Cyclobenzaprine hydrochloride

Description

Cyclobenzaprine hydrochloride is a white, crystalline tricyclic amine salt with a molecular weight of 311.9 g/mol. It is chemically designated as 3-(5-H-dibenzoa,dcyclohepten-5-ylidene)-N,N-dimethyl-1-propanamine, hydrochloride. The compound 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.

Cyclobenzaprine hydrochloride is available in tablet form for oral administration, with dosages of 5 mg, 7.5 mg, and 10 mg. Each tablet contains the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, dibasic calcium phosphate, hydroxypropyl cellulose, hypromellose, polyethylene glycol, magnesium stearate, microcrystalline cellulose, and titanium dioxide.

Uses and Indications

Cyclobenzaprine HCl is indicated as an adjunct to rest and physical therapy for the relief of muscle spasm associated with acute, painful musculoskeletal conditions. The therapeutic effects are characterized by the alleviation of muscle spasm and its associated signs and symptoms, including pain, tenderness, limitation of motion, and restrictions in activities of daily living.

This medication is intended for short-term use, specifically for periods not exceeding two to three weeks. This limitation is based on the lack of adequate evidence supporting the effectiveness of cyclobenzaprine HCl for prolonged use, as muscle spasms related to acute, painful musculoskeletal conditions are typically of short duration. Therefore, specific therapy for extended periods is seldom warranted.

Cyclobenzaprine HCl has not demonstrated efficacy in treating spasticity associated with cerebral or spinal cord diseases, nor is it indicated for use in children with cerebral palsy.

Dosage and Administration

The recommended dose of cyclobenzaprine HCl for most patients is 5 mg administered three times a day. Based on individual patient response, the dosage may be increased to either 7.5 mg or 10 mg, also taken three times a day.

It is important to note that the use of cyclobenzaprine HCl for periods longer than two to three weeks is not recommended. For patients who are hepatically impaired or elderly, less frequent dosing should be considered to ensure safety and efficacy.

Contraindications

Use of this product is contraindicated in the following situations:

• Patients with hypersensitivity to any component of the product.

• Concomitant use with monoamine oxidase (MAO) inhibitors or within 14 days of their discontinuation, due to the risk of hyperpyretic crisis, seizures, and fatalities associated with cyclobenzaprine or structurally similar tricyclic antidepressants.

• Individuals in the acute recovery phase of myocardial infarction, as well as those with arrhythmias, heart block, conduction disturbances, or congestive heart failure.

• Patients with hyperthyroidism.

Warnings and Precautions

Cyclobenzaprine is structurally related to tricyclic antidepressants, such as amitriptyline and imipramine. Caution is advised when prescribing cyclobenzaprine, particularly in short-term studies for indications beyond muscle spasm associated with acute musculoskeletal conditions. In these studies, and typically at doses exceeding those recommended for muscle spasm, serious central nervous system reactions similar to those observed with tricyclic antidepressants have been reported.

Healthcare professionals should be vigilant regarding the potential for arrhythmias, sinus tachycardia, and prolongation of conduction time associated with tricyclic antidepressants, which may lead to severe cardiovascular events, including myocardial infarction and stroke.

Additionally, cyclobenzaprine hydrochloride may potentiate the effects of alcohol, barbiturates, and other central nervous system depressants. It is imperative to monitor patients for increased sedation and respiratory depression when these substances are co-administered. Regular assessment of cardiovascular status and central nervous system function is recommended to ensure patient safety during treatment with cyclobenzaprine.

Side Effects

Patients receiving treatment may experience a range of adverse reactions. The most common adverse reactions, occurring in more than 3% of participants, include drowsiness (29% at 5 mg, 38% at 10 mg, and 10% in the placebo group), dry mouth (21% at 5 mg, 32% at 10 mg, and 7% in the placebo group), fatigue (6% at both 5 mg and 10 mg, and 3% in the placebo group), and headache (5% at both 5 mg and 10 mg, and 8% in the placebo group). Additional common adverse reactions reported in clinical studies include drowsiness (39%) and dry mouth (27%), with lower incidences noted in a surveillance program (16% and 7%, respectively). Dizziness was reported in 11% of clinical studies and 3% in the surveillance program.

Adverse reactions occurring in 1% to 3% of patients include abdominal pain, acid regurgitation, constipation, diarrhea, dizziness, nausea, irritability, decreased mental acuity, nervousness, upper respiratory infection, and pharyngitis. Less frequent adverse reactions may include fatigue, asthenia, nausea, constipation, dyspepsia, unpleasant taste, blurred vision, headache, nervousness, and confusion.

