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 g/mol. It exhibits a melting point of 217˚C and a pKa of 8.47 at 25˚C. The compound is freely soluble in water and alcohol, sparingly soluble in isopropanol, and insoluble in hydrocarbon solvents. When aqueous solutions are made alkaline, the free base separates.

Chemically, cyclobenzaprine HCl is designated as 3-(5H–dibenzoa,dcyclohepten-5-ylidene)-N,N-dimethyl-1-propanamine hydrochloride. The structural formula is provided in the accompanying documentation.

Cyclobenzaprine HCl, USP is available in two oral tablet formulations: 5 mg and 10 mg. The 5 mg tablets contain the following inactive ingredients: lactose monohydrate, microcrystalline cellulose, pregelatinized starch, colloidal silicon dioxide, magnesium stearate, and opadry beige (composed of hypromellose 6cP, titanium dioxide, PEG 400, iron oxide yellow, and iron oxide red). The 10 mg tablets include lactose monohydrate, microcrystalline cellulose, pregelatinized starch, colloidal silicon dioxide, magnesium stearate, and opadry yellow (composed of hypromellose 3cp, hypromellose 6cp, titanium dioxide, PEG 400, iron oxide yellow, and polysorbate 80).

Uses and Indications

Cyclobenzaprine HCl tablets USP are indicated as an adjunct to rest and physical therapy for the relief of muscle spasm associated with acute, painful musculoskeletal conditions. The therapeutic benefit 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 drug should be utilized for short durations, specifically up to two or three weeks, as there is insufficient evidence supporting its effectiveness for extended use. Muscle spasms related to acute, painful musculoskeletal conditions are typically of brief duration, and prolonged specific therapy is rarely necessary.

Cyclobenzaprine HCl is not indicated for the treatment of spasticity associated with cerebral or spinal cord diseases, nor is it effective in pediatric patients with cerebral palsy.

Dosage and Administration

The recommended dose of cyclobenzaprine HCl tablets USP for most patients is 5 mg administered three times a day. Based on individual patient response, the dosage may be increased to 10 mg three times a day.

It is important to note that the use of cyclobenzaprine HCl tablets USP for periods 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 the product.

Concomitant use with monoamine oxidase (MAO) inhibitors or within 14 days of their discontinuation is contraindicated due to the risk of hyperpyretic crisis, seizures, and fatalities associated with the combination of cyclobenzaprine and MAO inhibitors.

The product is contraindicated in the acute recovery phase of myocardial infarction, as well as in patients with arrhythmias, heart block or conduction disturbances, or congestive heart failure, due to potential cardiovascular risks.

Use is also contraindicated in patients with hyperthyroidism, as it may exacerbate the condition.

Warnings and Precautions

The use of Cyclobenzaprine Hydrochloride necessitates careful consideration of potential risks associated with its administration, particularly concerning serotonin syndrome and interactions with other medications.

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 inhibitors (MAOIs), 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 concurrent use of Cyclobenzaprine Hydrochloride and other serotonergic drugs, careful observation is advised, particularly during the initiation of treatment or when increasing the dosage.

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, which share pharmacological properties with Cyclobenzaprine, have been associated with arrhythmias, sinus tachycardia, and prolongation of conduction time, potentially leading to myocardial infarction and stroke.

CNS Depressant Interactions Cyclobenzaprine Hydrochloride may potentiate the effects of alcohol, barbiturates, and other central nervous system depressants, necessitating caution when these substances are used concurrently.

Healthcare professionals are advised to monitor patients closely for any signs of adverse reactions, particularly when initiating treatment or adjusting dosages, to ensure patient safety and mitigate risks associated with Cyclobenzaprine Hydrochloride.

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, dry mouth, and dizziness.

Less common adverse reactions, with an incidence between 1% and 3%, encompass a variety of symptoms such as abdominal pain, acid regurgitation, constipation, diarrhea, dizziness, nausea, irritability, decreased mental acuity, nervousness, upper respiratory infections, pharyngitis, fatigue, asthenia, dyspepsia, unpleasant taste, blurred vision, headache, and confusion.

Additional adverse reactions, reported in less than 1% of patients, include serious and potentially severe effects across multiple systems. Notable reactions in the body as a whole include syncope and malaise. Cardiovascular effects may involve tachycardia, arrhythmia, vasodilatation, palpitations, and hypotension. Digestive system reactions can include vomiting, anorexia, gastrointestinal pain, gastritis, thirst, flatulence, edema of the tongue, abnormal liver function, and rare reports of hepatitis, jaundice, and cholestasis. Hypersensitivity reactions may manifest as anaphylaxis, angioedema, pruritus, facial edema, urticaria, and rash.

Nervous system and psychiatric adverse reactions are particularly concerning and may include seizures, ataxia, vertigo, dysarthria, tremors, hypertonia, convulsions, muscle twitching, disorientation, insomnia, depressed mood, anxiety, agitation, psychosis, abnormal thinking and dreaming, hallucinations, excitement, paresthesia, and diplopia. 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.

