Cyclobenzaprine hydrochloride

Description

Cyclobenzaprine hydrochloride, USP is a tricyclic amine salt presented as a white to off-white, odourless, crystalline powder. Its molecular formula is C20H21N • HCl, and it has a molecular weight of 311.9 g/mol. The compound has a melting point of 217°C and a pKa of 8.47 at 25°C. Cyclobenzaprine hydrochloride is freely soluble in water, alcohol, and methanol; it is sparingly soluble in isopropanol, slightly soluble in chloroform and methylene chloride, and insoluble in n-hexane. Chemically, it is designated as 3-(5H-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. Each tablet contains cyclobenzaprine hydrochloride along with inactive ingredients, which include crospovidone, hypromellose, lactose anhydrous, macrogol, magnesium stearate, polysorbate 80, pregelatinized starch, silicified microcrystalline cellulose, and titanium dioxide. The 5 mg and 10 mg tablets also contain D&C Yellow #10 Aluminum Lake and FD&C Yellow #6 Sunset Yellow FCF Aluminum Lake, while the 5 mg tablets additionally contain FD&C Blue #2/INDIGO Carmine Aluminum Lake.

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 2 to 3 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 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 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 for periods longer than 2 to 3 weeks is not recommended. 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 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 several critical warnings and precautions to ensure patient safety.

Serotonin Syndrome The concomitant use of cyclobenzaprine hydrochloride with other serotonergic agents, including selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), tramadol, bupropion, meperidine, verapamil, or monoamine oxidase (MAO) inhibitors, has been associated with the development of serotonin syndrome, a potentially life-threatening condition. The use of cyclobenzaprine hydrochloride in conjunction with MAO inhibitors is contraindicated. Symptoms of serotonin syndrome may manifest as mental status changes (e.g., confusion, agitation, hallucinations), autonomic instability (e.g., diaphoresis, tachycardia, labile blood pressure, hyperthermia), neuromuscular abnormalities (e.g., tremor, ataxia, hyperreflexia, clonus, muscle rigidity), and gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Should these symptoms occur, immediate discontinuation of cyclobenzaprine hydrochloride and any concomitant serotonergic agents is imperative, along with the initiation of supportive symptomatic treatment. If the clinical decision is made to continue treatment with cyclobenzaprine hydrochloride alongside other serotonergic drugs, careful observation is essential, particularly during the initiation of therapy or when increasing doses.

CNS Reactions Cyclobenzaprine hydrochloride shares structural similarities with tricyclic antidepressants such as amitriptyline and imipramine. In short-term studies involving indications beyond 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.

Arrhythmias Tricyclic antidepressants, including cyclobenzaprine, have been linked to the occurrence of arrhythmias, sinus tachycardia, and prolongation of conduction time, which may lead to serious cardiovascular events such as myocardial infarction and stroke.

CNS Depressants Cyclobenzaprine hydrochloride may potentiate the effects of alcohol, barbiturates, and other central nervous system depressants. Caution is advised when prescribing cyclobenzaprine to patients who are concurrently using these substances, as the risk of enhanced CNS depression may increase.

Healthcare professionals are encouraged to monitor patients closely for the emergence of these adverse effects and to conduct appropriate laboratory tests as necessary to ensure safe use of 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 (29% at 5 mg, 38% at 10 mg, and 10% for placebo), dry mouth (21% at 5 mg, 32% at 10 mg, and 7% for placebo), fatigue (6% for both 5 mg and 10 mg, and 3% for placebo), and headache (5% for both 5 mg and 10 mg, and 8% for placebo).

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

Additional adverse reactions reported from clinical studies and postmarketing experience 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 cases 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 adverse reactions include seizures, ataxia, vertigo, dysarthria, tremors, hypertonia, convulsions, muscle twitching, disorientation, insomnia, depressed mood, abnormal sensations, anxiety, agitation, psychosis, abnormal thinking and dreaming, hallucinations, excitement, paresthesia, diplopia, and serotonin syndrome. Other reactions include local weakness (musculoskeletal), sweating (skin), ageusia and tinnitus (special senses), and urinary frequency and/or retention (urogenital).

