Cyclobenzaprine hydrochloride

Description

Cyclobenzaprine hydrochloride 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. The compound 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. It is supplied as a 10 mg tablet for oral administration. Each 10 mg tablet contains the following inactive ingredients: croscarmellose sodium, D and C Yellow No. 10 aluminum lake, FD and C Blue No. 2 aluminum lake, FD and C Yellow No. 6 aluminum lake, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, silicon dioxide, talc, and titanium dioxide.

Uses and Indications

Cyclobenzaprine hydrochloride 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. There is insufficient evidence to support the effectiveness of cyclobenzaprine hydrochloride 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 hydrochloride has not demonstrated efficacy in the treatment of 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 hydrochloride for most patients is 5 mg administered three times a day. Based on individual patient response, the dosage may be increased to 10 mg three times a day.

It is important to note that the use of cyclobenzaprine hydrochloride for periods longer than two to three weeks is not recommended. For patients who are elderly or have hepatic impairment, 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 should not use it due to the risk of severe allergic reactions.

Concomitant use with monoamine oxidase (MAO) inhibitors or within 14 days of their discontinuation is contraindicated. This is due to the potential for hyperpyretic crisis, seizures, and fatalities associated with the concurrent administration of cyclobenzaprine or structurally similar tricyclic antidepressants.

The product is also contraindicated in patients in the acute recovery phase of myocardial infarction, as well as those with arrhythmias, heart block or conduction disturbances, or congestive heart failure, due to the risk of exacerbating these cardiovascular conditions.

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

Warnings and Precautions

Cyclobenzaprine is structurally related to tricyclic antidepressants, such as amitriptyline and imipramine. In short-term studies conducted for indications beyond muscle spasm associated with acute musculoskeletal conditions, and typically at doses exceeding those recommended for skeletal 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, 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 signs of excessive 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.

Side Effects

Patients may experience a range of adverse reactions while using the medication. Common adverse reactions, occurring in more than 3% of participants, include drowsiness (29% at 5 mg, 38% at 10 mg, and 10% for placebo), dry mouth (21% at 5 mg, 32% at 10 mg, and 7% for placebo), fatigue (6% at both 5 mg and 10 mg, and 3% for placebo), and headache (5% at both 5 mg and 10 mg, and 8% for placebo).

Adverse reactions with an incidence of 1% to 3% include abdominal pain, acid regurgitation, constipation, diarrhea, dizziness, nausea, irritability, decreased mental acuity, nervousness, upper respiratory infection, pharyngitis, fatigue/tiredness, asthenia, dyspepsia, unpleasant taste, blurred vision, and confusion.

Less frequent adverse reactions, occurring in less than 1% of patients, encompass a variety of systems. Notable reactions include syncope and malaise (body as a whole), tachycardia, arrhythmia, vasodilatation, palpitation, and hypotension (cardiovascular). Digestive system reactions may include vomiting, anorexia, gastrointestinal pain, gastritis, thirst, flatulence, edema of the tongue, abnormal liver function, and rare reports of hepatitis, jaundice, and cholestasis. Hypersensitivity reactions can manifest as anaphylaxis, angioedema, pruritus, facial edema, urticaria, and rash.

Nervous system and psychiatric reactions may 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. Other less frequent reactions include local weakness (musculoskeletal), sweating (skin), ageusia and tinnitus (special senses), and urinary frequency and/or retention (urogenital).

Additional adverse reactions or important notes include chest pain and edema (body as a whole), hypertension, myocardial infarction, heart block, and stroke (cardiovascular). Digestive issues may involve paralytic ileus, tongue discoloration, stomatitis, and parotid swelling. Endocrine reactions can include inappropriate ADH syndrome. Hematic and lymphatic reactions may present as purpura, bone marrow depression, leukopenia, eosinophilia, and thrombocytopenia. Metabolic, nutritional, and immune reactions may involve elevation and lowering of blood sugar levels, as well as weight gain or loss. Musculoskeletal reactions can include myalgia.

Nervous system and psychiatric reactions may also 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, while skin reactions can manifest as photosensitization and alopecia. Urogenital reactions may involve impaired urination, dilatation of the urinary tract, impotence, testicular swelling, gynecomastia, breast enlargement, and galactorrhea.

