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. Cyclobenzaprine hydrochloride 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. The drug 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.

These capsules are intended for short-term use, specifically for periods not exceeding 2 to 3 weeks. It is important to note that cyclobenzaprine hydrochloride extended-release capsules have not demonstrated efficacy in the treatment of spasticity or cerebral palsy.

There are no teratogenic or nonteratogenic effects associated with the use of this medication.

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 doses be taken 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 patients 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 lead to increased 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 elderly patients is not recommended due to an increased risk of adverse effects. Similarly, it is contraindicated in individuals with hepatic impairment, as the drug's metabolism may be significantly affected, leading to increased systemic exposure and potential toxicity.

Healthcare professionals should exercise caution when prescribing cyclobenzaprine to patients with a history of urinary retention, angle-closure glaucoma, or increased intraocular pressure. Additionally, patients taking anticholinergic medications may be at heightened risk for adverse effects, and careful monitoring is advised in these cases. Regular assessment of the patient's condition and any relevant laboratory tests should be conducted to ensure safe use of cyclobenzaprine.

Side Effects

Patients may experience a range of adverse reactions while using cyclobenzaprine, which can be categorized into common and serious reactions.

The most common adverse reactions reported include dry mouth, dizziness, fatigue, constipation, nausea, dyspepsia, and somnolence. These effects are typically mild to moderate in severity.

Serious adverse reactions have also been observed. 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 regarding the use of cyclobenzaprine indicate that it is not recommended for use in elderly patients or those with hepatic impairment. Caution is advised for patients with a history of urinary retention, angle-closure glaucoma, increased intraocular pressure, and for those taking anticholinergic medications. Furthermore, hypersensitivity to any component of this product has been noted as a potential adverse reaction. The concomitant use of monoamine oxidase (MAO) inhibitors or use within 14 days after their discontinuation is contraindicated. Cyclobenzaprine should also be avoided during the acute recovery phase of myocardial infarction and in patients with arrhythmias, heart block or conduction disturbances, or congestive heart failure, as well as in those with hyperthyroidism.

In cases of overdose, the most common effects include drowsiness and tachycardia. 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. Clinically significant changes in the electrocardiogram, particularly in QRS axis or width, are important indicators of cyclobenzaprine toxicity.

Drug Interactions

There are currently no documented drug interactions associated with this medication. Additionally, there is no information available regarding interactions with laboratory tests. As such, no specific recommendations for dosage adjustments or monitoring are warranted at this time.

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, and therefore, caution is advised when considering treatment in this population.

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 is 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 rats, decreased pup body weight and survival were observed at doses of cyclobenzaprine ≥10 mg/kg/day (approximately ≥3 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 to mice and rabbits at maternal doses up to 20 mg/kg/day (approximately 3 and 15 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 approached with caution, as the use of this medication is not recommended in individuals with hepatic impairment. It is essential for healthcare professionals to consider the potential impact of reduced kidney function on drug clearance and efficacy. Regular monitoring of renal function may be necessary to ensure patient safety and optimal therapeutic outcomes.

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, the prescribing information advises against its use in this population.

Overdosage

In cases of overdosage with cyclobenzaprine hydrochloride extended-release capsules, although rare, fatalities may occur. It is crucial for healthcare professionals to recognize that signs and symptoms of toxicity can develop rapidly, necessitating immediate hospital monitoring.

Common Symptoms of Overdosage The most frequently observed effects of cyclobenzaprine overdose include drowsiness and tachycardia. Other less common manifestations may present as tremor, agitation, coma, ataxia, hypertension, slurred speech, confusion, dizziness, nausea, vomiting, and hallucinations. Rarely, critical symptoms such as cardiac arrest, chest pain, cardiac dysrhythmias, severe hypotension, seizures, and neuroleptic malignant syndrome may occur. Clinically significant changes in the electrocardiogram, particularly alterations in the QRS axis or width, serve as important indicators of cyclobenzaprine toxicity.

Recommended Actions Upon suspicion of an overdose, it is recommended that the physician contact a poison control center for the most current treatment information. Immediate actions should include obtaining an electrocardiogram (ECG) and initiating cardiac monitoring to protect against potentially critical manifestations. Additionally, securing the patient's airway, establishing an intravenous line, and initiating gastric decontamination are essential steps. 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, airway protection should be prioritized prior to lavage, and emesis is contraindicated.

Monitoring and Management Continuous observation with cardiac monitoring is necessary to assess for signs of central nervous system (CNS) or respiratory depression, hypotension, cardiac dysrhythmias, and seizures. Extended monitoring is warranted if any signs of toxicity arise during this period. It is important to note that monitoring plasma drug levels should not guide patient management, and dialysis is likely of no value due to the low plasma concentrations of the drug.

In cases where dysrhythmias and/or QRS widening are present, serum alkalinization to a pH of 7.45 to 7.55 using intravenous sodium bicarbonate, along with hyperventilation, should be initiated. For patients exhibiting CNS depression, early intubation is advised due to the risk of abrupt deterioration. Seizures should be managed with benzodiazepines or other anticonvulsants if benzodiazepines prove ineffective. The use of physostigmine is not recommended except in instances of life-threatening symptoms that have not responded to other therapies.

Given that overdosage is often deliberate, a psychiatric referral may be appropriate. The management principles for both child and adult overdosage are similar; therefore, it is strongly advised that the physician consult 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 twice 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 fertility, cyclobenzaprine HCl was administered to male and female rats at doses up to 20 mg/kg/day, approximately 6.5 times the MRHD on a mg/m² basis, for 70 and 14 days prior to mating, respectively. 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. These microscopic changes were evident in higher dose groups after 26 weeks and earlier in rats that died prior to this time; lower doses did not show these changes until after 26 weeks.

A 26-week study with Cynomolgus monkeys receiving cyclobenzaprine at oral doses of 2.5, 5, 10, or 20 mg/kg/day revealed that 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; fluctuations in 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 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 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 regarding the operation of automobiles or 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)