Certain adverse reactions have been reported with an unknown causal relationship, including 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, and myalgia (musculoskeletal) have also been noted. Additional nervous system and psychiatric reactions include 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 been reported as well.

A significant warning includes the potential development of serotonin syndrome, which can be life-threatening, particularly when the medication is used in combination with other drugs such as selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (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 overdosage, the most common effects observed include drowsiness and tachycardia. Less frequent manifestations may include tremor, agitation, coma, ataxia, hypertension, slurred speech, confusion, dizziness, nausea, vomiting, and hallucinations. Rare but potentially critical manifestations can include cardiac arrest, chest pain, cardiac dysrhythmias, severe hypotension, seizures, and neuroleptic malignant syndrome.

Drug Interactions

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

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

Central Nervous System (CNS) Depressants The use of cyclobenzaprine may enhance the effects of alcohol, barbiturates, and other CNS depressants. Caution is advised when these substances are co-administered, and dosage adjustments may be necessary to mitigate the risk of excessive sedation.

Tricyclic Antidepressants (TCAs) Tricyclic antidepressants may interfere with the antihypertensive effects of guanethidine and similar agents. Clinicians should be aware of this interaction and consider monitoring blood pressure in patients receiving both medications. Additionally, TCAs may increase the risk of seizures in patients taking tramadol, necessitating careful patient evaluation and monitoring for seizure activity.

No further drug interactions or laboratory test interactions have been identified.

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 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 AUC values for cyclobenzaprine in individuals aged 65 years and older were approximately 1.7-fold higher than those observed in younger adults. Notably, elderly male subjects exhibited the highest mean increase, approximately 2.4-fold, while elderly females showed a lesser increase of about 1.2-fold.

Given these pharmacokinetic findings, it is recommended that therapy with cyclobenzaprine in geriatric patients be initiated at a 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 an increased potential for drug-drug and drug-disease interactions in this population.

Therefore, cyclobenzaprine should be prescribed to elderly patients only when clearly indicated, and close monitoring for adverse effects is advised throughout the course of treatment.

Pregnancy

Pregnancy Category B indicates that 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 due to cyclobenzaprine. 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 any possible risks when considering the use of this medication in 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 before prescribing this medication to 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

In cases of cyclobenzaprine overdosage, although rare, fatalities may occur, particularly when multiple substances, including alcohol, are ingested deliberately. The onset of toxicity symptoms can be rapid, necessitating immediate hospital monitoring.

The acute oral LD50 of cyclobenzaprine has been established at approximately 338 mg/kg in mice and 425 mg/kg in rats. The most frequently observed effects of 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.

Clinicians should be vigilant for changes in the electrocardiogram, particularly alterations in the QRS axis or width, as these are significant indicators of cyclobenzaprine toxicity. All patients suspected of an 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 prior to lavage is essential, and emesis is contraindicated.

A maximal limb-lead QRS duration of ≥ 0.10 seconds may indicate the severity of the overdose. For patients exhibiting dysrhythmias and/or QRS widening, serum alkalinization with intravenous sodium bicarbonate should be initiated. In cases of central nervous system (CNS) depression, early intubation is recommended due to the risk of sudden deterioration. Seizures should be managed with benzodiazepines or other anticonvulsants.

It is strongly advised that healthcare professionals contact a poison control center for the most current information regarding overdose management and treatment protocols.

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. 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.

In terms of non-teratogenic effects, cyclobenzaprine did not influence the onset, incidence, or distribution of neoplasia in an 81-week study in mice or a 105-week study in rats. Additionally, at oral doses up to 10 times the human dose, cyclobenzaprine did not adversely affect the reproductive performance or fertility of male or female rats. Furthermore, cyclobenzaprine did not exhibit mutagenic activity in male mice at dose levels up to 20 times the human dose.

In long-term studies involving rats treated with cyclobenzaprine for up to 67 weeks at doses ranging from approximately 5 to 40 times the maximum recommended human dose, observations included pale and sometimes enlarged livers, along with dose-related hepatocyte vacuolation with lipidosis. In higher dose groups, these microscopic changes were noted 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.