Postmarketing experience has identified additional adverse reactions with an incidence of less than 1%. These include syncope and malaise (body as a whole), tachycardia, arrhythmia, vasodilatation, palpitation, and hypotension (cardiovascular). Digestive system reactions may include vomiting, anorexia, diarrhea, gastrointestinal pain, gastritis, thirst, flatulence, edema of the tongue, abnormal liver function, and rare reports of hepatitis, jaundice, and cholestasis. Hypersensitivity reactions such as anaphylaxis, angioedema, pruritus, facial edema, urticaria, and rash have also been reported.

Nervous system and psychiatric reactions may include seizures, ataxia, vertigo, dysarthria, tremors, hypertonia, convulsions, muscle twitching, disorientation, insomnia, depressed mood, anxiety, agitation, psychosis, abnormal thinking and dreaming, hallucinations, excitement, paresthesia, and diplopia. Other less common reactions include sweating (skin) and ageusia or tinnitus (special senses). Urogenital reactions may involve urinary frequency and/or retention.

Rarely reported adverse reactions with an unknown causal relationship include chest pain and edema (body as a whole), hypertension, myocardial infarction, heart block, and stroke (cardiovascular). Digestive issues such as paralytic ileus, tongue discoloration, stomatitis, and parotid swelling have also been noted. Endocrine reactions may include inappropriate ADH syndrome, while hematologic and lymphatic reactions can involve purpura, bone marrow depression, leukopenia, eosinophilia, and thrombocytopenia. Metabolic, nutritional, and immune reactions may manifest as elevation or lowering of blood sugar levels, as well as weight gain or loss. Musculoskeletal reactions may include myalgia, while nervous system and psychiatric reactions can involve decreased or increased libido, abnormal gait, delusions, aggressive behavior, paranoia, peripheral neuropathy, Bell’s palsy, alteration in EEG patterns, and extrapyramidal symptoms. Respiratory reactions may include dyspnea, and skin reactions can involve photosensitization and alopecia. Urogenital reactions may also include impaired urination, dilatation of the urinary tract, impotence, testicular swelling, gynecomastia, breast enlargement, and galactorrhea.

Drug Interactions

Concomitant use of cyclobenzaprine HCl with monoamine oxidase (MAO) inhibitors, or within 14 days of their discontinuation, is contraindicated due to the risk of severe adverse effects, including hyperpyretic crisis, seizures, and fatalities.

Pharmacokinetic interactions indicate that the co-administration of cyclobenzaprine HCl and aspirin does not significantly affect the plasma levels or bioavailability of either drug, suggesting that no dosage adjustments are necessary when these medications are used together.

In terms of pharmacodynamic interactions, the combination of cyclobenzaprine HCl with naproxen or diflunisal has been found to be well tolerated, with no unexpected adverse effects reported. However, it is important to note that the combination of cyclobenzaprine HCl with naproxen may lead to an increased incidence of side effects, particularly drowsiness, compared to naproxen alone. Therefore, monitoring for increased sedation is advisable when these medications are used in conjunction.

Additionally, cyclobenzaprine HCl may potentiate the effects of alcohol, barbiturates, and other central nervous system (CNS) depressants. Caution is recommended when these substances are used concurrently, and monitoring for enhanced CNS depression is warranted.

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

Safety and effectiveness of cyclobenzaprine HCl in pediatric patients below 15 years of age have not been established. Therefore, caution is advised when considering the use of this medication in this age group.

Geriatric Use

Elderly patients may experience increased plasma concentrations of cyclobenzaprine, which necessitates careful consideration when prescribing this medication. Due to this heightened concentration, geriatric patients are at an elevated risk for central nervous system (CNS) adverse events, including hallucinations and confusion. Additionally, there is a concern for cardiac events in this population, which may lead to falls or other serious complications.

Given the potential for drug-drug and drug-disease interactions, cyclobenzaprine should be prescribed to elderly patients only when clearly indicated. When initiating treatment in this demographic, it is recommended that cyclobenzaprine HCl be started at a dose of 5 mg, with a gradual titration to higher doses as necessary. Close monitoring for adverse effects and therapeutic efficacy is advised throughout the treatment process to ensure patient safety.

Pregnancy

Pregnancy Category B. Reproduction studies have been conducted in rats, mice, and rabbits at doses up to 20 times the human dose, demonstrating no evidence of impaired fertility or harm to the fetus associated with cyclobenzaprine HCl. However, there are no adequate and well-controlled studies in pregnant women. Due to the limitations of animal reproduction studies in predicting human response, cyclobenzaprine HCl should be used during pregnancy only if clearly needed. Healthcare professionals are advised to weigh the potential benefits against any possible risks when considering this medication for pregnant patients.

