Cyclobenzaprine hydrochloride

Description

Cyclobenzaprine hydrochloride, USP is a white, crystalline tricyclic amine salt with a melting point of 217°C and a pKa of 8.47 at 25°C. It is freely soluble in water and alcohol, sparingly soluble in isopropanol, and insoluble in hydrocarbon solvents. The chemical designation of cyclobenzaprine HCl, USP is 3-(5-H-dibenzoa,dcyclohepten-5-ylidene)-N,N-dimethyl-1-propanamine hydrochloride. Cyclobenzaprine hydrochloride tablets, USP are available for oral administration in strengths of 5 mg, 7.5 mg, and 10 mg. The tablets contain the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, dibasic calcium phosphate, hydroxypropyl cellulose, hypromellose, polyethylene glycol, magnesium stearate, microcrystalline cellulose, and titanium dioxide.

Uses and Indications

Cyclobenzaprine HCl is 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 HCl 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 HCl has not demonstrated efficacy in treating spasticity associated with cerebral or spinal cord diseases, nor is it indicated for use in children with cerebral palsy.

Dosage and Administration

The recommended dose of cyclobenzaprine HCl for most patients is 5 mg administered three times a day. Based on individual patient response, the dosage may be increased to either 7.5 mg or 10 mg, also taken three times a day.

Cyclobenzaprine HCl is not recommended for use beyond two to three weeks. For patients who are elderly or have hepatic impairment, 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 should not use it due to the risk of severe allergic reactions.

Concomitant use with monoamine oxidase (MAO) inhibitors or within 14 days of their discontinuation is contraindicated, as this combination has been associated with hyperpyretic crisis, seizures, and fatalities in patients receiving cyclobenzaprine or similar tricyclic antidepressants.

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

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

Warnings and Precautions

The use of Cyclobenzaprine Hydrochloride carries significant warnings and precautions that healthcare professionals must consider to ensure patient safety.

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 inhibitors (MAOIs), has been associated with the development of potentially life-threatening serotonin syndrome. 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, treatment with Cyclobenzaprine Hydrochloride and any concomitant serotonergic agents must be discontinued immediately, and supportive symptomatic treatment should be initiated. 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 doses.

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. Additionally, tricyclic antidepressants are known to cause arrhythmias, sinus tachycardia, and prolongation of conduction time, which may lead to myocardial infarction and stroke.

Caution in Specific Populations Due to its atropine-like properties, Cyclobenzaprine Hydrochloride should be administered with caution in patients who have a history of urinary retention, angle-closure glaucoma, or increased intraocular pressure. This caution extends to patients who are concurrently taking anticholinergic medications.

CNS Depressant Interaction Cyclobenzaprine Hydrochloride may potentiate the effects of alcohol, barbiturates, and other central nervous system depressants, necessitating careful monitoring of patients who are using these substances concurrently.

In summary, healthcare professionals should remain vigilant regarding the potential for serious adverse effects associated with Cyclobenzaprine Hydrochloride, particularly in the context of polypharmacy and specific patient histories.

Side Effects

Common adverse reactions observed in clinical trials include drowsiness, which occurred in 29% of patients receiving Cyclobenzaprine HCl 5 mg and 39% of those receiving Cyclobenzaprine HCl 10 mg, compared to 10% in the placebo group. Dry mouth was reported by 21% of patients on Cyclobenzaprine HCl 5 mg and 27% on Cyclobenzaprine HCl 10 mg, with 7% in the placebo group. Fatigue and headache were also common, affecting 6% of patients on both dosages of Cyclobenzaprine HCl, while 3% and 8% of placebo participants reported these symptoms, respectively.

Adverse reactions occurring in 1% to 3% of patients included abdominal pain, acid regurgitation, constipation, diarrhea, dizziness, nausea, irritability, decreased mental acuity, nervousness, upper respiratory infections, pharyngitis, asthenia, dyspepsia, unpleasant taste, blurred vision, and confusion.

