Cyclobenzaprine hydrochloride

Description

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

Chemically, cyclobenzaprine hydrochloride is designated as 3-(5H-dibenzoa,dcyclohepten-5-ylidene)-N,N-dimethyl-1-propanamine hydrochloride. Cyclobenzaprine Hydrochloride Tablets, USP are available in 5 mg and 10 mg dosages for oral administration. Each tablet contains the following inactive ingredients: croscarmellose sodium, FD&C Yellow #6, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, and titanium dioxide. The 5 mg tablets also include FD&C Red #40, while the 10 mg tablets contain D&C Yellow #10 and polysorbate.

Uses and Indications

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

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

Cyclobenzaprine hydrochloride tablets are not indicated for the treatment of spasticity associated with cerebral or spinal cord disease, nor are they effective in pediatric patients 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 two to three 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 this 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, as well as in patients with arrhythmias, heart block, conduction disturbances, or congestive heart failure, due to potential cardiovascular complications.

Additionally, use 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 (MAO) inhibitors, 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, it is imperative to discontinue treatment with Cyclobenzaprine Hydrochloride and any concomitant serotonergic agents immediately, and to initiate supportive symptomatic treatment.

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 with a history of urinary retention, angle-closure glaucoma, or increased intraocular pressure. Special care should also be taken with patients who are concurrently using anticholinergic medications.

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

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

Side Effects

Patients receiving treatment with Cyclobenzaprine Hydrochloride may experience a range of adverse reactions. The most common adverse reactions, occurring in more than 3% of participants, include drowsiness (29% at 5 mg, 38% at 10 mg, compared to 10% in the placebo group), dry mouth (21% at 5 mg, 32% at 10 mg, versus 7% in the placebo group), fatigue (6% at both 5 mg and 10 mg, 3% in the placebo group), and headache (5% at both dosages, 8% in the placebo group).

Adverse reactions 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 have been reported across various systems. In the body as a whole, patients may experience syncope and malaise. Cardiovascular effects may include tachycardia, arrhythmia, vasodilatation, palpitations, and hypotension. Digestive system reactions can involve vomiting, anorexia, gastrointestinal pain, gastritis, thirst, flatulence, edema of the tongue, abnormal liver function, and rare cases of hepatitis, jaundice, and cholestasis. Hypersensitivity reactions may manifest as anaphylaxis, angioedema, pruritus, facial edema, urticaria, and rash.

Nervous system and psychiatric adverse reactions are notable and may include seizures, ataxia, vertigo, dysarthria, tremors, hypertonia, convulsions, muscle twitching, disorientation, insomnia, depressed mood, anxiety, agitation, psychosis, abnormal thinking and dreaming, hallucinations, excitement, paresthesia, diplopia, and serotonin syndrome. Musculoskeletal effects may present as local weakness, while skin reactions can include sweating. Special senses may be affected, leading to ageusia and tinnitus, and urogenital issues may involve urinary frequency and/or retention.

Certain adverse reactions have an unknown causal relationship with the medication. These include chest pain and edema in the body as a whole; hypertension, myocardial infarction, heart block, and stroke in the cardiovascular system; paralytic ileus, tongue discoloration, stomatitis, and parotid swelling in the digestive system; inappropriate ADH syndrome in the endocrine system; purpura, bone marrow depression, leukopenia, eosinophilia, and thrombocytopenia in the hematologic and lymphatic systems; and fluctuations in blood sugar levels, weight gain or loss in metabolic, nutritional, and immune responses. Musculoskeletal complaints may include myalgia, while nervous system and psychiatric effects can involve decreased or increased libido, abnormal gait, delusions, aggressive behavior, paranoia, peripheral neuropathy, Bell's palsy, alterations in EEG patterns, and extrapyramidal symptoms. Respiratory issues may present as dyspnea, skin reactions can include photosensitization and alopecia, and urogenital effects may involve impaired urination, dilatation of the urinary tract, impotence, testicular swelling, gynecomastia, breast enlargement, and galactorrhea.

