Cyclobenzaprine hydrochloride

Description

Cyclobenzaprine hydrochloride, USP is a white, crystalline tricyclic amine salt with the empirical formula C20H21N•HCl and a molecular weight of 311.9. It has a melting point of 217º C and a pKa of 8.47 at 25º C. The compound is freely soluble in water and alcohol, sparingly soluble in isopropanol, and insoluble in hydrocarbon solvents. When aqueous solutions are made alkaline, the free base separates. Chemically, cyclobenzaprine hydrochloride is designated as 3-(5H-dibenzo a,d cyclohepten-5-ylidene)-N,N-dimethyl-1-propanamine hydrochloride.

Cyclobenzaprine hydrochloride tablets USP are formulated for oral administration and are available in strengths of 5 mg, 7.5 mg, and 10 mg. Each tablet contains the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, lactose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide. The 5 mg tablet includes FD&C yellow # 6, while both the 5 mg and 10 mg tablets contain iron oxide yellow.

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 benefits 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 2 to 3 weeks, as there is insufficient evidence to support the effectiveness of prolonged treatment. Muscle spasms related to acute, painful musculoskeletal conditions are typically of short duration, and extended therapy is rarely necessary.

Cyclobenzaprine hydrochloride tablets are not indicated for the treatment of spasticity associated with cerebral or spinal cord disease, nor are they effective in pediatric patients 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 if necessary.

It is important to note that the use of cyclobenzaprine hydrochloride tablets for periods longer than 2 or 3 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 potential cardiovascular complications.

Additionally, use is contraindicated in patients with hyperthyroidism, as it may exacerbate the condition.

Warnings and Precautions

The use of cyclobenzaprine hydrochloride necessitates careful consideration of several critical warnings 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, has been associated with the development of serotonin syndrome, a potentially life-threatening condition. The use of cyclobenzaprine hydrochloride in conjunction with MAO inhibitors is contraindicated. Clinicians should be vigilant for symptoms indicative of serotonin syndrome, which may include mental status changes (such as confusion, agitation, or hallucinations), autonomic instability (including diaphoresis, tachycardia, labile blood pressure, and hyperthermia), neuromuscular abnormalities (such as tremor, ataxia, hyperreflexia, clonus, and muscle rigidity), and gastrointestinal symptoms (including nausea, vomiting, and diarrhea). Should these symptoms arise, immediate discontinuation of cyclobenzaprine hydrochloride and any concomitant serotonergic agents is warranted, 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 monitoring is essential, particularly during the initiation of therapy or when adjusting dosages.

Tricyclic Antidepressants Cyclobenzaprine hydrochloride shares structural similarities with tricyclic antidepressants, such as amitriptyline and imipramine. Serious central nervous system reactions observed with tricyclic antidepressants may also occur with cyclobenzaprine. These reactions can include arrhythmias, sinus tachycardia, and prolongation of conduction time, which may lead to severe cardiovascular events such as myocardial infarction and stroke. Healthcare professionals should exercise caution when prescribing cyclobenzaprine to patients with a history of cardiovascular disease or those taking other medications that may affect cardiac conduction.

CNS Depressants The sedative effects of cyclobenzaprine hydrochloride may be potentiated when used in conjunction with alcohol, barbiturates, and other central nervous system (CNS) depressants. Clinicians should advise patients to avoid the consumption of alcohol and the use of other CNS depressants while undergoing treatment with cyclobenzaprine to mitigate the risk of excessive sedation and respiratory depression.

In summary, healthcare professionals must remain vigilant regarding the potential for serious adverse effects associated with cyclobenzaprine hydrochloride, particularly in the context of polypharmacy and patient-specific risk factors. Regular monitoring and patient education are essential components of safe prescribing practices.

Side Effects

Patients receiving treatment have reported a range of adverse reactions, categorized by frequency and seriousness.

Common adverse reactions, occurring in more than 3% of patients, include drowsiness (29% at 5 mg, 38% at 10 mg, and 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 5 mg and 10 mg, and 8% in the placebo group). Additional common adverse reactions noted in clinical studies include drowsiness (39%) and dry mouth (27%), with lower incidences reported in a surveillance program (16% for drowsiness and 7% for dry mouth). Dizziness was reported in 11% of clinical studies and 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 experiences have identified additional adverse reactions with an incidence of less than 1%. 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 adverse 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, diplopia, and serotonin syndrome. Other reactions include local weakness (musculoskeletal), sweating (skin), ageusia and tinnitus (special senses), and urinary frequency and/or retention (urogenital).

Certain adverse reactions have been reported where a causal relationship is unknown, including 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 changes like 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 encompass decreased or increased libido, abnormal gait, delusions, aggressive behavior, paranoia, peripheral neuropathy, Bell’s palsy, alterations in EEG patterns, and extrapyramidal symptoms. Respiratory reactions such as dyspnea, skin reactions including photosensitization and alopecia, and urogenital issues like impaired urination, dilatation of the urinary tract, impotence, testicular swelling, gynecomastia, breast enlargement, and galactorrhea have also been reported.

It is important to note that the development of serotonin syndrome, a potentially life-threatening condition, has been reported when cyclobenzaprine hydrochloride is used in combination with other drugs, including 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, 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 include cardiac arrest, chest pain, cardiac dysrhythmias, severe hypotension, seizures, and neuroleptic malignant syndrome.

Drug Interactions

Cyclobenzaprine has several significant drug interactions that require careful consideration.

