment, 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 this 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 and in patients with arrhythmias, heart block, conduction disturbances, or congestive heart failure due to potential cardiovascular risks.

Patients with hyperthyroidism should not use this product, as it may exacerbate their condition.

Warnings and Precautions

The use of cyclobenzaprine hydrochloride necessitates careful consideration of potential risks and the implementation of appropriate precautions to ensure patient safety.

Serotonin Syndrome The concomitant use of cyclobenzaprine hydrochloride with 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. The use of cyclobenzaprine hydrochloride in conjunction with MAO inhibitors is contraindicated. Symptoms of serotonin syndrome may 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 reactions, immediate discontinuation of cyclobenzaprine hydrochloride and any concomitant serotonergic agents is required, along with the initiation of supportive symptomatic treatment. If the clinical decision is made to continue treatment with cyclobenzaprine hydrochloride alongside other serotonergic drugs, careful observation is essential, particularly during the initiation of therapy or when increasing doses.

Central Nervous System Effects Cyclobenzaprine hydrochloride shares structural similarities with 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 exceeding those recommended for muscle spasm, serious central nervous system reactions similar to those observed with tricyclic antidepressants have been reported.

Cardiovascular Risks Tricyclic antidepressants, which are closely related to cyclobenzaprine, have been associated with cardiovascular complications, including arrhythmias, sinus tachycardia, and prolongation of conduction time, which may lead to myocardial infarction and stroke.

CNS Depressant Interactions Cyclobenzaprine hydrochloride may potentiate the effects of alcohol, barbiturates, and other central nervous system (CNS) depressants. Caution is advised when prescribing cyclobenzaprine to patients who are concurrently using these substances, as the risk of additive CNS depression may increase.

Healthcare professionals are encouraged to monitor patients closely for any signs of adverse reactions and to conduct appropriate laboratory tests as necessary to ensure safe use of cyclobenzaprine hydrochloride.

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

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.

Serious adverse reactions have also been documented. These include syncope and malaise under the body as a whole category, as well as cardiovascular events such as tachycardia, arrhythmia, vasodilatation, palpitations, and hypotension. Digestive system reactions may involve vomiting, anorexia, gastrointestinal pain, gastritis, thirst, flatulence, edema of the tongue, and abnormal liver function, with rare reports of hepatitis, jaundice, and cholestasis. Hypersensitivity reactions can manifest as anaphylaxis, angioedema, pruritus, facial edema, urticaria, and rash.

Nervous system and psychiatric adverse reactions are notable, including 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. Additional reactions may include local weakness in the musculoskeletal system, sweating in the skin, ageusia and tinnitus in the special senses, and urinary frequency and/or retention in the urogenital system.

Rare adverse reactions, for which a causal relationship is unknown, encompass a variety of systems. These include chest pain and edema under the body as a whole, hypertension, myocardial infarction, heart block, and stroke in the cardiovascular system. Digestive system reactions may involve paralytic ileus, tongue discoloration, stomatitis, and parotid swelling. Endocrine reactions can include inappropriate ADH syndrome, while hematologic and lymphatic reactions may present as purpura, bone marrow depression, leukopenia, eosinophilia, and thrombocytopenia. Metabolic, nutritional, and immune reactions may involve elevation and lowering of blood sugar levels, as well as weight gain or loss. Musculoskeletal reactions can include myalgia, while nervous system and psychiatric reactions may present as decreased or increased libido, abnormal gait, delusions, aggressive behavior, paranoia, peripheral neuropathy, Bell’s palsy, alteration in EEG patterns, and extrapyramidal symptoms. Respiratory reactions may include dyspnea, and skin reactions can manifest as photosensitization and alopecia. Urogenital reactions may involve impaired urination, dilatation of the urinary tract, impotence, testicular swelling, gynecomastia, breast enlargement, and galactorrhea.

