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 exhibits 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 strengths of 15 mg and 30 mg. 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 (20-25 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 for cyclobenzaprine hydrochloride extended-release capsules include a recommendation for administration only for short periods, 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. 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 disease, 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 to ensure proper dosing.

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 of their discontinuation, due to the risk of hypertensive crisis.

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

• Patients with hyperthyroidism, due to the potential for increased sensitivity to the product's 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 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 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 commonly observed effects 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

Life-threatening interactions may occur when this medication is co-administered 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. Close monitoring for signs of serotonin syndrome is recommended when these agents are used together.

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. It is recommended to monitor patients closely for seizure activity and consider dosage adjustments as appropriate.

When administered with guanethidine, the antihypertensive effect of guanethidine may be blocked. Monitoring of blood pressure is advised, and adjustments to antihypertensive therapy may be required to maintain effective blood pressure control.

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 studied 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 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 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. Caution is advised, particularly in the context of higher doses that may lead to adverse outcomes in animal studies.

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 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 individuals with reduced kidney function, as the lack of information necessitates careful clinical judgment. Regular monitoring of renal function may be advisable in these patients to ensure safety and efficacy.

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 a patient with hepatic impairment. However, the prescribing physician should weigh the risks and benefits before initiating treatment in this population.

Overdosage

Although rare, cyclobenzaprine hydrochloride extended-release capsules can lead to fatal outcomes in cases of overdosage. It is important to note that deliberate overdose often involves the ingestion of multiple substances, including alcohol.

Recommended Actions

In managing an overdose, it is crucial for healthcare professionals to contact a poison control center for the most current treatment information, as the management of overdose is complex and subject to change. 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 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 the QRS axis or width, serve as important indicators of cyclobenzaprine toxicity.

Management Procedures

To mitigate the risk of severe symptoms, it is imperative to obtain an electrocardiogram (ECG) and initiate cardiac monitoring without delay. Protecting the patient's airway, establishing an intravenous line, and commencing gastric decontamination are essential steps. 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 critical, and emesis should be avoided.

Continuous observation with cardiac monitoring is necessary to detect signs of central nervous system (CNS) or respiratory depression, hypotension, cardiac dysrhythmias, 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 the drug.

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 needed. A maximal limb-lead QRS duration of 0.10 seconds may indicate the severity of the overdose. If dysrhythmias do not respond to sodium bicarbonate therapy or hyperventilation, alternative treatments such as lidocaine, bretylium, or phenytoin may be considered, while Type 1A and 1C antiarrhythmics (e.g., quinidine, disopyramide, 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 ineffective, other 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.

Additional Considerations

Given that overdosage is often intentional, there is a risk that patients may attempt suicide by other means during the recovery phase, making psychiatric referral a consideration. The management principles for both child and adult overdosage are similar; however, 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 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; 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 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 of 25°C (77°F), with permissible excursions between 15°C and 30°C (59°F to 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 Teva Pharmaceuticals USA, Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)