Postmarketing experience has revealed additional adverse reactions occurring in less than 1% of patients. These include serious reactions such as syncope and malaise, as well as cardiovascular events like tachycardia, arrhythmia, vasodilatation, palpitation, and hypotension. Digestive system reactions reported include vomiting, anorexia, gastrointestinal pain, gastritis, thirst, flatulence, edema of the tongue, abnormal liver function, and rare instances of hepatitis, jaundice, and cholestasis. Hypersensitivity reactions such as anaphylaxis, angioedema, pruritus, facial edema, urticaria, and rash have also been documented.

Serious side effects include serotonin syndrome, which can be life-threatening, particularly when Cyclobenzaprine is used in conjunction with other serotonergic drugs. Symptoms of serotonin syndrome may encompass 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).

Rare but serious reactions, for which a causal relationship is unknown, include chest pain, edema, hypertension, myocardial infarction, heart block, and stroke. Other serious reactions may involve paralytic ileus, tongue discoloration, stomatitis, parotid swelling, inappropriate ADH syndrome, purpura, bone marrow depression, leukopenia, eosinophilia, thrombocytopenia, and metabolic changes such as elevation or lowering of blood sugar levels, as well as weight gain or loss. Musculoskeletal reactions like myalgia, nervous system and psychiatric effects including decreased or increased libido, abnormal gait, delusions, aggressive behavior, paranoia, peripheral neuropathy, Bell’s palsy, alterations in EEG patterns, and extrapyramidal symptoms have also been reported. Respiratory issues such as dyspnea, skin reactions including photosensitization and alopecia, and urogenital effects like impaired urination, dilatation of the urinary tract, impotence, testicular swelling, gynecomastia, breast enlargement, and galactorrhea are among the additional adverse reactions noted.

Drug Interactions

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

Monoamine Oxidase Inhibitors (MAOIs) and Serotonergic Drugs Cyclobenzaprine HCl may lead to life-threatening interactions when administered concurrently with MAO inhibitors. It is essential to monitor patients closely for signs of serotonin syndrome when cyclobenzaprine is used alongside other serotonergic medications.

Central Nervous System (CNS) Depressants The use of cyclobenzaprine HCl may potentiate the effects of alcohol, barbiturates, and other CNS depressants. Caution is advised, and dosage adjustments may be necessary to mitigate the risk of excessive sedation.

Tricyclic Antidepressants Tricyclic antidepressants may interfere with the antihypertensive effects of guanethidine and similar agents. Clinicians should consider monitoring blood pressure and adjusting antihypertensive therapy as needed. Additionally, tricyclic antidepressants can increase the risk of seizures in patients taking tramadol, necessitating careful patient evaluation and monitoring for seizure activity.

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 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, 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 the most significant increase, with levels approximately 2.4 times higher, while elderly females showed a lesser increase of about 1.2 times.

Due to these elevated plasma levels, geriatric patients may be at a greater 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. Additionally, elderly patients may be more susceptible to drug-drug and drug-disease interactions.

Given these considerations, cyclobenzaprine should be prescribed to elderly patients only when clearly necessary. When initiating treatment, it is recommended that cyclobenzaprine HCl be started at a dose of 5 mg, with careful and gradual titration to achieve the desired therapeutic effect. Furthermore, less frequent dosing should be considered to minimize the risk of adverse effects in this population. Regular monitoring for potential side effects is advised to ensure patient safety.

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. 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

There is no specific information available regarding dosage adjustments, special monitoring, or safety considerations for patients with renal impairment. Healthcare professionals should exercise caution when prescribing to patients with reduced kidney function, as the absence of detailed guidance necessitates careful clinical judgment. Regular monitoring of renal function may be advisable in these patients to ensure safety and efficacy.

Hepatic Impairment

Patients with hepatic impairment have not been specifically studied in relation to the use of this medication. Consequently, there are no established dosage adjustments, special monitoring requirements, or precautions for individuals with compromised liver function. It is recommended that healthcare providers exercise caution when prescribing this medication to patients with hepatic impairment, given the lack of data on its safety and efficacy in this population. Regular monitoring of liver function may be prudent in these cases, although specific parameters are not defined in the available information.