Lactation

It is not known whether this drug is excreted in human milk. Due to the structural similarity of cyclobenzaprine to tricyclic antidepressants, some of which are known to be excreted in human milk, caution should be exercised when administering cyclobenzaprine HCl to lactating mothers. The potential effects on breastfed infants have not been established, and healthcare professionals should consider the risks and benefits of treatment in nursing women.

Renal Impairment

Patients with renal impairment have not been specifically addressed in the available prescribing information. There are no dosage adjustments, special monitoring requirements, or safety considerations outlined for individuals with reduced kidney function. Healthcare professionals should exercise caution and consider the lack of data when prescribing to this patient population.

Hepatic Impairment

Patients with hepatic impairment have not been specifically studied in relation to the use of this medication. Consequently, there are no established dosage adjustments, special monitoring requirements, or precautions outlined for individuals with compromised liver function. It is recommended that healthcare providers exercise caution when prescribing this medication to patients with hepatic impairment, given the lack of data on its safety and efficacy in this population. Regular monitoring of liver function may be prudent in these cases, although specific parameters are not defined in the available information.

Overdosage

In cases of cyclobenzaprine HCl overdosage, although rare, fatalities may occur. It is important to note that deliberate overdose often involves the ingestion of multiple drugs, including alcohol. Due to the complexity and evolving nature of overdose management, healthcare professionals are advised to contact a poison control center for the most current treatment information.

Signs and Symptoms of Toxicity Symptoms of cyclobenzaprine overdose can develop rapidly, necessitating immediate hospital monitoring. The acute oral LD50 for cyclobenzaprine HCl is approximately 338 mg/kg in mice and 425 mg/kg in rats. The most frequently observed effects include drowsiness and tachycardia. Other less common symptoms may include tremor, agitation, coma, ataxia, hypertension, slurred speech, confusion, dizziness, nausea, vomiting, and hallucinations. Rare but critical manifestations can involve cardiac arrest, chest pain, cardiac dysrhythmias, severe hypotension, seizures, and neuroleptic malignant syndrome. 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 manifestations, it is essential to obtain an electrocardiogram (ECG) and initiate cardiac monitoring immediately. 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 critical, and emesis is contraindicated.

Monitoring should focus on 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 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 a maximal limb-lead QRS duration of ≥0.10 seconds, this may indicate the severity of the overdose. In such cases, serum alkalinization to a pH of 7.45 to 7.55 using intravenous sodium bicarbonate, along with hyperventilation as needed, should be initiated for those with dysrhythmias or QRS widening. A pH greater than 7.60 or a pCO2 below 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, 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. The use of physostigmine is not recommended except for life-threatening symptoms unresponsive to other treatments, and only after consultation with a poison control center.

Given that overdosage is often intentional, there is a risk that patients may attempt suicide by other means during recovery. Therefore, psychiatric referral may be appropriate. The management principles for both child and adult overdosages are similar, and it is strongly recommended that physicians consult the local poison control center for specific pediatric treatment guidance.

Nonclinical Toxicology

In nonclinical studies, cyclobenzaprine demonstrated no teratogenic effects. Non-teratogenic effects were observed in reproductive performance and fertility assessments, where oral doses of cyclobenzaprine up to 10 times the human dose did not adversely affect male or female rats. Additionally, cyclobenzaprine did not exhibit mutagenic activity in male mice at dose levels up to 20 times the human dose.

In long-term toxicity studies, rats treated with cyclobenzaprine HCl for up to 67 weeks at doses ranging from approximately 5 to 40 times the maximum recommended human dose exhibited pale and occasionally enlarged livers. There was a dose-related occurrence of hepatocyte vacuolation with lipidosis, with these microscopic changes observed in higher dose groups as early as 26 weeks, and in some cases, even earlier in rats that died prior to this time. At lower doses, these changes were not evident until after 26 weeks of treatment.

Furthermore, cyclobenzaprine did not influence the onset, incidence, or distribution of neoplasia in an 81-week study conducted in mice or in a 105-week study in rats.

Postmarketing Experience

Postmarketing experience has identified several adverse reactions reported voluntarily or through surveillance programs, with an incidence of less than 1% of patients in clinical trials involving the 10 mg tablet.

Body as a Whole: Reports include syncope and malaise.

Cardiovascular: Adverse events such as tachycardia, arrhythmia, vasodilatation, palpitation, and hypotension have been noted.

Digestive: Reactions include vomiting, anorexia, diarrhea, gastrointestinal pain, gastritis, thirst, flatulence, edema of the tongue, and abnormal liver function, with rare cases of hepatitis, jaundice, and cholestasis.

