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 exhibits a melting point of 217° C and has 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. It is supplied in tablet form for oral administration, available in dosages of 5 mg, 7.5 mg, and 10 mg. The inactive ingredients in the 5 mg and 10 mg tablets include corn starch, ferric oxide red (for 5 mg tablets), ferric oxide yellow (for 10 mg tablets), FD&C yellow #6 aluminum lake (for 5 mg tablets), 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 should be utilized 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 extended therapy is rarely necessary.

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

Dosage and Administration

The recommended dose of cyclobenzaprine hydrochloride tablets is 5 mg administered three times a day. Based on individual patient response, the dose 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 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 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. This is due to the potential for hyperpyretic crisis, seizures, and fatalities associated with the combination of cyclobenzaprine 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, conduction disturbances, or congestive heart failure, due to the risk of exacerbating these conditions.

Patients with hyperthyroidism should not use this product, as it may worsen 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 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. 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). Should these symptoms occur, immediate discontinuation of cyclobenzaprine hydrochloride and any concomitant serotonergic agents is imperative, 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 dosages.

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. Healthcare professionals should exercise caution when prescribing cyclobenzaprine hydrochloride to patients who are concurrently using these substances, as the risk of additive CNS depression may be significant.

Monitoring parameters should include assessment of mental status, cardiovascular function, and any signs of serotonin syndrome, particularly in patients receiving concomitant serotonergic medications or CNS depressants.

Side Effects

Patients may experience a range of adverse reactions while using the medication. 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 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.

Additional adverse reactions have been reported across various systems. In the body as a whole, syncope and malaise have been noted. Cardiovascular effects include tachycardia, arrhythmia, vasodilatation, palpitations, and hypotension. Digestive system reactions may involve vomiting, anorexia, gastrointestinal pain, gastritis, thirst, flatulence, edema of the tongue, abnormal liver function, and rare instances of hepatitis, jaundice, and cholestasis. Hypersensitivity reactions can manifest as anaphylaxis, angioedema, pruritus, facial edema, urticaria, and rash.

Nervous system and psychiatric adverse reactions 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. Musculoskeletal reactions may present as local weakness, while skin reactions can include sweating. Special senses may be affected, leading to ageusia and tinnitus, and urogenital issues may involve urinary frequency and/or retention.

Rare adverse reactions, for which a causal relationship is unknown, include chest pain and edema in the body as a whole, hypertension, myocardial infarction, heart block, and stroke in the cardiovascular system. Digestive system reactions may include paralytic ileus, tongue discoloration, stomatitis, and parotid swelling. Endocrine reactions can involve inappropriate ADH syndrome. Hematic and lymphatic reactions may present as purpura, bone marrow depression, leukopenia, eosinophilia, and thrombocytopenia. Metabolic, nutritional, and immune reactions may lead to elevation and lowering of blood sugar levels, as well as weight gain or loss. Musculoskeletal reactions can include myalgia, while psychiatric effects may involve decreased or increased libido, abnormal gait, delusions, aggressive behavior, paranoia, peripheral neuropathy, Bell’s palsy, alteration in EEG patterns, and extrapyramidal symptoms. Respiratory reactions 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 the medication is used in combination with other drugs 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 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 notable drug interactions that warrant careful consideration, particularly regarding the potential for serious adverse effects.

Monoamine Oxidase Inhibitors (MAOIs) Cyclobenzaprine may cause life-threatening interactions when used in conjunction with MAO inhibitors. Co-administration is contraindicated due to the risk of severe reactions.

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

• Selective serotonin reuptake inhibitors (SSRIs)

• Serotonin norepinephrine reuptake inhibitors (SNRIs)

• Tricyclic antidepressants (TCAs)

• Tramadol

• Bupropion

• Meperidine

• Verapamil

If the use of cyclobenzaprine hydrochloride alongside these serotonergic drugs is deemed necessary, it is essential to implement careful monitoring, 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, there is an increased risk of seizures in patients taking tramadol when concurrently using tricyclic antidepressants. Monitoring for these effects 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

The 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 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 hydrochloride in geriatric patients should be initiated at a lower dose of 5 mg, with a gradual titration to achieve the desired therapeutic effect. It is crucial to monitor these patients closely, as they may be at an elevated risk for central nervous system (CNS) adverse events, including hallucinations and confusion, as well as cardiac events that could lead to falls or other complications.

