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 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.

Cyclobenzaprine hydrochloride is supplied in tablet form for oral administration, available in dosages of 5 mg and 10 mg. The tablets contain the following inactive ingredients: croscarmellose sodium, D&C Yellow #10 aluminum lake, FD&C Blue #2 aluminum lake, FD&C Yellow #6 aluminum lake, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, silicon dioxide, talc, and titanium dioxide.

Uses and Indications

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

This medication is intended for short-term use, specifically for periods not exceeding two to three weeks. There is insufficient evidence to support the effectiveness of cyclobenzaprine hydrochloride for prolonged use, as muscle spasms related to acute, painful musculoskeletal conditions typically resolve within a short duration. Therefore, extended therapy is seldom warranted.

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, 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 periods longer than two or 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 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 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 Risk 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.

Monitoring During Concomitant Use In cases where the clinical decision is made to use Cyclobenzaprine Hydrochloride alongside other serotonergic medications, it is essential to implement careful observation, particularly during the initiation of treatment or when increasing dosages.

CNS Effects and Cardiac Considerations 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, serious central nervous system reactions similar to those observed with tricyclic antidepressants have been reported, particularly at doses exceeding those typically recommended for muscle spasm. Additionally, tricyclic antidepressants are known to potentially induce 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 depressants, necessitating caution in patients who consume these substances concurrently.

Healthcare professionals are advised to remain vigilant regarding these warnings and to monitor patients closely for any adverse effects associated with the use of Cyclobenzaprine Hydrochloride, particularly in the context of polypharmacy.

Side Effects

Patients receiving treatment may experience a range of adverse reactions. 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, 7% in placebo), fatigue (6% at both 5 mg and 10 mg, 3% in placebo), and headache (5% at both doses, 8% in placebo).

Adverse reactions with an incidence of 1% to 3% 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 experience has revealed additional adverse reactions occurring in less than 1% of patients. 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. Musculoskeletal reactions may include local weakness, while nervous system and psychiatric effects can encompass 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 reactions include sweating (skin), ageusia and tinnitus (special senses), and urinary frequency and/or retention (urogenital).

Rare adverse reactions, for which a causal relationship is unknown, 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 effects may involve inappropriate ADH syndrome, while hematologic and lymphatic reactions can include purpura, bone marrow depression, leukopenia, eosinophilia, and thrombocytopenia. Metabolic, nutritional, and immune reactions may manifest as elevation or lowering of blood sugar levels, weight gain or loss, and musculoskeletal symptoms such as myalgia. Nervous system and psychiatric reactions may include decreased or increased libido, abnormal gait, delusions, aggressive behavior, paranoia, peripheral neuropathy, Bell's palsy, alteration in EEG patterns, and extrapyramidal symptoms. Respiratory effects may include dyspnea, while skin reactions can involve photosensitization and alopecia. Urogenital reactions may consist of impaired urination, dilatation of the urinary tract, impotence, testicular swelling, gynecomastia, breast enlargement, and galactorrhea.

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 medications such as selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), tramadol, bupropion, meperidine, verapamil, or MAO inhibitors. Symptoms 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 overdosage, common effects may include drowsiness and tachycardia, while less frequent manifestations can involve tremor, agitation, coma, ataxia, hypertension, slurred speech, confusion, dizziness, nausea, vomiting, and hallucinations. Rare but potentially critical manifestations may include cardiac arrest, chest pain, cardiac dysrhythmias, severe hypotension, seizures, and neuroleptic malignant syndrome.

Drug Interactions

Cyclobenzaprine has several significant drug interactions that warrant careful consideration.

Monoamine Oxidase Inhibitors (MAOIs) Cyclobenzaprine may cause life-threatening interactions when used in conjunction with MAO inhibitors. It is advised that this combination be avoided.

Serotonergic Drugs Postmarketing reports indicate that the concurrent use 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 combination of Cyclobenzaprine Hydrochloride and other serotonergic drugs is deemed necessary, careful monitoring is recommended, especially during the initiation of treatment or when increasing dosages.

Central Nervous System (CNS) Depressants Cyclobenzaprine hydrochloride may potentiate the effects of alcohol, barbiturates, and other 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) 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 hydrochloride 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, with pharmacokinetic studies indicating that mean steady-state AUC values in individuals aged 65 years and older are approximately 1.7 times higher than those observed in younger adults. Notably, elderly male subjects exhibited an even greater increase, with levels approximately 2.4 times higher than their younger counterparts, while elderly females showed a lesser increase of about 1.2 times.

Due to these elevated plasma levels, elderly patients are at a heightened risk for central nervous system (CNS) adverse events, including hallucinations and confusion, as well as cardiac events that may lead to falls or other complications. The frequency and severity of adverse events associated with cyclobenzaprine use, whether administered alone or in conjunction with other medications, are also increased in this population.

For geriatric patients, it is recommended that cyclobenzaprine hydrochloride be initiated at a lower dose of 5 mg, with careful and gradual titration to achieve the desired therapeutic effect. Additionally, less frequent dosing should be considered to mitigate the risk of adverse effects. Healthcare providers should closely monitor elderly patients for potential drug-drug and drug-disease interactions, as these factors may further complicate treatment outcomes.