The development of serotonin syndrome, a potentially life-threatening condition, has been reported when cyclobenzaprine hydrochloride is used in combination with other drugs. Symptoms may include mental status changes, autonomic instability, neuromuscular abnormalities, and gastrointestinal symptoms.

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 potentially critical manifestations can include cardiac arrest, chest pain, cardiac dysrhythmias, severe hypotension, seizures, and neuroleptic malignant syndrome.

Drug Interactions

Cyclobenzaprine has several significant drug interactions that warrant careful consideration during treatment.

Monoamine Oxidase Inhibitors (MAOIs) Cyclobenzaprine may cause life-threatening interactions when used in conjunction with MAO inhibitors. It is advised to avoid this combination due to the potential for severe adverse effects.

Serotonergic Drugs Postmarketing reports indicate that the concurrent use of cyclobenzaprine hydrochloride with other serotonergic agents can lead to serotonin syndrome. This risk is particularly noted with the following drug classes and agents:

• Selective serotonin reuptake inhibitors (SSRIs)

• Serotonin norepinephrine reuptake inhibitors (SNRIs)

• Tricyclic antidepressants (TCAs)

• Tramadol

• Bupropion

• Meperidine

• Verapamil

If the combination of cyclobenzaprine hydrochloride and any serotonergic drugs is deemed necessary, careful monitoring is recommended, especially during the initiation of treatment or when adjusting dosages.

CNS Depressants Cyclobenzaprine hydrochloride may potentiate 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) The use of tricyclic antidepressants may interfere with the antihypertensive effects of guanethidine and similar medications. Additionally, TCAs can increase the risk of seizures in patients who are also taking tramadol. Monitoring for these interactions is recommended 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 tablets 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 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 AUC values approximately 2.4 times higher than their younger counterparts, while elderly females showed a lesser increase of about 1.2 times.

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

Cyclobenzaprine hydrochloride tablets should only be prescribed to elderly patients when clearly indicated, given the increased frequency and severity of adverse events associated with its use, whether alone or in conjunction with other medications. Caution is advised when considering treatment in this population, and ongoing assessment of the patient's response and tolerance to the medication is recommended.

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 tablets 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 patients with reduced kidney function, as the lack of information necessitates careful clinical judgment and monitoring of these patients.

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 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, healthcare professionals are strongly advised to contact a poison control center for the most current treatment information.

Signs and Symptoms of Toxicity

Symptoms of cyclobenzaprine overdose can develop rapidly, necessitating immediate hospital monitoring. The most common effects include drowsiness and tachycardia. Other less frequent manifestations may involve tremor, agitation, coma, ataxia, hypertension, slurred speech, confusion, dizziness, nausea, vomiting, and hallucinations. Rare but critical symptoms can include cardiac arrest, chest pain, cardiac dysrhythmias, severe hypotension, seizures, and neuroleptic malignant syndrome. Clinically significant changes in the electrocardiogram, particularly alterations in the QRS axis or width, should be closely monitored.

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. If the patient is unconscious, securing the airway is essential prior to lavage, and emesis is contraindicated. Continuous cardiac monitoring is necessary to observe for signs of central nervous system (CNS) or respiratory depression, hypotension, cardiac dysrhythmias, conduction blocks, and seizures. Extended monitoring is warranted if any signs of toxicity arise during this period.

In cases where dysrhythmias or QRS widening is present, serum alkalinization should be initiated using intravenous sodium bicarbonate, aiming for a pH of 7.45 to 7.55, along with hyperventilation as needed. A pH greater than 7.60 or a pCO2 less than 20 mmHg is considered undesirable. If dysrhythmias do not respond to sodium bicarbonate therapy or hyperventilation, alternative treatments such as lidocaine, bretylium, or phenytoin may be effective. It is important to avoid Type 1A and 1C antiarrhythmics, such as quinidine, disopyramide, and procainamide.