A serious warning regarding the potential development of serotonin syndrome has been noted, particularly when Cyclobenzaprine Hydrochloride is used in conjunction 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. Symptoms of serotonin syndrome may include mental status changes (e.g., confusion, agitation, hallucinations), autonomic instability (e.g., diaphoresis, tachycardia, labile blood pressure, hyperthermia), neuromuscular abnormalities (e.g., tremor, ataxia, hyperreflexia, clonus, muscle rigidity), and gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).

In cases of overdose, the most common effects reported 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 critical manifestations of overdose can include cardiac arrest, chest pain, cardiac dysrhythmias, severe hypotension, seizures, and neuroleptic malignant syndrome. Clinically significant changes in the electrocardiogram, particularly in QRS axis or width, may indicate cyclobenzaprine toxicity, and other potential effects of overdosage may include any of the symptoms listed under adverse reactions.

Drug Interactions

Cyclobenzaprine has several significant drug interactions that warrant careful consideration during clinical use.

Monoamine Oxidase Inhibitors (MAOIs) Cyclobenzaprine may cause life-threatening interactions when used in conjunction with MAO inhibitors. It is advised to avoid this combination due to the potential for severe adverse effects.

Serotonergic Drugs Postmarketing reports indicate that the concurrent use of Cyclobenzaprine Hydrochloride with other serotonergic agents can lead to serotonin syndrome. This risk is particularly noted with the following drug classes:

• Selective serotonin reuptake inhibitors (SSRIs)

• Serotonin norepinephrine reuptake inhibitors (SNRIs)

• Tricyclic antidepressants (TCAs)

• Tramadol

• Bupropion

• Meperidine

• Verapamil

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.

CNS Depressants Cyclobenzaprine may potentiate the effects of alcohol, barbiturates, and other central nervous system (CNS) depressants. Caution is advised when these substances are used concurrently, and dosage adjustments may be necessary to mitigate the risk of excessive sedation.

Tricyclic Antidepressants (TCAs) The use of tricyclic antidepressants may interfere with the antihypertensive effects of guanethidine and similar medications. Additionally, TCAs can increase the risk of seizures in patients who are also taking tramadol. 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, which necessitates careful consideration when prescribing this medication. Due to this heightened concentration, geriatric patients are at an elevated risk for central nervous system (CNS) adverse events, including hallucinations and confusion.

Additionally, elderly patients may be more susceptible to cardiac events, which can lead to falls or other serious complications. It is crucial to be vigilant regarding potential drug-drug and drug-disease interactions in this population, as these interactions can exacerbate existing health issues or lead to new complications.

Given these considerations, cyclobenzaprine should be prescribed to elderly patients only when clearly indicated. When initiating treatment, it is recommended to start with a lower dose of 5 mg and to titrate slowly upward, monitoring the patient closely for any adverse effects or changes in their clinical status.

Pregnancy

The use of this medication is contraindicated in pregnancy due to potential risks to the fetus. Healthcare professionals should be aware that administration during this period may lead to adverse fetal outcomes. Women of childbearing potential should be advised of these risks and the importance of effective contraception during treatment. It is essential to weigh the benefits of therapy against the potential harm to the developing fetus when considering treatment options 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 may not have specific dosage adjustments, special monitoring, or safety considerations outlined in the available information. Therefore, healthcare professionals should exercise caution when prescribing to patients with reduced kidney function, as the lack of detailed guidance necessitates careful clinical judgment and individualized assessment. Regular monitoring of renal function is advisable to ensure patient safety and therapeutic 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 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 overdose can lead to fatalities, particularly in cases involving multiple drug ingestion, including alcohol. The management of such overdoses is complex and subject to change; therefore, it is advisable for healthcare professionals 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. Other less frequent symptoms may present as 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, are important indicators of cyclobenzaprine toxicity.

Management Procedures

All patients suspected of cyclobenzaprine overdose should undergo gastrointestinal decontamination. This process should include large volume gastric lavage followed by the administration of activated charcoal. If the patient's consciousness is impaired, securing the airway is essential prior to performing lavage, and emesis is contraindicated.

