Cyclobenzaprine hydrochloride

Description

Cyclobenzaprine hydrochloride is a skeletal muscle relaxant that alleviates muscle spasms of local origin without impairing 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 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; 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. The extended-release capsules for oral administration are available in 15 mg and 30 mg strengths. The formulation of cyclobenzaprine hydrochloride extended-release capsules includes inactive ingredients such as 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 capsules also contain D&C yellow #10, FD&C green #3, and FD&C red #40, while the 30 mg capsules include 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. Consequently, specific therapy for extended periods is seldom warranted. 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 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 extended-release capsules 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 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, tremor, incoordination, stomach cramp, nausea, vomiting, and diarrhea.

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 warranted 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 common adverse reactions reported 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 observed in patients using cyclobenzaprine in conjunction with other serotonergic medications. Due to its structural similarity to tricyclic antidepressants, cyclobenzaprine may also produce adverse cardiovascular effects and 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 frequently observed effects include drowsiness and tachycardia. Less common symptoms may manifest as tremor, agitation, coma, ataxia, hypertension, slurred speech, confusion, dizziness, nausea, vomiting, and hallucinations. Rare but potentially life-threatening 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 alterations in the QRS axis or width, are indicators of cyclobenzaprine toxicity.

Drug Interactions

Life-threatening interactions may occur when this medication is used in conjunction with monoamine oxidase inhibitors (MAOIs). It is advised that concurrent use of MAOIs be avoided to prevent severe adverse effects.

The combination of this medication with serotonergic drugs can lead to serotonin syndrome, a potentially life-threatening condition characterized by symptoms such as confusion, agitation, and autonomic instability. Monitoring for signs of serotonin syndrome is recommended when these agents are co-administered.

Co-administration with central nervous system (CNS) depressants, including alcohol and barbiturates, may enhance the sedative effects of these substances. Caution is advised, and dosage adjustments may be necessary to mitigate the risk of excessive CNS depression.

The use of tramadol in conjunction with this medication may increase the risk of seizures. Clinicians should consider this potential interaction and monitor patients accordingly.

Additionally, the antihypertensive effect of guanethidine may be blocked when used with this medication. Blood pressure should be monitored, and alternative antihypertensive strategies may need to be considered.

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 adequately 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 significantly increased in elderly patients compared to the general patient population. Due to these pharmacokinetic changes, the use of cyclobenzaprine hydrochloride extended-release is not recommended in patients aged 65 and older.

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 demographic. Regular monitoring and assessment of treatment response and side effects are advised if cyclobenzaprine is deemed necessary for use in elderly patients.

Pregnancy

Available data from case reports regarding the use of cyclobenzaprine hydrochloride extended-release during 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 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 considering the observed effects in animal studies and the unknown background risks in human populations.

Lactation

Cyclobenzaprine is excreted in breast milk; however, specific data regarding its concentration in human breast milk and the effects on breastfed infants are not available. Animal studies have demonstrated that administration of cyclobenzaprine to lactating rats 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 effects on pup body weight and survival were observed in a prenatal and postnatal study with maternal doses of 10 and 20 mg/kg/day (approximately three and six times the maximum recommended human dose on a mg/m² basis).

Due to the potential risks observed in animal studies, healthcare professionals should exercise caution when prescribing cyclobenzaprine to lactating mothers. The benefits and risks should be carefully weighed, and alternative treatments may be considered.

Renal Impairment

Patients with renal impairment have not been specifically addressed in the available data regarding dosage adjustments, special monitoring, or safety considerations. Therefore, healthcare professionals should exercise caution when prescribing this medication to patients with reduced kidney function, as the lack of information necessitates careful clinical judgment and monitoring.

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 cyclobenzaprine hydrochloride extended-release overdosage, although rare, fatalities may occur. It is important to note that deliberate overdoses often involve the ingestion of multiple substances, including alcohol.

Recommended Actions

Management of cyclobenzaprine overdose is complex and may evolve; therefore, it is imperative for healthcare professionals to contact a poison control center for the most current treatment information. Immediate hospital monitoring is essential, as signs and symptoms of toxicity can develop rapidly following an overdose.

Symptoms of Overdosage

The most frequently observed effects of cyclobenzaprine overdose include drowsiness and tachycardia. Other less common symptoms may manifest, such as tremor, agitation, coma, ataxia, hypertension, slurred speech, confusion, dizziness, nausea, vomiting, and hallucinations. Rare but critical symptoms 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 toxicity.

Management Procedures

To mitigate the risk of severe symptoms, it is crucial 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 is unconscious, securing the airway prior to lavage is essential, and emesis is contraindicated.

Observation should include cardiac monitoring and vigilance for signs of central nervous system (CNS) or respiratory depression, hypotension, cardiac dysrhythmias or conduction blocks, 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 dictate patient management, and dialysis is likely ineffective due to the low plasma concentrations of cyclobenzaprine.

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 and hyperventilation as necessary. A pH greater than 7.60 or a pCO2 less than 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 advised except for life-threatening symptoms unresponsive to other treatments, and only after consulting a poison control center.

Given that overdosage is often intentional, there is a risk that patients may attempt suicide by other means during recovery. A psychiatric referral may be appropriate in such cases. The management principles for both child and adult overdosage are similar; thus, 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 fertility and reproductive performance, 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, 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 this time; at lower doses, these changes were not observed 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

Serious side effects have been reported in postmarketing experience with cyclobenzaprine hydrochloride extended-release capsules. Notably, serotonin syndrome has been identified as a serious medical condition that may occur when these capsules are taken 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, there have been reports of serious side effects that may lead to heart attack or stroke. Patients are advised to seek immediate medical attention if they experience irregular or abnormal heartbeats (arrhythmias) or a fast heartbeat (tachycardia).

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, including 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.

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 Amneal Pharmaceuticals of New York LLC. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)