Animal pharmacology and toxicology studies indicate that cyclobenzaprine effectively reduces or abolishes skeletal muscle hyperactivity across various animal models. It has been established that cyclobenzaprine does not act at the neuromuscular junction or directly on skeletal muscle. Instead, it primarily exerts its effects within the central nervous system, particularly at brain stem levels, although its action on spinal cord levels may also contribute to its overall skeletal muscle relaxant activity. Pharmacological studies in animals have demonstrated similarities between the effects of cyclobenzaprine and those of structurally related tricyclic antidepressants, including reserpine antagonism, norepinephrine potentiation, potent peripheral and central anticholinergic effects, and sedation. Additionally, cyclobenzaprine has been 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 or with an incidence of less than 1% of patients in clinical trials with the 10 mg tablet:

In the category of Body as a Whole, reactions include syncope and malaise. Cardiovascular events reported include tachycardia, arrhythmia, vasodilatation, palpitation, and hypotension. Digestive system reactions consist of vomiting, anorexia, diarrhea, gastrointestinal pain, gastritis, thirst, flatulence, edema of the tongue, abnormal liver function, and rare reports of hepatitis, jaundice, and cholestasis.

Hypersensitivity reactions noted include anaphylaxis, angioedema, pruritus, facial edema, urticaria, and rash. Musculoskeletal reactions include local weakness. Nervous system and psychiatric events reported are 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. Skin reactions include sweating, while special senses reactions consist of ageusia and tinnitus. Urogenital events reported are urinary frequency and/or retention.

Additionally, other reactions have been reported rarely for cyclobenzaprine under circumstances where a causal relationship could not be established, or reported for other tricyclic drugs, and are included to alert physicians. These include Body as a Whole reactions such as chest pain and edema. Cardiovascular events include hypertension, myocardial infarction, heart block, and stroke. Digestive reactions consist of paralytic ileus, tongue discoloration, stomatitis, and parotid swelling. Endocrine reactions include inappropriate ADH syndrome. Hematic and lymphatic reactions reported are 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. Nervous system and psychiatric events include decreased or increased libido, abnormal gait, delusions, aggressive behavior, paranoia, peripheral neuropathy, Bell's palsy, alteration in EEG patterns, and extrapyramidal symptoms. Respiratory reactions reported are dyspnea. Skin reactions include photosensitization and alopecia. Urogenital events consist of impaired urination, dilatation of the urinary tract, impotence, testicular swelling, gynecomastia, breast enlargement, and galactorrhea.

Patient Counseling

Patients should be cautioned about the risk of serotonin syndrome associated with the concomitant use of cyclobenzaprine hydrochloride and other medications, including 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, particularly when used in conjunction 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. Providers should emphasize the need for caution in these situations.

In elderly patients, the frequency and severity of adverse events associated with cyclobenzaprine use, whether alone or with other medications, may be increased. Therefore, healthcare providers should recommend initiating treatment with a 5 mg dose for elderly patients and advise that the dosage be titrated slowly upward as needed.

Patients should also 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. Furthermore, it is essential to inform patients that cyclobenzaprine should only be used for short periods, typically up to 2 or 3 weeks, as there is insufficient evidence to support its effectiveness for longer durations. Lastly, patients should be instructed to take cyclobenzaprine exactly as prescribed and not to exceed the recommended dose.

Storage and Handling

The product is supplied in a tight, light-resistant container that complies with the United States Pharmacopeia (USP) standards and features a child-resistant closure. It should be stored at a temperature range of 20°C to 25°C (68°F 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 should be aware that the medication may impair mental and physical abilities, particularly when combined with alcohol or other central nervous system (CNS) depressants, which can affect tasks such as operating machinery or driving. In elderly patients, the incidence and severity of adverse events may be heightened; therefore, it is recommended that treatment begins with a 5 mg dose, which should be titrated slowly.

Clinicians should inform patients about the potential risk of serotonin syndrome when cyclobenzaprine is used alongside other medications, including SSRIs, SNRIs, TCAs, tramadol, bupropion, meperidine, verapamil, or MAO inhibitors. Patients should be educated on the signs and symptoms of serotonin syndrome and advised to seek immediate medical attention if they experience any related symptoms.

FDA Insert (PDF)

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

View full prescribing information (PDF)