Furthermore, the frequency and severity of adverse events associated with cyclobenzaprine use are increased in elderly patients, regardless of whether they are taking concomitant medications. Therefore, cyclobenzaprine should only be prescribed to geriatric patients when clearly indicated, and ongoing assessment of the patient's response and tolerance to the medication is essential.

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 hydrochloride. 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

There is no specific information 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 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 overdosage can lead to fatal outcomes. It is important to note that multiple drug ingestion, including alcohol, is frequently associated with deliberate cyclobenzaprine overdose.

Signs and Symptoms

Toxicity symptoms may manifest rapidly following an overdose, necessitating immediate hospital monitoring. The most common effects observed include drowsiness and tachycardia. Other less frequent symptoms may encompass 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 the QRS axis or width, should be closely monitored.

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 protocols. 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 critical, and emesis should be avoided.

Immediate cardiac monitoring is essential, particularly for patients exhibiting signs of CNS or respiratory depression, hypotension, cardiac dysrhythmias, conduction blocks, or seizures. A maximal limb-lead QRS duration of ≥ 0.10 seconds may serve as a key indicator of overdose severity.

In cases of dysrhythmias or QRS widening, serum alkalinization should be initiated using intravenous sodium bicarbonate, with hyperventilation as necessary. It is important to maintain a pH between 7.45 and 7.55, as values exceeding 7.60 or a pCO2 below 20 mmHg are 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 patients exhibiting CNS depression, early intubation is recommended due to the risk of sudden deterioration. Seizures should be managed with benzodiazepines, or if ineffective, alternative anticonvulsants such as phenobarbital or phenytoin may be utilized. The use of physostigmine is not recommended except for life-threatening symptoms unresponsive to other treatments, and only after consulting a poison control center.

Additional Considerations

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; however, it is strongly recommended that physicians consult the local poison control center for specific pediatric treatment guidance. Monitoring of plasma drug levels should not dictate patient management, and dialysis is likely ineffective due to the low plasma concentrations of cyclobenzaprine.

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 either male or female rats.

Cyclobenzaprine did not exhibit mutagenic activity in male mice at dose levels of up to 20 times the human dose. Furthermore, in long-term studies, cyclobenzaprine did not influence the onset, incidence, or distribution of neoplasia in an 81-week study in mice or a 105-week study in rats.

In animal pharmacology and toxicology assessments, 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, occasionally enlarged livers. A dose-related hepatocyte vacuolation with lipidosis was observed, with this microscopic change appearing in higher dose groups after 26 weeks and even earlier in rats that died prior to this time. In lower dose groups, the change was not observed until after 26 weeks.

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 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 noted. 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 included for alerting information to physicians. 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 also include myalgia.

In the 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 encompass photosensitization and alopecia. Lastly, 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. It is important for healthcare providers to inform patients of the signs and symptoms of serotonin syndrome, advising them to seek medical care immediately if they experience any of these symptoms.

Healthcare providers should also discuss the potential for cyclobenzaprine hydrochloride to impair mental and/or physical abilities necessary for performing hazardous tasks, such as operating machinery or driving a motor vehicle, particularly when used in conjunction with alcohol or other central nervous system (CNS) depressants.

For elderly patients, it is recommended that cyclobenzaprine hydrochloride tablets be initiated at a 5 mg dose, with a gradual titration upward as needed. Patients should be informed that therapy with cyclobenzaprine hydrochloride is intended for short-term use only, typically up to two or three weeks, as there is insufficient evidence to support its effectiveness for longer durations.

Additionally, patients should be cautioned about their increased susceptibility to drugs with potentially sedating effects, including cyclobenzaprine, especially in those with hepatic impairment. Healthcare providers must advise patients to avoid the use of cyclobenzaprine hydrochloride in combination with MAO inhibitors due to the risk of life-threatening interactions.

Storage and Handling

The product is supplied in accordance with the National Drug Code (NDC) specifications. It should be stored at a temperature range of 20 to 25° C (68 to 77° F), adhering to the guidelines set forth by the United States Pharmacopeia (USP) for Controlled Room Temperature. Proper storage conditions are essential to maintain the integrity and efficacy of the product.

Additional Clinical Information

No additional information found.

FDA Insert (PDF)

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

View full prescribing information (PDF)