Hypersensitivity: Instances of anaphylaxis, angioedema, pruritus, facial edema, urticaria, and rash have been documented.

Musculoskeletal: Local weakness has been reported.

Nervous System and Psychiatric: Adverse events include seizures, ataxia, vertigo, dysarthria, tremors, hypertonia, convulsions, muscle twitching, disorientation, insomnia, depressed mood, abnormal sensations, anxiety, agitation, psychosis, abnormal thinking and dreaming, hallucinations, excitement, paresthesia, and diplopia.

Skin: Increased sweating has been observed.

Special Senses: Reports of ageusia and tinnitus have been noted.

Urogenital: Urinary frequency and/or retention have been reported.

Additionally, other reactions have been reported rarely for cyclobenzaprine HCl, where a causal relationship could not be established, or have been associated with other tricyclic drugs. These include:

Body as a Whole: Chest pain and edema.

Cardiovascular: Hypertension, myocardial infarction, heart block, and stroke.

Digestive: Paralytic ileus, tongue discoloration, stomatitis, and parotid swelling.

Endocrine: Inappropriate ADH syndrome.

Hematic and Lymphatic: Purpura, bone marrow depression, leukopenia, eosinophilia, and thrombocytopenia.

Metabolic, Nutritional and Immune: Elevation and lowering of blood sugar levels, as well as weight gain or loss.

Musculoskeletal: Myalgia has been reported.

Nervous System and Psychiatric: Decreased or increased libido, abnormal gait, delusions, aggressive behavior, paranoia, peripheral neuropathy, Bell’s palsy, alteration in EEG patterns, and extrapyramidal symptoms have been documented.

Respiratory: Instances of dyspnea have been noted.

Skin: Reports of photosensitization and alopecia have been observed.

Urogenital: Impaired urination, dilatation of the urinary tract, impotence, testicular swelling, gynecomastia, breast enlargement, and galactorrhea have been reported.

Patient Counseling

Healthcare providers should advise patients that cyclobenzaprine HCl may impair mental and physical abilities necessary for performing hazardous tasks, such as operating machinery or driving a motor vehicle, particularly when used in conjunction with alcohol or other central nervous system (CNS) depressants.

Providers should inform elderly patients that they may experience an increased frequency and severity of adverse events associated with cyclobenzaprine, whether or not they are taking other medications. It is recommended that cyclobenzaprine HCl be initiated at a 5 mg dose for elderly patients, with careful titration to higher doses as needed.

Caution should be exercised when prescribing cyclobenzaprine HCl to patients with a history of urinary retention, angle-closure glaucoma, or increased intraocular pressure, as well as to those taking anticholinergic medications. For patients with mild hepatic impairment, it is advisable to start with a 5 mg dose and titrate slowly upward. Due to insufficient data regarding safety in patients with moderate to severe hepatic insufficiency, the use of cyclobenzaprine HCl in these individuals is not recommended.

Healthcare providers should discuss the lack of adequate and well-controlled studies in pregnant women, emphasizing that cyclobenzaprine HCl should only be used during pregnancy if clearly needed. Additionally, caution should be advised when administering this medication to nursing women, as it is not known whether cyclobenzaprine HCl is excreted in human milk.

Finally, providers should communicate that the safety and effectiveness of cyclobenzaprine HCl in pediatric patients under 15 years of age have not been established, and in elderly patients, the medication should only be used if clearly necessary.

Storage and Handling

The product is supplied in a well-closed container equipped with a child-resistant closure. It should be stored at a temperature range of 20°-25°C (68°-77°F), in accordance with USP controlled room temperature guidelines. Proper storage conditions are essential to maintain the integrity and efficacy of the product.

Additional Clinical Information

Patients receiving cyclobenzaprine HCl should be aware of potential withdrawal symptoms, such as nausea, headache, and malaise, which may occur with abrupt cessation after prolonged use, although these symptoms are not indicative of addiction. The recommended starting dose for most patients is 5 mg three times a day, with the possibility of increasing to 7.5 mg or 10 mg three times a day based on individual response. Prolonged use beyond two to three weeks is not advised.

Clinicians should counsel patients on the risks of impaired mental and physical abilities when cyclobenzaprine HCl is used in conjunction with alcohol or other CNS depressants, particularly regarding activities that require alertness, such as driving or operating machinery. In elderly patients, the initial dose should be 5 mg, with careful titration due to an increased frequency and severity of adverse events. Post-marketing experience has revealed a range of adverse reactions occurring in less than 1% of patients, including cardiovascular, gastrointestinal, nervous system, and hypersensitivity reactions, among others.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Cyclobenzaprine Hydrochloride as submitted by RedPharm Drug Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)