Cyclobenzaprine hydrochloride

Description

Cyclobenzaprine hydrochloride is a white, crystalline tricyclic amine salt with the empirical formula C20H21N•HCl and a molecular weight of 311.9 g/mol. It has a melting point of 217°C and a pKa of 8.47 at 25°C. The compound is freely soluble in water and alcohol, sparingly soluble in isopropanol, and insoluble in hydrocarbon solvents. When aqueous solutions are made alkaline, the free base separates.

Chemically, cyclobenzaprine hydrochloride is designated as 3-(5H-dibenzo a,d cyclohepten-5-ylidene)-N,N-dimethyl-1-propanamine hydrochloride. The structural formula is provided in the accompanying documentation.

For oral administration, cyclobenzaprine hydrochloride is available in tablet form. Each 5 mg tablet contains 5 mg of cyclobenzaprine hydrochloride, while each 10 mg tablet contains 10 mg of cyclobenzaprine hydrochloride. The tablets include the following inactive ingredients: lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, silicon dioxide, magnesium stearate, carnauba wax, titanium dioxide, polyethylene glycol, and iron oxide yellow. Additionally, the 5 mg tablets contain polyvinyl alcohol, talc, lecithin, and FD&C yellow #6/sunset yellow FCF aluminum lake, whereas the 10 mg tablets also contain D&C yellow #10 aluminum lake, FD&C yellow #6 aluminum lake, and hypromellose.

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 are typically of 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, 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 hydrochloride tablets, USP for durations exceeding two to three weeks is not recommended. For patients who are hepatically impaired or elderly, consideration should be given to less frequent dosing 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 cyclobenzaprine or structurally similar tricyclic antidepressants.

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 complications.

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 its relationship to tricyclic antidepressants.

Serotonin Syndrome The concomitant use of Cyclobenzaprine Hydrochloride with other serotonergic agents, including selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), tramadol, bupropion, meperidine, verapamil, or monoamine oxidase (MAO) inhibitors, may lead to the development of serotonin syndrome, a potentially life-threatening condition. Symptoms of serotonin syndrome can manifest as mental status changes (e.g., confusion, agitation, hallucinations), autonomic instability (e.g., diaphoresis, tachycardia, labile blood pressure, hyperthermia), neuromuscular abnormalities (e.g., tremor, ataxia, hyperreflexia, clonus, muscle rigidity), and gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Should these symptoms arise, it is imperative to discontinue treatment with Cyclobenzaprine Hydrochloride and any concomitant serotonergic agents immediately, while initiating 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.

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 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, including Cyclobenzaprine Hydrochloride, have been associated with cardiovascular effects such as arrhythmias, sinus tachycardia, and prolongation of conduction time, which may increase the risk of myocardial infarction and stroke.

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

In summary, healthcare professionals should remain vigilant regarding the potential for serotonin syndrome, central nervous system reactions, cardiovascular risks, and interactions with other CNS depressants when prescribing Cyclobenzaprine Hydrochloride.

Side Effects

Patients receiving treatment with Cyclobenzaprine Hydrochloride 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% in the placebo group), dry mouth (21% at 5 mg, 32% at 10 mg, versus 7% in the placebo group), fatigue (6% at both 5 mg and 10 mg, 3% in the placebo group), and headache (5% at both dosages, 8% in the placebo group).

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.

Less frequent adverse reactions, occurring in less than 1% of patients, encompass a variety of systems. Notable reactions 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 documented.

Nervous system and psychiatric reactions may 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. Other less frequent reactions involve sweating (skin), ageusia and tinnitus (special senses), and urinary frequency and/or retention (urogenital).

There are also adverse reactions with a causal relationship that is unknown, which have been rarely reported. These include 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 been noted. Musculoskeletal reactions may include myalgia, while nervous system and psychiatric reactions can 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 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.

A serious warning regarding the potential development of serotonin syndrome has been issued. This life-threatening condition may occur when Cyclobenzaprine Hydrochloride is used in conjunction with other medications, including 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 manifestations include drowsiness and tachycardia, while less frequent effects may involve 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. Clinically significant changes in the electrocardiogram, particularly in QRS axis or width, may indicate cyclobenzaprine toxicity, and other symptoms listed under adverse reactions may also occur.

Drug Interactions

Cyclobenzaprine hydrochloride tablets are associated with several significant drug interactions that warrant careful consideration.

Monoamine Oxidase Inhibitors (MAOIs) The concomitant use of cyclobenzaprine hydrochloride and MAO inhibitors may lead to life-threatening interactions. It is advised that cyclobenzaprine should not be used in patients receiving MAOIs or within 14 days of discontinuing such therapy.

Serotonergic Agents Postmarketing reports indicate that the combination of cyclobenzaprine hydrochloride with serotonergic agents, including selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), tramadol, bupropion, meperidine, and verapamil, may increase the risk of serotonin syndrome. Clinicians should monitor patients closely for symptoms of serotonin syndrome when these medications are used together.

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.

Antihypertensive Agents Tricyclic antidepressants may interfere with the antihypertensive effects of guanethidine and similar compounds. Clinicians should consider monitoring blood pressure and adjusting antihypertensive therapy as needed when these medications are prescribed together.

Seizure Risk The use of tricyclic antidepressants in conjunction with tramadol may increase the risk of seizures. It is recommended that healthcare providers assess the seizure history of patients and consider alternative therapies if necessary.

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, USP, have not been established in pediatric patients below 15 years of age. Therefore, caution is advised when considering the use of this medication in this population.

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 tablets 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, whether administered alone or in conjunction with other medications, tend to be higher in elderly patients. Therefore, clinicians should consider less frequent dosing regimens for this population and ensure that cyclobenzaprine is prescribed only when clearly indicated.

