Cyclobenzaprine hydrochloride

Description

Cyclobenzaprine hydrochloride extended-release capsules USP are skeletal muscle relaxants that relieve muscle spasm of local origin without interfering with muscle function. The active ingredient is cyclobenzaprine hydrochloride, USP, which is a white, crystalline tricyclic amine salt with the empirical formula C20H21N·HCl and a molecular weight of 311.9. It has a melting point of 217°C and a pKa of 8.47 at 25°C. Cyclobenzaprine hydrochloride 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. The chemical designation of cyclobenzaprine HCl is 3-(5H-dibenzoa,dcyclohepten-5-ylidene)-N,N-dimethyl-1-propanamine hydrochloride. The capsules are available for oral administration in strengths of 15 mg and 30 mg. Inactive ingredients in the capsules include 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 contains 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. Furthermore, 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 for most patients is 15 mg of cyclobenzaprine hydrochloride extended-release capsules taken once daily. In certain cases, some patients may require an increased dose of 30 mg taken once daily. It is advised that doses be administered 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 should not use this product due to the risk of severe allergic reactions.

Concomitant use with monoamine oxidase (MAO) inhibitors or within 14 days following their discontinuation is contraindicated, as this may lead to serious drug interactions.

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

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

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 medication. The most common adverse reactions reported include dry mouth, dizziness, fatigue, constipation, nausea, dyspepsia, and somnolence.

Serious adverse reactions have also been noted. Notably, serotonin syndrome has been reported in patients using cyclobenzaprine in combination 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 regarding the use of this medication indicate that it is not recommended for use in the elderly or in patients with hepatic impairment. Caution is advised for patients with a history of urinary retention, angle-closure glaucoma, increased intraocular pressure, and those taking anticholinergic medications. Hypersensitivity reactions may occur in individuals with an allergy to any component of the product. The concomitant use of monoamine oxidase (MAO) inhibitors or within 14 days of their discontinuation is contraindicated. Furthermore, the medication should not be used during the acute recovery phase of myocardial infarction, nor in patients with arrhythmias, heart block or conduction disturbances, or congestive heart failure, and is also contraindicated in individuals with hyperthyroidism.

In cases of overdose, the most common effects include drowsiness and tachycardia. Less frequent symptoms may involve tremor, agitation, coma, ataxia, hypertension, slurred speech, confusion, dizziness, nausea, vomiting, and hallucinations. Rare but potentially critical symptoms of overdose include cardiac arrest, chest pain, cardiac dysrhythmias, severe hypotension, seizures, neuroleptic malignant syndrome, and rhabdomyolysis. Clinically significant changes in the electrocardiogram, particularly 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 symptoms such as 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 consider this potential interaction when prescribing tramadol and may need to adjust dosages accordingly.

Additionally, the antihypertensive effect of guanethidine may be blocked when used with this medication. Monitoring of blood pressure is advised, and adjustments to antihypertensive therapy may be required.

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. Therefore, the use of this medication in children and adolescents is not recommended due to the lack of clinical data supporting its use in these populations. Healthcare professionals should exercise caution when considering treatment options for pediatric patients.

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 geriatric patients.

Healthcare providers should exercise caution when considering treatment options for elderly patients, taking into account the potential for increased drug exposure and the associated risks. Monitoring for adverse effects is advised if cyclobenzaprine is deemed necessary in this population.

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 of major birth defects and miscarriage in clinically recognized pregnancies in the US general population being 2% to 4% and 15% to 20%, respectively.

Animal studies have provided some insights into the potential effects of cyclobenzaprine during pregnancy. In studies involving rats, decreased pup body weight and survival were observed at cyclobenzaprine doses of 10 mg/kg/day or greater (approximately three times the maximum recommended human dose (MRHD) of 30 mg/day) when administered orally during pregnancy and lactation. Additionally, no adverse embryofetal effects were reported following oral administration of cyclobenzaprine during organogenesis in mice and rabbits at maternal doses up to 20 mg/kg/day (approximately three and fifteen times the MRHD, respectively, on a mg/m² basis). Maternal toxicity, characterized by decreased body weight gain, was noted only in mice at the highest tested dose of 20 mg/kg/day.

Given these findings, healthcare professionals should weigh the potential benefits and risks of cyclobenzaprine use in pregnant patients, particularly at higher doses, and consider monitoring for any adverse outcomes.

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 safety and efficacy. Caution is advised when prescribing to individuals with reduced kidney function, as they may experience increased drug exposure and a higher risk of adverse effects.

Hepatic Impairment

Use in patients with hepatic impairment is not recommended. Due to the potential for altered pharmacokinetics and the risk of adverse effects, it is advised that these patients avoid the use of this medication. Monitoring of liver function is essential in patients with compromised liver function, and alternative therapeutic options should be considered 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. Critical symptoms, although rare, 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, should be closely monitored as indicators of cyclobenzaprine toxicity.

Management Procedures To mitigate the risk of severe complications, it is essential to obtain an electrocardiogram (ECG) and initiate cardiac monitoring without delay. The patient's airway must be protected, an intravenous line established, and gastric decontamination initiated. 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 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 is necessary, focusing on 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; 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 mutagenic potential and was found to be neither mutagenic nor clastogenic 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 terms of 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. The treatment did not affect fertility or reproductive performance.

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 observed. In the higher dose groups, these microscopic changes were noted 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 tachycardia should seek immediate medical attention.

Healthcare providers and patients are encouraged to report 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 care immediately if they experience these symptoms.

Patients should also be advised to stop taking cyclobenzaprine hydrochloride extended-release capsules and 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 therapy will not adversely affect their ability to engage in 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 Upsher-Smith Laboratories, LLC. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)