In patients exhibiting CNS depression, early intubation is recommended due to the risk of sudden deterioration. Seizures should be managed with benzodiazepines, and if these are ineffective, other anticonvulsants such as phenobarbital or phenytoin may be utilized. The use of physostigmine is not recommended except for life-threatening symptoms that do not respond to other therapies, and only after consulting 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, and it is strongly recommended that physicians contact 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. Additionally, oral administration of cyclobenzaprine at doses up to 10 times the human dose did not adversely affect the reproductive performance or fertility of male or female rats.

In long-term animal studies, rats treated with cyclobenzaprine hydrochloride for up to 67 weeks at doses ranging from approximately 5 to 40 times the maximum recommended human dose exhibited pale, sometimes enlarged livers, along with dose-related hepatocyte vacuolation and lipidosis. In the higher dose groups, these microscopic changes were observed after 26 weeks, and even earlier in rats that died prior to this time. At lower doses, these changes were not evident until after 26 weeks of treatment.

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. Furthermore, cyclobenzaprine did not demonstrate mutagenic activity in male mice at dose levels of up to 20 times the human dose.

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, diplopia, and serotonin syndrome. 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 hydrochloride under circumstances where a causal relationship could not be established, or reported for other tricyclic drugs, and are provided as alerting information to physicians. These include:

In the Body as a Whole category, chest pain and edema have been noted. Cardiovascular reactions include hypertension, myocardial infarction, heart block, and stroke. Digestive system reactions consist of paralytic ileus, tongue discoloration, stomatitis, and parotid swelling. Endocrine reactions include inappropriate ADH syndrome. Hematic and lymphatic reactions reported are purpura, bone marrow depression, leukopenia, eosinophilia, and thrombocytopenia.

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

Patient Counseling

Patients should be cautioned about the risk of serotonin syndrome associated with the concomitant use of cyclobenzaprine hydrochloride and 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. Healthcare providers should advise patients to be aware of the signs and symptoms of serotonin syndrome, such as confusion, rapid heart rate, and severe muscle rigidity, and instruct them to seek medical care immediately if they experience these symptoms.

It is important to inform patients that cyclobenzaprine hydrochloride, particularly when used in conjunction with alcohol or other central nervous system (CNS) depressants, may impair their mental and/or physical abilities necessary for performing hazardous tasks, including operating machinery or driving a motor vehicle.

In elderly patients, the frequency and severity of adverse events associated with cyclobenzaprine use, whether alone or with other medications, may be increased. Therefore, healthcare providers should recommend initiating treatment with a 5 mg dose in this population and titrating slowly upward as needed.

Patients should also 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. Furthermore, it is essential to inform patients that cyclobenzaprine hydrochloride tablets are intended for short-term use only, typically up to two or three weeks, as there is insufficient evidence to support the effectiveness of prolonged use. Lastly, patients should be advised to avoid using cyclobenzaprine hydrochloride in combination with MAO inhibitors due to the risk of serious interactions.

Storage and Handling

The product is supplied in various package configurations, with specific NDC numbers available for identification. 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. Proper storage conditions must be maintained to ensure the integrity and efficacy of the product.

Additional Clinical Information

Pharmacologic similarities among tricyclic drugs necessitate consideration of potential withdrawal symptoms when administering cyclobenzaprine hydrochloride, despite such symptoms not being reported with this medication. Abrupt discontinuation after prolonged use may rarely lead to nausea, headache, and malaise, which are not indicative of addiction.

Clinicians should counsel patients regarding the potential impairment of mental and physical abilities when cyclobenzaprine hydrochloride is used in conjunction with alcohol or other CNS depressants, particularly in relation to hazardous activities such as operating machinery or driving. Additionally, there is a risk of serotonin syndrome when cyclobenzaprine hydrochloride 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 advised to seek immediate medical attention if they occur. A postmarketing surveillance program involving 7,607 patients with acute musculoskeletal disorders indicated that the overall effectiveness of cyclobenzaprine hydrochloride was consistent 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 Doc Rx. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)