Drug Interactions

Cyclobenzaprine hydrochloride is associated with significant drug interactions that warrant careful consideration.

Monoamine Oxidase Inhibitors (MAOIs) Cyclobenzaprine hydrochloride may lead to life-threatening interactions when administered concurrently with MAO inhibitors. It is advised that cyclobenzaprine should not be used in patients receiving MAOIs or within 14 days of discontinuing such therapy.

Central Nervous System (CNS) Depressants The use of cyclobenzaprine hydrochloride may enhance the effects of alcohol, barbiturates, and other CNS depressants. Caution is recommended when these substances are co-administered, and monitoring for increased sedation and respiratory depression is advised.

Tricyclic Antidepressants (TCAs) Tricyclic antidepressants may interfere with the antihypertensive effects of guanethidine and similar agents. Clinicians should consider monitoring blood pressure and adjusting the dosage of antihypertensive medications as necessary.

Additionally, tricyclic antidepressants may increase the risk of seizures in patients taking tramadol. It is advisable to monitor patients closely for seizure activity and consider alternative therapies if necessary.

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 hydrochloride 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, necessitating careful consideration when prescribing this medication. In a pharmacokinetic study involving individuals aged 65 years and older, the mean steady-state area under the curve (AUC) values for cyclobenzaprine were found to be approximately 1.7 times higher than those observed in younger adults. Notably, elderly male subjects exhibited the most significant increase, with AUC values approximately 2.4 times higher, while elderly females showed a lesser increase of about 1.2 times.

Given these pharmacokinetic differences, therapy with cyclobenzaprine hydrochloride in geriatric patients should be initiated at a lower dose of 5 mg, with a gradual titration to achieve the desired therapeutic effect. It is crucial to monitor these patients closely, as they may be at an elevated risk for central nervous system (CNS) adverse events, including hallucinations and confusion, as well as cardiac events that could lead to falls or other complications.

Furthermore, the frequency and severity of adverse events associated with cyclobenzaprine use, whether alone or in conjunction with other medications, tend to be higher in the elderly population. Therefore, cyclobenzaprine hydrochloride should be prescribed to elderly patients only when clearly indicated, and ongoing assessment of the patient's response and any potential drug-drug or drug-disease interactions is essential.

Pregnancy

Reproduction studies conducted in rats, mice, and rabbits at doses up to 20 times the human dose have shown no evidence of impaired fertility or harm to the fetus associated with cyclobenzaprine hydrochloride. This medication is classified as Pregnancy Category B. However, there are no adequate and well-controlled studies in pregnant women to confirm its safety during pregnancy.

Due to the limitations of animal reproduction studies in predicting human response, cyclobenzaprine hydrochloride should be used during pregnancy only if clearly needed. Healthcare professionals are advised to weigh the potential benefits against the 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 hydrochloride to lactating mothers. The potential effects on breastfed infants have not been established, and healthcare professionals should consider the risks and benefits before prescribing this medication to 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

Overdosage with cyclobenzaprine hydrochloride, although rare, can lead to severe outcomes, including death. It is important to note that multiple drug ingestion, often involving alcohol, is frequently observed in cases of deliberate overdose.

Signs and Symptoms of Overdosage

Toxicity symptoms may manifest rapidly following an overdose, necessitating immediate hospital monitoring. The most common effects include drowsiness and tachycardia. Other less frequent symptoms may encompass tremor, agitation, coma, ataxia, hypertension, slurred speech, confusion, dizziness, nausea, vomiting, and hallucinations. Rare but critical manifestations can include 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, should be closely monitored.

Management of Overdosage

Due to the complexity and evolving nature of overdose management, it is strongly recommended that healthcare professionals contact a poison control center for the most current treatment information. 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.

Immediate actions should include obtaining an electrocardiogram (ECG) and initiating cardiac monitoring to protect against potentially critical manifestations. An intravenous line should be established, and gastric decontamination should be initiated. Continuous observation for signs of central nervous system (CNS) or respiratory depression, hypotension, cardiac dysrhythmias, conduction blocks, and seizures is essential. Extended monitoring is warranted if any signs of toxicity arise during this period.