Overdosage

In cases of cyclobenzaprine HCl overdosage, although rare, fatalities may occur. It is important to note that deliberate overdoses often involve the co-ingestion of multiple substances, including alcohol. Due to the rapid onset of toxicity symptoms, immediate hospital monitoring is essential.

Signs and Symptoms

The most frequently observed effects of cyclobenzaprine overdose include drowsiness and tachycardia. Other less common symptoms may manifest as tremor, agitation, coma, ataxia, hypertension, slurred speech, confusion, dizziness, nausea, vomiting, and hallucinations. Critical manifestations, though 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, serve as important indicators of toxicity.

Recommended Actions

Upon suspicion of an overdose, it is imperative for the physician to contact a poison control center for the most current treatment recommendations. Initial management should include obtaining an electrocardiogram (ECG) and initiating cardiac monitoring. The patient's airway must be protected, an intravenous line established, and gastric decontamination commenced. 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 is contraindicated.

Monitoring and Management

Continuous observation with cardiac monitoring is necessary to detect signs of central nervous system (CNS) or respiratory depression, hypotension, cardiac dysrhythmias or 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. Dialysis is generally considered ineffective due to the low plasma concentrations of cyclobenzaprine.

In cases where dysrhythmias or QRS widening is present, serum alkalinization to a pH of 7.45 to 7.55 using intravenous sodium bicarbonate, along with hyperventilation as needed, should be initiated. For patients exhibiting CNS depression, early intubation is recommended due to the risk of sudden deterioration. Seizures should be managed with benzodiazepines, and if these are ineffective, alternative anticonvulsants such as phenobarbital or phenytoin may be utilized.

Physostigmine is not advised except in life-threatening situations that do not respond to other treatments, and its use should only occur in close consultation with a poison control center. The management principles for both child and adult overdosages are similar; therefore, it is strongly recommended that physicians consult the local poison control center for specific pediatric treatment guidance.

Nonclinical Toxicology

In nonclinical studies, cyclobenzaprine demonstrated no adverse effects on reproductive performance or fertility in male or female rats at oral doses up to 10 times the human dose.

In long-term studies involving rats treated with cyclobenzaprine HCl 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. The microscopic changes were noted in higher dose groups as early as 26 weeks, and in some cases, even earlier in rats that succumbed prior to this time. At lower doses, these changes were not observed until after 26 weeks of treatment.

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

Postmarketing Experience

A postmarketing surveillance program involving 7,607 patients with acute musculoskeletal disorders included 297 patients treated with cyclobenzaprine HCl 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 reported.

The following adverse reactions have been documented in postmarketing experience or occurred in less than 1% of patients during 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; serotonin syndrome. Skin: Sweating. Special Senses: Ageusia; tinnitus. Urogenital: Urinary frequency and/or retention.

Additionally, 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 physical abilities necessary for performing hazardous tasks, including operating machinery or driving a motor vehicle, particularly when used in conjunction with alcohol or other central nervous system (CNS) depressants.

It is important to inform elderly patients that they may experience an increased frequency and severity of adverse events associated with cyclobenzaprine, whether or not they are taking other medications. For this population, healthcare providers should recommend initiating treatment with a 5 mg dose of cyclobenzaprine HCl and advise a gradual titration upward.

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

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

Storage and Handling

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

Additional Clinical Information

Patients using cyclobenzaprine HCl should be aware that the medication may impair mental and physical abilities, particularly when combined with alcohol or other CNS depressants, which can affect tasks such as operating machinery or driving. Clinicians should note that elderly patients may experience an increased frequency and severity of adverse events; therefore, it is recommended to initiate treatment with a 5 mg dose and titrate slowly.

Additionally, patients must be cautioned about the risk of serotonin syndrome when cyclobenzaprine is used alongside other medications, including SSRIs, SNRIs, TCAs, tramadol, bupropion, meperidine, verapamil, or MAO inhibitors. They should be informed of the signs and symptoms of serotonin syndrome and instructed to seek immediate medical attention if these occur.

FDA Insert (PDF)

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

View full prescribing information (PDF)