Cyclobenzaprine hydrochloride

Description

Cyclobenzaprine hydrochloride, USP is a tricyclic amine salt characterized as a white to off-white, odorless, crystalline powder. Its chemical formula is C20H21N • HCl, with 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. When aqueous solutions are made alkaline, the free base separates.

Chemically, cyclobenzaprine hydrochloride is designated as 3-(5H-dibenzoa,dcyclohepten-5-ylidene)-N,N-dimethyl-1-propanamine hydrochloride. Cyclobenzaprine hydrochloride tablets, USP are formulated for oral administration and are available in strengths of 5 mg, 7.5 mg, and 10 mg. Each tablet contains cyclobenzaprine hydrochloride along with inactive ingredients, including 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 include 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 risks.

Additionally, use is contraindicated in patients with hyperthyroidism.

Warnings and Precautions

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

Serotonin Syndrome The concomitant use of cyclobenzaprine hydrochloride with 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). In the event of these reactions, treatment with cyclobenzaprine hydrochloride and any concomitant serotonergic agents should 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 the dosage.

CNS Reactions Cyclobenzaprine hydrochloride shares structural similarities with 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, which are closely related to cyclobenzaprine, have been associated with arrhythmias, sinus tachycardia, and prolongation of conduction time, potentially leading to myocardial infarction and stroke. Therefore, caution is advised when prescribing cyclobenzaprine hydrochloride, particularly in patients with pre-existing cardiovascular conditions.

CNS Depressant Interactions Cyclobenzaprine hydrochloride may potentiate the effects of alcohol, barbiturates, and other central nervous system depressants. Healthcare professionals should advise patients to avoid the concurrent use of these substances to mitigate the risk of enhanced sedation and respiratory depression.

In summary, the administration of cyclobenzaprine hydrochloride requires vigilant monitoring for signs of serotonin syndrome, awareness of potential CNS and cardiovascular reactions, and caution regarding interactions with other CNS depressants.

Side Effects

Common adverse reactions observed in clinical trials, occurring in more than 3% of patients, 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 the placebo group), fatigue (6% at both 5 mg and 10 mg, 3% in the placebo group), and headache (5% at both 5 mg and 10 mg, 8% in the placebo group).

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 include syncope and malaise (body as a whole); tachycardia, arrhythmia, vasodilatation, palpitation, and hypotension (cardiovascular); vomiting, anorexia, gastrointestinal pain, gastritis, thirst, flatulence, edema of the tongue, abnormal liver function, and rare reports of hepatitis, jaundice, and cholestasis (digestive); and hypersensitivity reactions such as anaphylaxis, angioedema, pruritus, facial edema, urticaria, and rash. Musculoskeletal reactions include local weakness, while nervous system and psychiatric reactions 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. Skin reactions include sweating, and special senses may be affected by ageusia and tinnitus. Urogenital adverse reactions include urinary frequency and/or retention.

Certain adverse reactions have an unknown causal relationship, including chest pain and edema (body as a whole); hypertension, myocardial infarction, heart block, and stroke (cardiovascular); paralytic ileus, tongue discoloration, stomatitis, and parotid swelling (digestive); inappropriate ADH syndrome (endocrine); purpura, bone marrow depression, leukopenia, eosinophilia, and thrombocytopenia (hematic and lymphatic); elevation and lowering of blood sugar levels, weight gain or loss (metabolic, nutritional, and immune); myalgia (musculoskeletal); decreased or increased libido, abnormal gait, delusions, aggressive behavior, paranoia, peripheral neuropathy, Bell's palsy, alteration in EEG patterns, and extrapyramidal symptoms (nervous system and psychiatric); dyspnea (respiratory); photosensitization and alopecia (skin); and impaired urination, dilatation of the urinary tract, impotence, testicular swelling, gynecomastia, breast enlargement, and galactorrhea (urogenital).

