Cyclobenzaprine hydrochloride

Description

Cyclobenzaprine hydrochloride (HCl) is a white, crystalline tricyclic amine salt with the empirical formula C20H21N·HCl and a molecular weight of 311.9 g/mol. It has a melting point of 217°C and a pKa of 8.47 at 25°C. The compound is freely soluble in water and alcohol, sparingly soluble in isopropanol, and insoluble in hydrocarbon solvents. Chemically, it is designated as 3-(5H-dibenzoa,dcyclohepten-5-ylidene)-N,N-dimethyl-1-propanamine hydrochloride. Cyclobenzaprine hydrochloride is available in extended-release capsules for oral administration, supplied in strengths of 15 mg and 30 mg. The extended-release capsules contain inactive ingredients including colloidal silicon dioxide, ethyl alcohol, ethylcellulose, FDC yellow #6, gelatin, hydroxypropyl cellulose, isopropyl alcohol, potassium hydroxide, sugar spheres (which contain sucrose and corn starch), and titanium dioxide. The 15 mg strength also includes red iron oxide.

Uses and Indications

Cyclobenzaprine hydrochloride extended-release capsules are indicated as an adjunct to rest and physical therapy for the relief of muscle spasm associated with acute, painful musculoskeletal conditions. The therapeutic benefit is characterized by the alleviation of muscle spasm and its associated signs and symptoms, including pain, tenderness, and limitation of motion.

Limitations of use include the recommendation that cyclobenzaprine hydrochloride extended-release capsules be utilized only for short durations, specifically up to 2 or 3 weeks. This limitation is based on the lack of adequate evidence supporting the effectiveness of prolonged use, as muscle spasms related to acute, painful musculoskeletal conditions are typically of short duration, and specific therapy for extended periods is rarely justified. Additionally, cyclobenzaprine hydrochloride extended-release capsules 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 adult dose of cyclobenzaprine hydrochloride extended-release capsules for most patients is 15 mg, administered once daily. In certain cases, a dose of 30 mg once daily may be necessary. It is advised that patients take their doses at approximately the same time each day to maintain consistent therapeutic levels.

Patients should be instructed to swallow the capsules intact. Alternatively, if they have difficulty swallowing, the contents of the capsule may be sprinkled on a tablespoon of applesauce and swallowed immediately without chewing.

Prolonged use of cyclobenzaprine hydrochloride beyond 2 to 3 weeks is not recommended, and healthcare professionals should monitor the duration of therapy accordingly.

Contraindications

Use of this product is contraindicated in the following situations:

• Patients with hypersensitivity to any component of the formulation.

• Concurrent use with monoamine oxidase (MAO) inhibitors or within 14 days following their discontinuation, due to the potential for serious interactions.

• During the acute recovery phase of myocardial infarction, and in individuals with arrhythmias, heart block, conduction disturbances, or congestive heart failure, as these conditions may be exacerbated.

• Patients with hyperthyroidism, as this may increase the risk of adverse effects.

Warnings and Precautions

Serotonin syndrome has been reported in patients receiving cyclobenzaprine in conjunction with other serotonergic agents. Healthcare professionals should remain vigilant for symptoms of serotonin syndrome, which may include confusion, hallucination, seizure, extreme changes in blood pressure, increased heart rate, fever, excessive sweating, shivering, blurred vision, muscle spasm or stiffness, and gastrointestinal symptoms.

Cyclobenzaprine shares structural similarities with tricyclic antidepressants, which are known to potentially cause adverse cardiovascular effects and central nervous system (CNS) depressant effects. Therefore, caution is advised when prescribing cyclobenzaprine, particularly in patients with pre-existing cardiovascular conditions or those who may be sensitive to CNS depressants.

The use of cyclobenzaprine in the elderly population is not recommended due to an increased risk of adverse effects. Similarly, patients with hepatic impairment should avoid the use of this medication, as it may exacerbate liver-related complications.

Additionally, cyclobenzaprine should be used with caution in individuals with a history of urinary retention, angle-closure glaucoma, or increased intraocular pressure. Patients taking anticholinergic medications may also be at heightened risk for adverse effects, necessitating careful monitoring and consideration of alternative therapies.

