Cyclobenzaprine hydrochloride

Description

Cyclobenzaprine hydrochloride is a skeletal muscle relaxant that alleviates muscle spasms of local origin without affecting muscle function. The active ingredient in cyclobenzaprine hydrochloride extended-release capsules is cyclobenzaprine hydrochloride, USP. This compound 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. Chemically, it is designated as 3-(5H-dibenzoa,dcyclohepten-5-ylidene)-N,N-dimethyl-1-propanamine hydrochloride.

Cyclobenzaprine hydrochloride extended-release capsules are available for oral administration in strengths of 15 mg and 30 mg. The capsules contain several inactive ingredients, including diethyl phthalate NF, ethylcellulose NF (Ethocel Standard 10 Premium), gelatin, Opadry Clear YS-1-7006, sugar spheres NF (20 to 25 mesh), and titanium dioxide. The 15 mg extended-release capsules also include D&C yellow #10, FD&C green #3, and FD&C red #40, while the 30 mg extended-release capsules contain FD&C blue #1, FD&C blue #2, FD&C red #40, and FD&C yellow #6.

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. Furthermore, specific therapy for extended periods is seldom warranted. It is important to note that 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 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 regularly assess the necessity of continued therapy.

Contraindications

Use of this product is contraindicated in the following situations:

• Patients with hypersensitivity to any component of the formulation.

• Individuals currently taking monoamine oxidase (MAO) inhibitors or those who have discontinued MAO inhibitors within the past 14 days, due to the risk of serious interactions.

• Patients in the acute recovery phase of myocardial infarction, as well as those with arrhythmias, heart block, conduction disturbances, or congestive heart failure, due to potential cardiovascular complications.

• Individuals with hyperthyroidism, as this condition may exacerbate the effects of the product.

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, tremor, incoordination, stomach cramp, nausea, vomiting, and diarrhea.

Cyclobenzaprine shares structural similarities with tricyclic antidepressants, which have been associated with 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 susceptible to CNS depression.

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 in these populations.

Side Effects

Patients receiving cyclobenzaprine may experience a range of adverse reactions. The most commonly reported adverse reactions include dry mouth, dizziness, fatigue, constipation, nausea, dyspepsia, and somnolence.

In addition to these common reactions, there are important safety considerations associated with cyclobenzaprine. Serotonin syndrome has been reported in patients using cyclobenzaprine in conjunction with other serotonergic drugs. Due to its structural similarity to tricyclic antidepressants, cyclobenzaprine may also produce adverse cardiovascular effects or central nervous system (CNS) depressant effects.

The use of cyclobenzaprine is not recommended in elderly patients or those with hepatic impairment. Caution is advised when prescribing to patients with a history of urinary retention, angle-closure glaucoma, increased intraocular pressure, or those taking anticholinergic medications.

In cases of overdose, the most common effects observed include drowsiness and tachycardia. Less frequent symptoms may manifest as 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 the QRS axis or width, are indicators of cyclobenzaprine toxicity.

Drug Interactions

There are currently no documented drug interactions associated with the use of 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 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.

Geriatric Use

Clinical studies of cyclobenzaprine hydrochloride extended-release 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 has been observed 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 differences and the lack of adequate clinical data, the use of cyclobenzaprine hydrochloride extended-release is not recommended in elderly patients.

Healthcare providers should exercise caution when considering treatment options for geriatric patients, taking into account the potential for increased drug exposure and the associated risks. Monitoring for adverse effects and considering alternative therapies may be prudent in this population.

Pregnancy

Available data from case reports regarding the use of cyclobenzaprine hydrochloride extended-release 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. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is approximately 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 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.

In summary, while the available data do not indicate a significant risk associated with cyclobenzaprine use during pregnancy, caution is advised, particularly at higher doses, due to the observed effects in animal studies. Healthcare professionals should weigh the potential benefits against the risks when prescribing cyclobenzaprine to pregnant patients or women of childbearing potential.

Lactation

Cyclobenzaprine is excreted in breast milk; however, specific data regarding the concentration in human milk and the effects on breastfed infants are not available. Animal studies have demonstrated that lactating mothers administered cyclobenzaprine at doses of 10 mg/kg/day or higher (approximately three times the maximum recommended human dose of 30 mg/day) resulted in decreased body weight and survival of pups. Similar outcomes were observed in a prenatal and postnatal study where maternal doses of 10 and 20 mg/kg/day (approximately three and six times the maximum recommended human dose on a mg/m² basis) were associated with adverse effects on pup body weight and survival.

Given these findings, healthcare professionals should weigh the potential risks and benefits of cyclobenzaprine use in lactating mothers, considering the lack of human data and the observed effects in animal studies.

Renal Impairment

There is no specific information regarding dosage adjustments, special monitoring, or safety considerations for patients with renal impairment. Healthcare professionals should exercise caution when prescribing to patients with reduced kidney function, as the absence of detailed guidance necessitates careful clinical judgment. Regular monitoring of renal function may be advisable in this patient population.

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.

Overdosage

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

Signs and Symptoms Toxicity symptoms can manifest rapidly following an overdose, necessitating immediate hospital monitoring. The most prevalent effects include drowsiness and tachycardia. Other less common symptoms may present as tremor, agitation, coma, ataxia, hypertension, slurred speech, confusion, dizziness, nausea, vomiting, and hallucinations. Critical symptoms, though 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, serve as important indicators of cyclobenzaprine toxicity.

Management Procedures To mitigate the risk of critical 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 commenced. 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 is unconscious, securing the airway prior to lavage is crucial, and emesis is contraindicated.

Continuous observation with cardiac monitoring is necessary to detect 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 plasma drug level monitoring should not dictate patient management, and dialysis is likely ineffective due to the low plasma concentrations of cyclobenzaprine.

For patients exhibiting dysrhythmias and/or QRS widening, serum alkalinization to a pH of 7.45 to 7.55 should be achieved using intravenous sodium bicarbonate and hyperventilation. Dysrhythmias that do not respond to sodium bicarbonate therapy or hyperventilation may be treated with lidocaine, bretylium, or phenytoin. In cases of CNS depression, early intubation is recommended due to the risk of sudden deterioration. Seizures should be managed with benzodiazepines or other anticonvulsants if benzodiazepines prove ineffective.

Physostigmine is not advised except for the treatment of life-threatening symptoms that have not responded to other therapies. The management principles for both child and adult overdosage are similar; therefore, it is strongly recommended that physicians consult the local poison control center for specific pediatric treatment guidance.

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 hydrochloride was evaluated for mutagenicity and clastogenicity 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. The results indicated that cyclobenzaprine hydrochloride was not mutagenic or clastogenic.

In studies assessing reproductive toxicity, cyclobenzaprine hydrochloride was administered to male and female rats at oral 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. 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

Healthcare providers should instruct patients to swallow cyclobenzaprine hydrochloride extended-release capsules intact. Alternatively, patients may sprinkle the contents of the capsule on a tablespoon of applesauce and swallow it immediately without chewing.

Patients should 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 cyclobenzaprine hydrochloride extended-release capsules are used 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.

It is essential to inform patients 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 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 of 25°C (77°F), with permissible excursions between 15° and 30°C (59° and 86°F), in accordance with USP Controlled Room Temperature guidelines. Proper handling and storage conditions are essential to maintain the integrity 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)