Pregnancy

Reproduction studies have been conducted in rats, mice, and rabbits at doses up to 20 times the human dose of Cyclobenzaprine hydrochloride tablets, USP, and have shown 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 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, USP 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 prescribing information. There are no dosage adjustments, special monitoring requirements, or safety considerations outlined for individuals with reduced kidney function. Healthcare professionals should exercise caution and consider the lack of data when prescribing to this patient population.

Hepatic Impairment

Patients with hepatic impairment have not been specifically studied in clinical trials for this medication. Consequently, there is no available information regarding 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 warranted based on clinical judgment.

Overdosage

In cases of overdosage with Cyclobenzaprine hydrochloride tablets, USP, although rare, fatalities may occur. It is important to note that deliberate overdose often involves the ingestion of multiple drugs, including alcohol. Due to the complexity and evolving nature of overdose management, it is strongly advised that healthcare professionals consult a poison control center for the most current treatment recommendations.

Signs and symptoms of toxicity can manifest rapidly following an overdose, necessitating immediate hospital monitoring. The acute oral LD50 for Cyclobenzaprine hydrochloride is approximately 338 mg/kg in mice and 425 mg/kg in rats, indicating a significant potential for toxicity.

The most frequently observed effects of cyclobenzaprine overdose include drowsiness and tachycardia. Other less common symptoms may present as tremor, agitation, coma, ataxia, hypertension, slurred speech, confusion, dizziness, nausea, vomiting, and hallucinations.

Healthcare professionals should be vigilant for rare but critical manifestations of overdose, which may include cardiac arrest, chest pain, cardiac dysrhythmias, severe hypotension, seizures, and neuroleptic malignant syndrome. Changes in the electrocardiogram, particularly alterations in the QRS axis or width, serve as clinically significant indicators of cyclobenzaprine toxicity.

Additionally, other potential effects of overdosage may encompass any symptoms listed under ADVERSE REACTIONS. Prompt recognition and management of these symptoms are essential to mitigate the risks associated with cyclobenzaprine overdose.

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 tablets, USP. However, there are no adequate and well-controlled studies in pregnant women. Due to the limitations of animal reproduction studies in predicting human responses, the use of this drug during pregnancy should be considered only when clearly necessary.

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.

In long-term studies involving rats treated with Cyclobenzaprine hydrochloride tablets, USP for up to 67 weeks at doses ranging from approximately 5 to 40 times the maximum recommended human dose, observations included pale and occasionally enlarged livers, along with dose-related hepatocyte vacuolation and lipidosis. In higher dose groups, these microscopic changes were noted as early as 26 weeks, and in some cases, even earlier in rats that died prior to this time. At lower doses, these changes were not observed until after 26 weeks.

Cyclobenzaprine did not 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, demonstrating reserpine antagonism, norepinephrine potentiation, significant peripheral and central anticholinergic effects, and sedation. Furthermore, cyclobenzaprine was 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 for the 10 mg tablet, with an incidence of less than 1% of patients in clinical trials:

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 category, 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 hydrochloride tablets, USP, under circumstances where a causal relationship could not be established, or have been 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, while 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 category, 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, while skin reactions consist of photosensitization and alopecia. Urogenital reactions reported are 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 when using Cyclobenzaprine Hydrochloride in conjunction with other medications, including SSRIs, SNRIs, TCAs, tramadol, bupropion, meperidine, verapamil, or 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 tablets, USP, particularly when combined with alcohol or other central nervous system (CNS) depressants, may impair their mental and/or physical abilities necessary for performing hazardous tasks, including operating machinery or driving a motor vehicle.

Healthcare providers should also discuss the increased frequency and severity of adverse events associated with the use of Cyclobenzaprine in elderly patients, whether or not they are taking other medications. For elderly patients, it is recommended that Cyclobenzaprine hydrochloride tablets, USP be initiated at a 5 mg dose and titrated slowly upward to minimize risks.

Patients should be cautioned about the potential for drowsiness and advised not to drive or operate heavy machinery until they are aware of how Cyclobenzaprine hydrochloride affects them. Additionally, it is essential to inform patients that Cyclobenzaprine hydrochloride tablets, USP should only be used for short periods, typically up to two or three weeks, as there is insufficient evidence to support effectiveness for longer durations.

Finally, healthcare providers should emphasize the importance of taking Cyclobenzaprine hydrochloride tablets, USP exactly as prescribed and not exceeding the recommended dose to ensure safety and efficacy.

Storage and Handling

The product is supplied in a tight, well-closed container that meets the specifications outlined in the United States Pharmacopeia (USP), and it includes a child-resistant closure as required.

Storage conditions should maintain a temperature of 25°C (77°F), with permissible excursions between 15-30°C (59-86°F) in accordance with USP Controlled Room Temperature guidelines. Proper handling and storage are essential to ensure the integrity and efficacy of the product.

Additional Clinical Information

Laboratory tests specific to Cyclobenzaprine hydrochloride tablets, USP have not been detailed. Clinicians should be aware that while withdrawal symptoms such as nausea, headache, and malaise may occur with abrupt cessation after prolonged use, these symptoms are not indicative of addiction. The recommended dosing for most patients is 5 mg three times a day, with the possibility of increasing to 10 mg three times a day based on individual response. Prolonged use beyond two to three weeks is not advised.

Patient counseling is essential, particularly regarding the potential impairment of mental and physical abilities when Cyclobenzaprine is used in conjunction with alcohol or other CNS depressants. Additionally, there is a risk of serotonin syndrome when Cyclobenzaprine is taken 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 experience these symptoms. A post-marketing surveillance program involving 7,607 patients indicated that the effectiveness of Cyclobenzaprine hydrochloride tablets, USP 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 KVK-TECH, Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)