Side Effects

Patients may experience a range of adverse reactions while using this product. The most common adverse reactions reported include dry mouth, dizziness, fatigue, constipation, nausea, dyspepsia, and somnolence. These reactions are generally mild to moderate in severity.

Serious adverse reactions have also been noted. Notably, serotonin syndrome has been reported in patients using cyclobenzaprine in conjunction with other serotonergic drugs. Additionally, due to its structural similarity to tricyclic antidepressants, cyclobenzaprine may produce adverse cardiovascular effects or central nervous system (CNS) depressant effects.

Warnings associated with the use of this product include hypersensitivity to any component of the formulation. It is contraindicated for use in conjunction with monoamine oxidase (MAO) inhibitors or within 14 days following their discontinuation. The product should also be avoided during the acute recovery phase of myocardial infarction and in patients with arrhythmias, heart block or conduction disturbances, congestive heart failure, or hyperthyroidism.

In cases of overdose, the most frequently observed effects include drowsiness and tachycardia. Less common symptoms may involve tremor, agitation, coma, ataxia, hypertension, slurred speech, confusion, dizziness, nausea, vomiting, and hallucinations. Rare but potentially critical symptoms of overdose can include cardiac arrest, chest pain, cardiac dysrhythmias, severe hypotension, seizures, neuroleptic malignant syndrome, and rhabdomyolysis. Clinically significant changes in the electrocardiogram, particularly alterations in QRS axis or width, may indicate cyclobenzaprine toxicity.

It is important to note that abrupt cessation of treatment after prolonged administration may rarely lead to nausea, headache, and malaise; these symptoms are not indicative of addiction.

Drug Interactions

Life-threatening interactions may occur when this medication is used in conjunction with monoamine oxidase inhibitors (MAOIs). Caution is advised, and concurrent use should be avoided.

The combination of this medication with serotonergic drugs has been associated with the development of serotonin syndrome. Clinicians should monitor patients closely for symptoms of this condition, which may include agitation, confusion, rapid heart rate, and increased blood pressure.

When administered alongside central nervous system (CNS) depressants, such as alcohol and barbiturates, the effects of these substances may be significantly enhanced. It is recommended that patients be monitored for increased sedation and respiratory depression, and dosage adjustments may be necessary.

The use of tramadol in conjunction with this medication may increase the risk of seizures. Clinicians should evaluate the necessity of tramadol therapy in patients receiving this medication and consider alternative pain management strategies if appropriate.

Co-administration with guanethidine may result in a blocked antihypertensive effect. Blood pressure should be monitored, and alternative antihypertensive therapies should be considered if necessary.

No specific drug interactions or laboratory test interactions have been identified beyond those mentioned.

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

The safety and effectiveness of cyclobenzaprine hydrochloride extended-release capsules have not been established in pediatric patients. There are no available data to support its use in children or adolescents. Caution is advised when considering treatment options for this population, as the lack of clinical studies limits the understanding of potential risks and benefits.

Geriatric Use

Clinical studies of cyclobenzaprine hydrochloride extended-release capsules did not include a sufficient number of patients aged 65 and over to determine the safety and efficacy of this medication in the geriatric population.

It is important to note that the plasma concentration and half-life of cyclobenzaprine are substantially increased in elderly patients compared to the general patient population. Due to these pharmacokinetic changes, the use of cyclobenzaprine hydrochloride extended-release capsules is not recommended in elderly patients.

Healthcare providers should exercise caution when considering treatment options for geriatric patients, and alternative therapies should be evaluated to ensure safety and efficacy in this population. Regular monitoring and assessment of treatment response and side effects are advised if cyclobenzaprine is considered for use in older adults.

Pregnancy

Available data from case reports regarding the use of cyclobenzaprine hydrochloride extended-release capsules in pregnancy have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. However, it is important to note that the estimated background risk of major birth defects and miscarriage for the indicated populations remains unknown. All pregnancies carry a background risk of birth defects, loss, or other adverse outcomes, with the estimated background risk in the US general population for clinically recognized pregnancies being 2% to 4% for major birth defects and 15% to 20% for miscarriage.

Animal studies have shown that oral administration of cyclobenzaprine during organogenesis in mice and rabbits at maternal doses up to 20 mg/kg/day (approximately 3 and 15 times the maximum recommended human dose (MRHD) of 30 mg/day, respectively, on a mg/m² basis) did not result in adverse embryofetal effects. Maternal toxicity, characterized by decreased body weight gain, was observed only in mice at the highest tested dose of 20 mg/kg/day.