Certain adverse reactions have an unknown causal relationship with the medication. These include chest pain and edema in the body as a whole; hypertension, myocardial infarction, heart block, and stroke in the cardiovascular system; paralytic ileus, tongue discoloration, stomatitis, and parotid swelling in the digestive system; inappropriate ADH syndrome in the endocrine system; and various hematologic and lymphatic reactions such as purpura, bone marrow depression, leukopenia, eosinophilia, and thrombocytopenia. Metabolic, nutritional, and immune responses may include fluctuations in blood sugar levels and weight changes. Musculoskeletal symptoms may involve myalgia, while nervous system and psychiatric effects can include libido changes, abnormal gait, delusions, aggressive behavior, paranoia, peripheral neuropathy, Bell's palsy, alterations in EEG patterns, and extrapyramidal symptoms. Respiratory issues may present as dyspnea, and skin reactions can include photosensitization and alopecia. Urogenital effects may involve impaired urination, dilatation of the urinary tract, impotence, testicular swelling, gynecomastia, breast enlargement, and galactorrhea.

A serious warning is associated with the potential development of serotonin syndrome, which can occur when the medication is used in combination with other drugs such as SSRIs, SNRIs, TCAs, tramadol, bupropion, meperidine, verapamil, or MAO inhibitors. Symptoms of serotonin syndrome may include 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 cases of overdose, the most common effects reported are drowsiness and tachycardia. Less frequent manifestations may include tremor, agitation, coma, ataxia, hypertension, slurred speech, confusion, dizziness, nausea, vomiting, and hallucinations. Rare but critical manifestations of overdose can include cardiac arrest, chest pain, cardiac dysrhythmias, severe hypotension, seizures, and neuroleptic malignant syndrome.

Drug Interactions

Cyclobenzaprine HCl is associated with significant drug interactions that warrant careful consideration during concurrent therapy.

Serotonergic Drugs Cyclobenzaprine HCl may lead to life-threatening interactions when used in conjunction with monoamine oxidase inhibitors (MAOIs). There have been postmarketing reports of serotonin syndrome occurring with the combined use of Cyclobenzaprine Hydrochloride and other serotonergic agents, including selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), tramadol, bupropion, meperidine, and verapamil. If the combination of Cyclobenzaprine Hydrochloride and other serotonergic drugs is deemed necessary, it is essential to conduct careful observation, particularly during the initiation of treatment or when increasing dosages.

CNS Depressants Cyclobenzaprine HCl may potentiate the effects of alcohol, barbiturates, and other central nervous system (CNS) depressants. Caution is advised when these substances are used concurrently, as the risk of enhanced sedation and respiratory depression may increase.

Tricyclic Antidepressants Tricyclic antidepressants may interfere with the antihypertensive effects of guanethidine and similar compounds. Clinicians should monitor blood pressure closely in patients receiving this combination. Additionally, tricyclic antidepressants may increase the risk of seizures in patients taking tramadol, necessitating careful assessment of seizure history and monitoring for seizure activity in these patients.

Packaging & NDC

The table below lists all NDC Code configurations of Cyclobenzaprine Hydrochloride (cyclobenzaprine), the U.S. brand-name prescription product. Columns show Packaging, Formulation Type, and Active Ingredient Strength.

Pediatric Use

Safety and effectiveness of cyclobenzaprine HCl 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. A pharmacokinetic study demonstrated that mean steady-state area under the curve (AUC) values for cyclobenzaprine in individuals aged 65 years and older were approximately 1.7 times higher than those observed in younger adults. Notably, elderly male subjects exhibited the highest mean increase, approximately 2.4 times, while elderly females showed a lesser increase of about 1.2 times.

Given these pharmacokinetic findings, it is recommended that therapy with cyclobenzaprine HCl in geriatric patients be initiated at a lower dose of 5 mg, with careful and gradual titration to achieve the desired therapeutic effect.

Additionally, elderly patients 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. There is also a heightened potential for drug-drug and drug-disease interactions in this population. Therefore, cyclobenzaprine should be prescribed to elderly patients only when clearly indicated, with appropriate monitoring for adverse effects and therapeutic efficacy.

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 HCl. The drug is classified as Pregnancy Category B. 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 HCl 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 HCl 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 no specific information regarding dosage adjustments, special monitoring, or safety considerations provided in the text. Therefore, healthcare professionals should exercise caution and consider individual patient factors when prescribing to this population. Regular assessment of renal function may be warranted to ensure safe and effective use of the medication in patients with reduced kidney function.

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

Overdosage with cyclobenzaprine HCl, although rare, can lead to severe outcomes, including death. It is important to note that deliberate overdose often involves the co-ingestion of multiple substances, including alcohol.

Clinical Presentation and Symptoms

Signs and symptoms of cyclobenzaprine toxicity may manifest rapidly following an overdose. 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. Rarely, critical manifestations such as cardiac arrest, chest pain, cardiac dysrhythmias, severe hypotension, seizures, and neuroleptic malignant syndrome may occur. Clinicians should be vigilant for changes in the electrocardiogram, particularly alterations in the QRS axis or width, as these are significant indicators of toxicity.

