Cyclobenzaprine hydrochloride

Description

Cyclobenzaprine hydrochloride USP is a skeletal muscle relaxant. The active ingredient is cyclobenzaprine hydrochloride, USP, which has 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. The chemical designation of cyclobenzaprine HCl is 3-(5H-dibenzoa,dcyclohepten-5-ylidene)-N,N-dimethyl-1-propanamine hydrochloride.

Cyclobenzaprine hydrochloride extended-release capsules USP are available in 15 mg and 30 mg strengths. Inactive ingredients in these capsules include sugar spheres, hypromellose, colloidal silicon dioxide, and ethyl cellulose. The capsule shell is composed of gelatin, sodium lauryl sulfate, titanium dioxide, and FD & C Red 40. The 15 mg strength capsules also contain FD & C Green 3 and D & C Yellow 10, while the 30 mg strength capsules contain FD & C Yellow 6 and FD & C Blue 1.

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. 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 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.

Prolonged use of cyclobenzaprine hydrochloride extended-release capsules beyond 2 to 3 weeks is not recommended.

Contraindications

Use of this product is contraindicated in the following situations:

Patients with hypersensitivity to any component of the formulation should not use this product due to the risk of severe allergic reactions.

Concomitant use with monoamine oxidase (MAO) inhibitors or within 14 days of their discontinuation is contraindicated, as this may lead to serious drug interactions.

The product is contraindicated during the acute recovery phase of myocardial infarction and in patients with arrhythmias, heart block, conduction disturbances, or congestive heart failure, due to the potential for exacerbating these cardiovascular conditions.

Additionally, the use of this product is contraindicated in patients with hyperthyroidism, as it may worsen the condition.

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. Immediate discontinuation of cyclobenzaprine and supportive care are recommended if serotonin syndrome is suspected.

Cyclobenzaprine shares structural similarities with tricyclic antidepressants, which have been associated with adverse cardiovascular effects and central nervous system (CNS) depressant effects. Therefore, healthcare providers should exercise caution 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, including sedation and confusion. Similarly, it is contraindicated in patients with hepatic impairment, as the metabolism of the drug may be significantly affected, leading to increased systemic exposure and potential toxicity.

Caution is advised when prescribing cyclobenzaprine to patients with a history of urinary retention, angle-closure glaucoma, or increased intraocular pressure. Additionally, patients taking anticholinergic medications should be monitored closely, as the combined effects may exacerbate conditions related to urinary retention and ocular pressure. Regular assessment of these patients is recommended to mitigate potential complications.

Side Effects

Most common adverse reactions reported by patients include dry mouth, dizziness, fatigue, constipation, nausea, dyspepsia, and somnolence. These reactions are generally mild and may occur with varying frequency among participants.

Serious adverse reactions have been noted, particularly the risk of serotonin syndrome when cyclobenzaprine is used 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. Hypersensitivity to any component of this product has also been reported.

Concomitant use of monoamine oxidase (MAO) inhibitors or use within 14 days after their discontinuation is contraindicated. Cyclobenzaprine should not be administered during the acute recovery phase of myocardial infarction, nor in patients with arrhythmias, heart block or conduction disturbances, or congestive heart failure. Hyperthyroidism is another condition that warrants caution.

In cases of overdose, the most common effects observed include drowsiness and tachycardia. Less frequent symptoms may encompass tremor, agitation, coma, ataxia, hypertension, slurred speech, confusion, dizziness, nausea, vomiting, and hallucinations. Rare but potentially critical 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 in 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). Caution is advised, and concurrent use should be avoided.

The combination of this medication with serotonergic drugs has been associated with the development of serotonin syndrome. Clinicians should monitor patients closely for symptoms of this condition, particularly when initiating or adjusting dosages of either medication.

Co-administration with central nervous system (CNS) depressants, including alcohol and barbiturates, may enhance the sedative effects. It is recommended that patients be monitored 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 evaluate the necessity of tramadol and consider alternative pain management strategies if seizure risk is a concern.

When administered with guanethidine, the antihypertensive effect of guanethidine may be blocked. Blood pressure should be monitored, and alternative antihypertensive therapies should be considered if necessary.

No specific drug interactions or laboratory test interactions have been identified for this medication.

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 differences, 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 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, particularly at higher doses, and consider monitoring for any adverse outcomes.

Lactation

Lactating mothers should be aware that cyclobenzaprine has been associated with decreased pup body weight and survival when administered at doses of 10 mg/kg/day or higher during pregnancy and lactation. This dose is approximately three times the maximum recommended human dose (MRHD) of 30 mg/day.

In a prenatal and postnatal study involving pregnant rats, similar effects on pup body weight and survival were observed with maternal doses of 10 and 20 mg/kg/day, which correspond to approximately three and six times the MRHD on a mg/m² basis.

Given these findings, healthcare professionals should carefully consider the potential risks when prescribing cyclobenzaprine to lactating mothers, particularly at higher doses.

Renal Impairment

Patients with renal impairment have no specific information regarding dosage adjustments or monitoring provided in the text. Therefore, healthcare professionals should exercise caution when prescribing this medication to individuals with reduced kidney function, as the absence of guidance necessitates careful consideration of potential risks and benefits. 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, 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 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 symptoms may manifest as tremor, agitation, coma, ataxia, hypertension, slurred speech, confusion, dizziness, nausea, vomiting, and hallucinations. Healthcare providers should be vigilant for rare but potentially life-threatening symptoms, which 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.

Recommended Actions for Management 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. The patient's airway must be protected, an intravenous line established, and gastric decontamination initiated. This decontamination should consist of 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.

Monitoring and Further Interventions 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 dialysis is likely ineffective due to the low plasma concentrations of cyclobenzaprine.

In cases where dysrhythmias or QRS widening occurs, serum alkalinization should be achieved to a pH of 7.45 to 7.55 using intravenous sodium bicarbonate and hyperventilation. If dysrhythmias do not respond to sodium bicarbonate therapy or hyperventilation, alternative treatments such as lidocaine, bretylium, or phenytoin may be considered. 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.

Special Considerations Physostigmine is not recommended except in cases 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 advisable for physicians to 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 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. 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.

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

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 of their discontinuation. Providers should also 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 be advised to stop taking cyclobenzaprine hydrochloride extended-release capsules and notify their physician right away if they experience arrhythmias or tachycardia.

Additionally, healthcare providers should 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

Dispense in a tight, light-resistant container to ensure product integrity. The product should be stored at a temperature range of 20° to 25°C (68° to 77°F), with permissible excursions between 15° to 30°C (59° to 86°F) in accordance with USP Controlled Room Temperature guidelines.

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 Macleods Pharmaceuticals Limited. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)