To mitigate the risk of severe manifestations, it is critical to obtain an electrocardiogram (ECG) and initiate cardiac monitoring immediately. The patient's airway must be protected, an intravenous line established, and gastric decontamination initiated. Continuous observation for signs of central nervous system (CNS) or respiratory depression, hypotension, cardiac dysrhythmias, conduction blocks, and seizures is necessary. 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.

A maximal limb-lead QRS duration of ≥0.10 seconds may serve as a key indicator of overdose severity. 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, along with hyperventilation as needed. A pH exceeding 7.60 or a pCO2 below 20 mmHg is considered undesirable. Dysrhythmias that do not respond to sodium bicarbonate therapy or hyperventilation may be treated with lidocaine, bretylium, or phenytoin, 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, alternative anticonvulsants such as phenobarbital or phenytoin may be utilized. The use of physostigmine is not recommended except in life-threatening situations unresponsive to other therapies, and only after consultation with a poison control center.

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 responses, cyclobenzaprine should be used during pregnancy only if clearly needed.

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.

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 sometimes enlarged livers, 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.

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. Additionally, cyclobenzaprine did not demonstrate mutagenic activity in male mice at dose levels of up to 20 times the human dose.

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, abnormal liver function, and rare reports of hepatitis, jaundice, and cholestasis.

Hypersensitivity reactions reported include anaphylaxis, angioedema, pruritus, facial edema, urticaria, and rash. Musculoskeletal reactions feature 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 involve ageusia and tinnitus. Urogenital events reported are urinary frequency and/or retention.

Additionally, other reactions have been reported rarely for cyclobenzaprine hydrochloride under circumstances where a causal relationship could not be established, or 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 reactions 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 also include myalgia.

Nervous system and psychiatric reactions reported are 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 reactions reported are impaired urination, dilatation of the urinary tract, impotence, testicular swelling, gynecomastia, breast enlargement, and galactorrhea.

Patient Counseling

Patients should be cautioned about the risk of serotonin syndrome associated with the concomitant use of Cyclobenzaprine Hydrochloride and other medications, including 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 advise patients to be vigilant for 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 these symptoms occur.

It is important for healthcare providers to inform patients that Cyclobenzaprine hydrochloride tablets, particularly when used in conjunction with alcohol or other central nervous system (CNS) depressants, may impair mental and/or physical abilities necessary for the performance of hazardous tasks, including operating machinery or driving a motor vehicle.

In elderly patients, the frequency and severity of adverse events associated with the use of Cyclobenzaprine may be increased, whether or not other medications are being taken concurrently. Therefore, healthcare providers should recommend initiating treatment with a 5 mg dose in this population and advise a slow upward titration.

Patients should also be cautioned about the potential for drowsiness and advised to avoid engaging in activities that require mental alertness until they are aware of how Cyclobenzaprine affects them. Additionally, healthcare providers should inform patients that Cyclobenzaprine may enhance the effects of alcohol, barbiturates, and other CNS depressants.

Finally, patients should be encouraged to inform their healthcare provider of all medications they are currently taking, including over-the-counter drugs and herbal supplements, to help prevent potential drug interactions.

Storage and Handling

The product is supplied in accordance with the National Drug Code (NDC) specifications. It should be stored at a controlled room temperature of 20°-25°C (68°-77°F), as defined by the United States Pharmacopeia (USP). Proper storage conditions are essential to maintain the integrity and efficacy of the product.

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.

The recommended administration for most patients is 5 mg of cyclobenzaprine hydrochloride tablets three times daily, with the possibility of increasing to 10 mg three times daily based on individual response. Prolonged use beyond two to three weeks is not advised. Patients should be counseled on the potential impairment of mental and physical abilities when using cyclobenzaprine, particularly in conjunction with alcohol or other CNS depressants. 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 of the signs and symptoms of serotonin syndrome and instructed to seek immediate medical attention if they occur.

A post-marketing surveillance program involving 7,607 patients with acute musculoskeletal disorders indicated that the effectiveness of cyclobenzaprine was consistent with findings from controlled studies, while 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 Solco Healthcare U. S. , LLC. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)