In contrast, decreased pup body weight and survival were noted in rats treated orally with cyclobenzaprine during pregnancy and lactation at doses of 10 mg/kg/day and 20 mg/kg/day (approximately 3 and 6 times the MRHD on a mg/m² basis). Maternal toxicity was also observed in this study, characterized by decreased body weight gain, but only at the highest tested dose of 20 mg/kg/day.

Given these findings, healthcare professionals should weigh the potential benefits against the risks when considering cyclobenzaprine for use in pregnant patients.

Lactation

There are no data on the presence of cyclobenzaprine in either human or animal milk, nor are there any known effects on a breastfed infant or on milk production.

The developmental and health benefits of breastfeeding should be weighed against the clinical need for cyclobenzaprine hydrochloride extended-release capsules in lactating mothers. Additionally, potential adverse effects on the breastfed child from cyclobenzaprine hydrochloride extended-release capsules or from the underlying maternal condition should be considered.

Renal Impairment

Patients with renal impairment should be closely monitored due to the potential for altered pharmacokinetics. Dosing adjustments may be necessary based on the degree of renal function decline. It is essential to assess renal function prior to initiating treatment and periodically during therapy to ensure appropriate dosing and minimize the risk of adverse effects. Caution is advised when prescribing to this population, and alternative therapies should be considered if significant renal impairment is present.

Hepatic Impairment

Use in patients with hepatic impairment is not recommended. Due to the potential for altered pharmacokinetics and the risk of adverse effects, careful consideration should be given to the use of this medication in individuals with compromised liver function. Monitoring of liver function tests may be necessary if the medication is considered essential for treatment in these patients. However, it is advised to avoid use altogether to ensure patient safety.

Overdosage

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

Signs and Symptoms of Toxicity Symptoms of toxicity can manifest rapidly following an overdose, necessitating immediate hospital monitoring. The most prevalent effects include drowsiness and tachycardia. Other less common symptoms may encompass tremor, agitation, coma, ataxia, hypertension, slurred speech, confusion, dizziness, nausea, vomiting, and hallucinations. Rare but critical symptoms include cardiac arrest, chest pain, cardiac dysrhythmias, severe hypotension, seizures, neuroleptic malignant syndrome, and rhabdomyolysis. Clinically significant changes in the electrocardiogram, particularly alterations in QRS axis or width, serve as important indicators of cyclobenzaprine toxicity.

Management Procedures To mitigate the risk of severe symptoms, it is essential to obtain an electrocardiogram (ECG) and initiate cardiac monitoring without delay. The patient's airway should be protected, an intravenous line established, and gastric decontamination initiated. 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's consciousness is impaired, securing the airway prior to lavage is critical, and emesis is contraindicated.

In cases of central nervous system (CNS) depression, early intubation is recommended due to the potential for rapid deterioration. Continuous observation with cardiac monitoring is necessary, along with vigilance for signs of CNS or respiratory depression, hypotension, cardiac dysrhythmias, and seizures. If any signs of toxicity arise during this observation period, extended monitoring 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.

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 cases of life-threatening symptoms that do not respond to other treatments, and only after consultation with a poison control center.

Given that overdosage is often intentional, a psychiatric referral may be appropriate during the recovery phase. The management principles for both child and adult overdosage are similar; therefore, it is strongly advised that physicians contact the local poison control center for specific pediatric treatment recommendations.

Nonclinical Toxicology

Long-term studies were conducted in CD-1 mice and Sprague-Dawley rats to evaluate the carcinogenic potential of cyclobenzaprine. In an 81-week carcinogenicity study, metastatic hemangiosarcoma was observed in 3 of 21 male mice at a dose of 10 mg/kg/day, which is approximately two times the maximum recommended human dose (MRHD) of 30 mg/day on a mg/m² basis. In a separate 105-week carcinogenicity study, malignant astrocytoma was noted in 3 of 50 male rats at the same dose of 10 mg/kg/day, approximately three times the MRHD on a mg/m² basis. No tumor findings were reported in female mice or rats.