A warning regarding serotonin syndrome is pertinent, as this potentially life-threatening condition has been reported with the use of cyclobenzaprine hydrochloride in combination with other drugs, including 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 overdose, common effects include drowsiness and tachycardia, while less frequent manifestations may involve tremor, agitation, coma, ataxia, hypertension, slurred speech, confusion, dizziness, nausea, vomiting, and hallucinations. Rare but potentially critical manifestations include cardiac arrest, chest pain, cardiac dysrhythmias, severe hypotension, seizures, and neuroleptic malignant syndrome.

Drug Interactions

Cyclobenzaprine has several significant drug interactions that require careful consideration.

Monoamine Oxidase Inhibitors (MAOIs) Cyclobenzaprine may cause life-threatening interactions when used in conjunction with MAO inhibitors. It is advised that cyclobenzaprine not be administered to patients currently taking MAOIs.

Serotonergic Drugs Postmarketing reports indicate that the combined 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, has been associated with cases of serotonin syndrome. If the concomitant use of cyclobenzaprine and other serotonergic drugs is deemed clinically necessary, careful observation is recommended, particularly during the initiation of treatment or when increasing dosages.

Central Nervous System (CNS) Depressants Cyclobenzaprine may potentiate the effects of alcohol, barbiturates, and other CNS depressants. Caution is advised when these substances are used concurrently, and monitoring for increased sedation or respiratory depression may be warranted.

Tricyclic Antidepressants (TCAs) TCAs may interfere with the antihypertensive effects of guanethidine and similar compounds. Additionally, the use of TCAs in patients taking tramadol may increase the risk of seizures. Clinicians should consider these interactions when prescribing and may need to adjust dosages or monitor patients closely for adverse effects.

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, defined as those aged 65 years and older, may experience increased plasma concentrations of cyclobenzaprine. In pharmacokinetic studies, mean steady-state area under the curve (AUC) values for cyclobenzaprine in this population 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.

Due to these pharmacokinetic differences, elderly 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, this population may be more susceptible to drug-drug and drug-disease interactions.

For these reasons, cyclobenzaprine should be prescribed to elderly patients only when clearly indicated. When initiating treatment, it is recommended that cyclobenzaprine hydrochloride be started at a dose of 5 mg, with careful and gradual titration to achieve the desired therapeutic effect. Furthermore, consideration should be given to less frequent dosing regimens to minimize the risk of adverse effects in this vulnerable population. Monitoring for any adverse reactions is essential to ensure patient safety.

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 the 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 of treatment in nursing women.

Renal Impairment

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

Hepatic Impairment

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

Overdosage

In cases of cyclobenzaprine overdosage, although rare, fatalities may occur. It is important to note that multiple drug ingestion, including alcohol, is frequently associated with deliberate cyclobenzaprine overdose.

Management Recommendations Due to the complexity and evolving nature of overdose management, it is strongly advised that healthcare professionals contact a poison control center for the most current treatment information. Immediate hospital monitoring is essential, as signs and symptoms of toxicity can develop rapidly following an overdose.

Signs and Symptoms The most common effects observed in cyclobenzaprine overdose include drowsiness and tachycardia. Other less frequent manifestations may include tremor, agitation, coma, ataxia, hypertension, slurred speech, confusion, dizziness, nausea, vomiting, and hallucinations. Rare but critical complications can involve 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, should be closely monitored.

Initial Interventions To mitigate the risk of severe manifestations, an electrocardiogram (ECG) should be obtained, and cardiac monitoring should be initiated immediately. It is crucial to protect the patient's airway, establish an intravenous line, and commence gastric decontamination. All patients suspected of cyclobenzaprine overdose should undergo gastrointestinal decontamination, which includes large volume gastric lavage followed by activated charcoal. If the patient is unconscious, securing the airway prior to lavage is imperative, and emesis is contraindicated.

Monitoring and Supportive Care Continuous observation with cardiac monitoring is necessary to detect signs of central nervous system (CNS) or respiratory depression, hypotension, cardiac dysrhythmias, conduction blocks, and seizures. If any signs of toxicity arise during this monitoring period, extended observation is warranted. It is important to note that monitoring plasma drug levels should not dictate patient management, and dialysis is likely ineffective due to the low plasma concentrations of cyclobenzaprine.