Monoamine Oxidase Inhibitors (MAOIs) Cyclobenzaprine may cause life-threatening interactions when used in conjunction with MAO inhibitors. It is advised that cyclobenzaprine not be administered to patients currently taking MAOIs.

Serotonergic Drugs Postmarketing reports indicate that the combination 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 concurrent use of cyclobenzaprine 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 potentiate the effects of alcohol, barbiturates, and other central nervous system (CNS) depressants. Caution is advised when these substances are used together, 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 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 in pediatric patients below 15 years of age have not been established. Therefore, caution is advised when considering the use of this medication in younger populations.

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, 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, cyclobenzaprine should only be prescribed to elderly patients when clearly indicated, and consideration should be given to less frequent dosing regimens to minimize potential risks associated with increased plasma levels.

Pregnancy

Pregnancy Category B indicates that 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 due to 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 any possible 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 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

There is no specific information available regarding dosage adjustments, special monitoring, or safety considerations for patients with renal impairment. Healthcare professionals should exercise caution when prescribing to patients with reduced kidney function, as the absence of detailed guidance necessitates careful clinical judgment. Regular monitoring of renal function may be advisable in 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 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. Rare but critical complications 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. Additional symptoms may align with those listed under ADVERSE REACTIONS.

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, 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 ≥0.10 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 using intravenous sodium bicarbonate, along with hyperventilation as needed, should be initiated. 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, 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 ineffective, other anticonvulsants such as phenobarbital or phenytoin. The use of physostigmine is not advised except for life-threatening symptoms unresponsive to other treatments, and only after consultation with a poison control center.

Psychiatric Considerations Given that overdosage is often intentional, there is a risk that patients may attempt suicide by other means during the recovery phase. Therefore, a psychiatric referral may be appropriate.

The management principles for both child and adult overdosages are similar. It is highly recommended that physicians consult the local poison control center for specific pediatric treatment guidelines.

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. However, there are no adequate and well-controlled studies in pregnant women. Due to the limitations of animal reproduction studies in predicting human responses, cyclobenzaprine should be used during pregnancy only if clearly needed.

In terms of non-teratogenic effects, cyclobenzaprine did not adversely affect the reproductive performance or fertility of male or female rats at oral doses of up to 10 times the human dose. Additionally, cyclobenzaprine did not exhibit mutagenic activity in male mice at dose levels of up to 20 times the human dose.

Nonclinical studies involving rats treated with cyclobenzaprine for up to 67 weeks at doses ranging from approximately 5 to 40 times the maximum recommended human dose revealed pale, occasionally enlarged livers, along with dose-related hepatocyte vacuolation and lipidosis. In 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.

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, including reserpine antagonism, norepinephrine potentiation, and significant peripheral and central anticholinergic effects, as well as sedation. Cyclobenzaprine was also associated with a slight to moderate increase in heart rate in animal studies.

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, 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 noted are local weakness. In the Nervous System and Psychiatric categories, 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 have been reported.

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 under circumstances where a causal relationship could not be established, or reported for other tricyclic drugs. These include chest pain and edema in the Body as a Whole category; hypertension, myocardial infarction, heart block, and stroke in the Cardiovascular category; and paralytic ileus, tongue discoloration, stomatitis, and parotid swelling in the Digestive category. Endocrine reactions include inappropriate ADH syndrome.

Hematic and Lymphatic reactions consist of purpura, bone marrow depression, leukopenia, eosinophilia, and thrombocytopenia. Metabolic, Nutritional, and Immune reactions include elevation and lowering of blood sugar levels, as well as weight gain or loss. Musculoskeletal reactions noted are myalgia.

In the Nervous System and Psychiatric categories, decreased or increased libido, abnormal gait, delusions, aggressive behavior, paranoia, peripheral neuropathy, Bell’s palsy, alteration in EEG patterns, and extrapyramidal symptoms have been reported. Respiratory reactions include dyspnea. Skin reactions also include photosensitization and alopecia. Urogenital reactions reported are impaired urination, dilatation of the urinary tract, impotence, testicular swelling, gynecomastia, breast enlargement, and galactorrhea.

Patient Counseling

Healthcare providers should advise patients that cyclobenzaprine, 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, healthcare providers should recommend initiating treatment with a 5 mg dose of cyclobenzaprine and advise a gradual titration upward as needed.

Patients should also be cautioned about the potential risk of serotonin syndrome when cyclobenzaprine is used alongside other medications, such as selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), tramadol, bupropion, meperidine, verapamil, or monoamine oxidase inhibitors (MAOIs).

Healthcare providers should ensure that patients are aware of the signs and symptoms of serotonin syndrome, instructing them to seek immediate medical attention if they experience any of these symptoms.

Storage and Handling

The product is supplied in a tight, light-resistant container, compliant with USP standards, and features a child-resistant closure to ensure safety. It should be stored at a temperature range of 20º to 25°C (68º to 77°F), in accordance with USP Controlled Room Temperature guidelines. Proper storage conditions are essential to maintain the integrity and efficacy of the product.

Additional Clinical Information

Laboratory tests related to cyclobenzaprine do not provide additional information. 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 dosage for cyclobenzaprine hydrochloride tablets is 5 mg taken three times daily, with the possibility of increasing to 10 mg three times daily based on individual patient response. Prolonged use beyond 2 to 3 weeks is not advised. Patients should be counseled on the potential for impaired 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 postmarketing surveillance program involving 7,607 patients indicated that the effectiveness of cyclobenzaprine was consistent with 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 Jubilant Cadista Pharmaceuticals Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)