Cyclobenzaprine HCl was evaluated for mutagenicity and clastogenicity and was found to be non-mutagenic in several assays, including an in vitro Ames bacterial mutation assay, an in vitro Chinese hamster ovary (CHO) cell chromosomal aberration test, and an in vivo mouse bone marrow micronucleus assay.

In studies assessing reproductive toxicity, cyclobenzaprine HCl was administered to male and female rats 70 and 14 days prior to mating, respectively, at oral doses up to 20 mg/kg/day, which is approximately 6.5 times the MRHD on a mg/m² basis. No effects on fertility or reproductive performance were observed.

In a 67-week study involving rats receiving oral doses of cyclobenzaprine at 10, 20, or 40 mg/kg/day (3 to 15 times the MRHD on a mg/m² basis), liver findings included midzonal vacuolation with lipidosis in males and midzonal and centrilobular hepatocytic enlargement in females. Additionally, centrilobular coagulative necrosis was noted. In the higher dose groups, these microscopic changes were evident after 26 weeks and even earlier in rats that died prior to 26 weeks; at lower doses, these changes were not observed until after 26 weeks.

In a 26-week study with Cynomolgus monkeys receiving oral doses of cyclobenzaprine at 2.5, 5, 10, or 20 mg/kg/day, one monkey at the highest dose of 20 mg/kg/day (15 times the MRHD on a mg/m² basis) was euthanized in week 17 due to morbidity attributed to chronic pancreatitis, cholecystitis, cholangitis, and focal liver necrosis.

Postmarketing Experience

Postmarketing experience with cyclobenzaprine hydrochloride extended-release capsules has identified several serious side effects reported voluntarily or through surveillance programs.

Serotonin syndrome has been noted as a serious medical condition that may occur when cyclobenzaprine hydrochloride extended-release capsules are used in conjunction with certain other medications. Symptoms suggestive of serotonin syndrome include agitation, hallucinations, coma, or other changes in mental status; coordination problems or muscle twitching (overactive reflexes); fast heartbeat; high or low blood pressure; sweating or fever; nausea, vomiting, or diarrhea; and muscle stiffness or tightness.

Additionally, serious side effects that may lead to heart attack or stroke have been reported. Patients experiencing irregular or abnormal heartbeats (arrhythmias) or fast heartbeat (tachycardia) should seek immediate medical attention.

Healthcare providers and patients are encouraged to report any side effects to the FDA at 1-800-FDA-1088.

Patient Counseling

Patients should be instructed to swallow cyclobenzaprine hydrochloride extended-release capsules intact. Alternatively, they may sprinkle the contents of the capsule on a tablespoon of applesauce and swallow it immediately without chewing.

Patients must be advised to discontinue the use of cyclobenzaprine hydrochloride extended-release capsules and notify their physician immediately if they experience any symptoms of an allergic reaction, which may include difficulty breathing, hives, swelling of the face or tongue, or itching.

It is important to inform patients that cyclobenzaprine hydrochloride extended-release capsules should not be taken in conjunction with MAO inhibitors or within 14 days following their discontinuation.

Healthcare providers should caution patients about the risk of serotonin syndrome when using cyclobenzaprine hydrochloride extended-release capsules alongside other medications, such as SSRIs, SNRIs, TCAs, tramadol, bupropion, meperidine, verapamil, or MAO inhibitors. Patients should be made aware of the signs and symptoms of serotonin syndrome and instructed to seek medical attention immediately if they experience these symptoms.

Patients should also be advised to stop taking cyclobenzaprine hydrochloride extended-release capsules and to notify their physician right away if they experience arrhythmias or tachycardia.

Additionally, patients should be informed that cyclobenzaprine hydrochloride extended-release capsules may enhance the impairment effects of alcohol, and similar effects may occur when taken with other CNS depressants.

Healthcare providers should caution patients about operating an automobile or other hazardous machinery until it is reasonably certain that cyclobenzaprine hydrochloride extended-release capsules will not adversely affect their ability to perform such activities.

Finally, patients should be advised to take cyclobenzaprine hydrochloride extended-release capsules at approximately the same time each day to maintain consistent therapeutic levels.

Storage and Handling

The product is supplied in a tight, light-resistant container as defined in the USP/NF. 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

No further data are available.

FDA Insert (PDF)

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

View full prescribing information (PDF)