Management Recommendations

Given 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's consciousness is impaired, securing the airway is critical prior to performing lavage, and emesis is contraindicated.

A maximal limb-lead QRS duration of ≥0.10 seconds may serve as a key indicator of overdose severity. For patients exhibiting dysrhythmias and/or QRS widening, serum alkalinization should be initiated to achieve a pH of 7.45 to 7.55, utilizing intravenous sodium bicarbonate and hyperventilation as necessary. In cases where dysrhythmias do not respond to sodium bicarbonate therapy or hyperventilation, alternative treatments such as lidocaine, bretylium, or phenytoin may be effective.

In patients presenting with central nervous system (CNS) depression, early intubation is recommended due to the risk of sudden deterioration. Seizures should be managed with benzodiazepines; if these are ineffective, other anticonvulsants such as phenobarbital or phenytoin may be utilized. The use of physostigmine is not recommended except in life-threatening situations that do not respond to other therapies, and only after consulting with a poison control center.

Pediatric Considerations

The management principles for both child and adult overdosages are similar. However, it is imperative that physicians consult the local poison control center for specific treatment recommendations tailored to pediatric patients.

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 HCl. 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, mutagenicity studies indicated that cyclobenzaprine did not demonstrate mutagenic activity in male mice at dose levels of up to 20 times the human dose.

In nonclinical toxicology assessments, rats treated with cyclobenzaprine HCl 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 higher dose groups, these microscopic changes were observed after 26 weeks, and in some cases, even earlier in rats that died prior to 26 weeks. 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. Pharmacological studies in animals revealed effects similar to those of structurally related tricyclic antidepressants, including reserpine antagonism, norepinephrine potentiation, potent peripheral and central anticholinergic effects, and sedation. Furthermore, cyclobenzaprine caused a slight to moderate increase in heart rate in animal studies.

Postmarketing Experience

A post-marketing surveillance program involving 7,607 patients with acute musculoskeletal disorders included 297 patients treated with cyclobenzaprine HCl tablets, 10 mg for 30 days or longer. The overall effectiveness of cyclobenzaprine HCl was comparable to that observed in double-blind controlled studies, with a lower overall incidence of adverse effects.

The following adverse reactions have been reported in post-marketing experience or with an incidence of less than 1% of patients in clinical trials with the 10 mg tablet:

Body as a Whole: Syncope; malaise. Cardiovascular: Tachycardia; arrhythmia; vasodilatation; palpitation; hypotension. Digestive: Vomiting; anorexia; diarrhea; gastrointestinal pain; gastritis; thirst; flatulence; edema of the tongue; abnormal liver function; rare reports of hepatitis, jaundice, and cholestasis. Hypersensitivity: Anaphylaxis; angioedema; pruritus; facial edema; urticaria; rash. Musculoskeletal: Local weakness. Nervous System and Psychiatric: 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. Skin: Sweating. Special Senses: Ageusia; tinnitus. Urogenital: Urinary frequency and/or retention.

Other reactions reported rarely for cyclobenzaprine HCl, where a causal relationship could not be established, or reported for other tricyclic drugs, include:

Body as a Whole: Chest pain; edema. Cardiovascular: Hypertension; myocardial infarction; heart block; stroke. Digestive: Paralytic ileus; tongue discoloration; stomatitis; parotid swelling. Endocrine: Inappropriate ADH syndrome. Hematic and Lymphatic: Purpura; bone marrow depression; leukopenia; eosinophilia; thrombocytopenia. Metabolic, Nutritional and Immune: Elevation and lowering of blood sugar levels; weight gain or loss. Musculoskeletal: Myalgia. Nervous System and Psychiatric: Decreased or increased libido; abnormal gait; delusions; aggressive behavior; paranoia; peripheral neuropathy; Bell's palsy; alteration in EEG patterns; extrapyramidal symptoms. Respiratory: Dyspnea. Skin: Photosensitization; alopecia. Urogenital: Impaired urination; dilatation of urinary tract; impotence; testicular swelling; gynecomastia; breast enlargement; galactorrhea.

Patient Counseling

Healthcare providers should advise patients that cyclobenzaprine HCl may 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.

In elderly patients, it is important to communicate that the frequency and severity of adverse events associated with cyclobenzaprine may be increased, whether or not other medications are being taken concurrently. Therefore, cyclobenzaprine HCl should be initiated at a lower dose of 5 mg in this population, with careful and gradual titration as needed.

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

It is essential to inform patients about the signs and symptoms of serotonin syndrome, and they should be instructed to seek immediate medical attention if they experience any of these symptoms.

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° to 25°C (68° to 77°F), as defined by the United States Pharmacopeia (USP) guidelines. Proper storage conditions are essential to maintain the integrity and efficacy of the product.

Additional Clinical Information

Laboratory tests specific to cyclobenzaprine HCl have not been detailed. Clinicians should be aware that while withdrawal symptoms have not been reported with cyclobenzaprine HCl, 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 HCl tablets USP 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 HCl, particularly in conjunction with alcohol or other CNS depressants. Additionally, there is a risk of serotonin syndrome when cyclobenzaprine HCl 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 HCl 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 Cipla USA Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)