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. 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 hydrochloride should be used during pregnancy only if clearly needed. Healthcare professionals are advised to weigh the potential benefits against any possible 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 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 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 observed in cases of deliberate overdose. Due to the complexity and evolving nature of overdose management, healthcare professionals are advised to contact a poison control center for the most current treatment information.

Signs and Symptoms of Overdosage

Toxicity symptoms may manifest rapidly following an overdose of cyclobenzaprine. Common effects include drowsiness and tachycardia, while less frequent symptoms may involve tremor, agitation, coma, ataxia, hypertension, slurred speech, confusion, dizziness, nausea, vomiting, and hallucinations. Rare but critical manifestations 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.

Management of Overdosage

Immediate hospital monitoring is essential for all patients suspected of cyclobenzaprine overdose. An electrocardiogram (ECG) should be obtained, and cardiac monitoring should commence without delay. It is crucial to protect the patient's airway, establish an intravenous line, and initiate gastric decontamination, which includes large volume gastric lavage followed by activated charcoal. If the patient is unconscious, airway protection must be secured prior to lavage, and emesis is contraindicated.

Observation should include monitoring for signs of central nervous system (CNS) or respiratory depression, hypotension, cardiac dysrhythmias, conduction blocks, and seizures. Extended monitoring is warranted if any signs of toxicity arise during this period. It is important to note that plasma drug level monitoring should not dictate patient management, and dialysis is likely ineffective due to the low plasma concentrations of cyclobenzaprine.

For patients exhibiting dysrhythmias or QRS widening, serum alkalinization to a pH of 7.45 to 7.55 should be initiated using intravenous sodium bicarbonate and hyperventilation as necessary. A maximal limb-lead QRS duration of ≥0.10 seconds may indicate the severity of the overdose. If dysrhythmias do not respond to sodium bicarbonate therapy or hyperventilation, alternative treatments such as lidocaine, bretylium, or phenytoin may be considered, while Type 1A and 1C antiarrhythmics 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 may be utilized. The use of physostigmine is not advised unless life-threatening symptoms are unresponsive to other treatments, and this should only occur in close consultation with a poison control center.

Given the potential for deliberate overdose, psychiatric referral may be appropriate during the recovery phase, as patients may attempt suicide by other means. The management principles for both child and adult overdosages are similar; therefore, it is strongly recommended that healthcare professionals contact the local poison control center for specific pediatric treatment guidance.

Nonclinical Toxicology

Reproduction studies conducted in rats, mice, and rabbits at doses up to 20 times the human dose have shown no evidence of impaired fertility or teratogenic effects associated with cyclobenzaprine hydrochloride. 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.

At oral doses of up to 10 times the human dose, cyclobenzaprine did not adversely affect the reproductive performance or fertility of male or female rats. 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 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 have demonstrated effects of cyclobenzaprine that 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. 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:

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; serotonin syndrome. Skin: Sweating. Special Senses: Ageusia; tinnitus. Urogenital: Urinary frequency and/or retention.

Additionally, other reactions have been reported rarely for cyclobenzaprine hydrochloride, where a causal relationship could not be established, or have been reported for other tricyclic drugs. These 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

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, 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 note that the frequency and severity of adverse events associated with the use of Cyclobenzaprine may be increased in elderly patients, whether or not they are taking other medications. Therefore, in elderly patients, Cyclobenzaprine Hydrochloride should be initiated at a lower dose of 5 mg and titrated slowly upward to minimize the risk of adverse effects.

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 affects them. Additionally, it should be communicated that Cyclobenzaprine is not recommended for use in children under 15 years of age.

Finally, healthcare providers should advise patients to use Cyclobenzaprine Hydrochloride only for short periods, typically up to two or three weeks, as there is insufficient evidence to support its effectiveness for prolonged use.

Storage and Handling

The product is supplied in a tight, light-resistant container, compliant with USP standards, and dispensed with a child-resistant closure as required.

Storage conditions must be maintained at a temperature range of 20° to 25°C (68° to 77°F), with permissible excursions between 15° to 30°C (59° to 86°F) in accordance with USP Controlled Room Temperature guidelines.

Additional Clinical Information

Laboratory tests specific to cyclobenzaprine hydrochloride have not been detailed. 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.

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. Patients should also be informed about the risk of serotonin syndrome when cyclobenzaprine is taken with certain medications, including SSRIs, SNRIs, TCAs, tramadol, bupropion, meperidine, verapamil, or MAO inhibitors. They should be educated on the signs and symptoms of serotonin syndrome and advised to seek immediate medical attention if these occur.

In a post-marketing surveillance program involving 7,607 patients with acute musculoskeletal disorders, including 297 patients treated with cyclobenzaprine hydrochloride for 30 days or longer, the overall effectiveness was consistent with findings from controlled studies, and 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 Amneal Pharmaceuticals LLC. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)