Cyclobenzaprine hydrochloride

Description

Cyclobenzaprine hydrochloride is a skeletal muscle relaxant. The active ingredient in cyclobenzaprine hydrochloride extended-release capsules is cyclobenzaprine hydrochloride, USP. 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. When aqueous solutions of cyclobenzaprine hydrochloride are made alkaline, the free base separates. Chemically, cyclobenzaprine HCl is designated as 3-(5H-dibenzoa,dcyclohepten-5-ylidene)-N,N-dimethyl-1-propanamine hydrochloride.

Cyclobenzaprine hydrochloride extended-release capsules for oral administration are available in 15 mg and 30 mg strengths. The capsules contain inactive ingredients including 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 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, and specific therapy for extended periods is rarely justified. 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 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 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.

• 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 risk of adverse effects related to thyroid function.

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 is structurally related to 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 susceptible to CNS depression.

The use of cyclobenzaprine in the elderly population is not recommended due to an increased risk of adverse effects. Similarly, it is contraindicated in patients with hepatic impairment, as the drug's metabolism may be significantly affected, leading to increased risk of 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 may experience a range of adverse reactions while using cyclobenzaprine. The most common adverse reactions reported include dry mouth, dizziness, fatigue, constipation, nausea, dyspepsia, and somnolence.

Serious adverse reactions have also been noted. Cyclobenzaprine has been associated with serotonin syndrome, particularly when used 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.

The use of cyclobenzaprine is not recommended 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 those taking anticholinergic medications. Hypersensitivity reactions to any component of the product have been reported, as well as adverse effects when used concomitantly with monoamine oxidase (MAO) inhibitors or within 14 days of their discontinuation. Cyclobenzaprine should also be avoided during the acute recovery phase of myocardial infarction and in patients with arrhythmias, heart block, 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, while 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 can 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.

Patients who abruptly cease treatment after prolonged administration may experience nausea, headache, and malaise; however, 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). 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. Caution is recommended when prescribing these agents together, and monitoring for signs of serotonin syndrome should be implemented.

Co-administration with central nervous system (CNS) depressants, including alcohol and barbiturates, may enhance the sedative effects of these substances. Patients should be monitored closely 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 alternative pain management strategies or closely monitor patients for seizure activity if these medications are used together.

Additionally, the antihypertensive effect of guanethidine may be blocked when administered with this medication. Blood pressure should be monitored, and alternative antihypertensive therapies 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 capsules 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, as the lack of clinical studies precludes any definitive conclusions regarding dosing or therapeutic outcomes in 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 pregnant patients 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. 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 in 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 the observed effects in animal studies, and the decision to use this medication should involve careful consideration of the individual patient's circumstances.

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 patients with reduced kidney function, as the lack of information necessitates careful clinical judgment and monitoring of these patients.

Hepatic Impairment

Use in patients with hepatic impairment is not recommended. Due to the potential for altered pharmacokinetics and increased risk of adverse effects, caution should be exercised when considering treatment in this population. Monitoring of liver function is advised, and alternative therapeutic options should be explored for patients with compromised liver function.

Overdosage

Overdosage with cyclobenzaprine hydrochloride extended-release capsules, while rare, can lead to serious outcomes, including death. It is important to note that multiple drug ingestion, often involving alcohol, is frequently observed in cases of deliberate overdose.

Clinical Presentation and Symptoms

Signs and symptoms of toxicity may 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. Clinicians should be vigilant for changes in the electrocardiogram, particularly alterations in QRS axis or width, as these are significant indicators of cyclobenzaprine toxicity.

Initial Management

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 should be protected, an intravenous line established, and gastric decontamination commenced. 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 is unconscious, securing the airway prior to lavage is critical, and emesis is contraindicated.

Monitoring and Supportive Care

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 monitoring plasma drug levels should not dictate patient management, and dialysis is unlikely to be beneficial due to the low plasma concentrations of cyclobenzaprine.

Specific Interventions

In cases where dysrhythmias or QRS widening occurs, serum alkalinization to a pH of 7.45 to 7.55 using intravenous sodium bicarbonate and hyperventilation should be initiated. If dysrhythmias do not respond to sodium bicarbonate therapy and hyperventilation, alternative treatments such as lidocaine, bretylium, or phenytoin may be considered. For patients exhibiting 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 life-threatening symptoms that do not respond to other treatments, and its use should be in close consultation with a poison control center. Given that overdosage is often intentional, a psychiatric referral may be appropriate. The management principles for both child and adult overdosage are similar; therefore, it is strongly recommended that physicians contact 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 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 reproductive toxicity, 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.

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; 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.

It is important to advise patients 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.

Patients should be informed that cyclobenzaprine hydrochloride extended-release capsules must 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. Patients should be cautioned 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 REMEDYREPACK INC.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)