Specific Treatment Considerations For patients exhibiting dysrhythmias and/or QRS widening, serum alkalinization to a pH of 7.45 to 7.55 using intravenous sodium bicarbonate, along with hyperventilation as needed, should be initiated. 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 (e.g., quinidine, disopyramide, and procainamide) 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 these are ineffective, other anticonvulsants such as phenobarbital or phenytoin may be utilized. The use of physostigmine is not recommended except for life-threatening symptoms unresponsive to other therapies, and only after consultation with a poison control center.

Psychiatric Considerations Given that overdosage is often intentional, there is a risk that patients may attempt suicide by other means during the recovery phase. A psychiatric referral may be appropriate in such cases. 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

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 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.

Nonclinical toxicology studies revealed that in rats treated with cyclobenzaprine for up to 67 weeks at doses approximately 5 to 40 times the maximum recommended human dose, pale and sometimes enlarged livers were observed, along with dose-related hepatocyte vacuolation and lipidosis. In higher dose groups, these microscopic changes were noted after 26 weeks, and even earlier in rats that died prior to this time; at lower doses, the changes were not observed until after 26 weeks. Furthermore, cyclobenzaprine did not affect the onset, incidence, or distribution of neoplasia in an 81-week study in mice or in a 105-week study in rats.

Pharmacological studies in animals indicated that the effects of cyclobenzaprine are similar to those of structurally related tricyclic antidepressants, including reserpine antagonism, norepinephrine potentiation, and potent peripheral and central anticholinergic effects, as well as sedation. Cyclobenzaprine was also 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 such as syncope and malaise have been noted. Cardiovascular events 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 reported include anaphylaxis, angioedema, pruritus, facial edema, urticaria, and rash. Musculoskeletal reactions have included local weakness.

Nervous system and psychiatric events 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. 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, 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. Hematic and lymphatic events consist of purpura, bone marrow depression, leukopenia, eosinophilia, and thrombocytopenia. Metabolic, nutritional, and immune reactions involve elevation and lowering of blood sugar levels, as well as weight gain or loss. Musculoskeletal reactions include myalgia.

Nervous system and psychiatric events reported 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 include dyspnea. Skin reactions also encompass photosensitization and alopecia. Urogenital events reported are impaired urination, dilatation of the urinary tract, impotence, testicular swelling, gynecomastia, breast enlargement, and galactorrhea.

Patient Counseling

Healthcare providers should advise patients that cyclobenzaprine, particularly when used in conjunction with alcohol or other central nervous system (CNS) depressants, may impair their mental and physical abilities necessary for performing hazardous tasks, including operating machinery or driving a motor vehicle.

It is important to inform elderly patients that they may experience an increased frequency and severity of adverse events associated with the use of 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 hydrochloride and advise a gradual titration upward to minimize potential risks.

Patients should also be cautioned about the risk of serotonin syndrome when cyclobenzaprine hydrochloride 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 tight, light-resistant container, compliant with USP standards, and features a child-resistant closure to ensure safety. It should be stored at a controlled room temperature of 20°C to 25°C (68°F to 77°F), in accordance with USP guidelines. Proper storage conditions are essential to maintain the integrity and efficacy of the product.

Additional Clinical Information

Patients receiving cyclobenzaprine should be aware that abrupt cessation of the medication after prolonged use may lead to withdrawal symptoms such as nausea, headache, and malaise, although these symptoms are not indicative of addiction. The medication is administered orally.

Clinicians should counsel patients on the potential impairment of mental and physical abilities when cyclobenzaprine is used, particularly in conjunction with alcohol or other central nervous system depressants, which may affect tasks such as driving or operating machinery. Additionally, there is a risk of serotonin syndrome when cyclobenzaprine is used with certain medications, including SSRIs, SNRIs, TCAs, tramadol, bupropion, meperidine, verapamil, or MAO inhibitors. Patients should be informed about the signs and symptoms of serotonin syndrome and advised 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 was consistent with 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 TruPharma LLC. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)