In cases of dysrhythmias or QRS widening, serum alkalinization to a pH of 7.45 to 7.55 using intravenous sodium bicarbonate, along with hyperventilation as needed, should be implemented. It is important to avoid a pH greater than 7.60 or a pCO2 less than 20 mmHg. 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 patients exhibiting CNS depression, early intubation is advised due to the risk of abrupt 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 recommended except for life-threatening symptoms unresponsive to other therapies, and only in close consultation with a poison control center.

Given that overdosage is often deliberate, 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 overdosages are similar; however, it is strongly advised that physicians consult the local poison control center for specific pediatric treatment recommendations.

Nonclinical Toxicology

Reproduction studies conducted in rats, mice, and rabbits at doses up to 20 times the human dose have indicated that cyclobenzaprine hydrochloride is not teratogenic. There was no evidence of impaired fertility or fetal harm associated with the administration of this compound, classifying it as Pregnancy Category B.

In terms of non-teratogenic effects, cyclobenzaprine did not adversely affect reproductive performance or fertility in male or female rats at oral doses of up to 10 times the human dose. Additionally, mutagenicity studies demonstrated that cyclobenzaprine did not exhibit mutagenic activity in male mice at dose levels reaching up to 20 times the human dose.

Long-term animal studies involving rats treated with cyclobenzaprine hydrochloride for up to 67 weeks at doses approximately 5 to 40 times the maximum recommended human dose revealed notable findings. Pale and occasionally enlarged livers were observed, alongside dose-related hepatocyte vacuolation with lipidosis. In higher dose groups, these microscopic changes were evident after 26 weeks, and in some cases, even earlier in rats that succumbed prior to this time frame. Conversely, at lower doses, these changes were not observed until after 26 weeks.

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.

Pharmacological evaluations in animal models have shown that the effects of cyclobenzaprine are comparable to those of structurally related tricyclic antidepressants. These effects include reserpine antagonism, norepinephrine potentiation, significant peripheral and central anticholinergic effects, and sedation. Additionally, cyclobenzaprine was associated with a slight to moderate increase in heart rate in animal subjects.

Postmarketing Experience

The following adverse reactions have been reported in the postmarketing experience with the 10 mg tablet, occurring in less than 1% of patients in clinical trials:

In the category of Body as a Whole, reactions include syncope and malaise. Cardiovascular events reported include tachycardia, arrhythmia, vasodilatation, palpitation, and hypotension. Digestive system reactions consist of vomiting, anorexia, diarrhea, gastrointestinal pain, gastritis, thirst, flatulence, edema of the tongue, and abnormal liver function, with rare reports of hepatitis, jaundice, and cholestasis.

Hypersensitivity reactions include anaphylaxis, angioedema, pruritus, facial edema, urticaria, and rash. Musculoskeletal reactions noted are local weakness. In the Nervous System and Psychiatric categories, 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 have been reported. Skin reactions include sweating, while special senses reactions consist of ageusia and tinnitus. Urogenital reactions reported are urinary frequency and/or retention.

Additionally, other reactions have been reported rarely for cyclobenzaprine hydrochloride, where a causal relationship could not be established, or have been reported for other tricyclic drugs. These include chest pain and edema in the Body as a Whole category; hypertension, myocardial infarction, heart block, and stroke in the Cardiovascular category; and paralytic ileus, tongue discoloration, stomatitis, and parotid swelling in the Digestive category. Endocrine reactions include inappropriate ADH syndrome. Hematic and Lymphatic reactions consist of purpura, bone marrow depression, leukopenia, eosinophilia, and thrombocytopenia. Lastly, metabolic, nutritional, and immune reactions include elevation and lowering of blood sugar levels, as well as weight gain or loss.

Patient Counseling

Healthcare providers should advise patients that cyclobenzaprine hydrochloride may impair mental and/or 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.

It is important to inform elderly patients that they may experience an increased frequency and severity of adverse events associated with the use of cyclobenzaprine, whether or not they are taking other medications. For these patients, cyclobenzaprine hydrochloride should be initiated at a dose of 5 mg, with careful titration to a higher dose as needed.

Healthcare providers must caution patients about the potential for life-threatening interactions with monoamine oxidase (MAO) inhibitors and the possibility that cyclobenzaprine may enhance the effects of alcohol, barbiturates, and other CNS depressants. Additionally, patients with hepatic impairment should be closely monitored, as the plasma concentration of cyclobenzaprine is increased in these individuals. For patients with mild hepatic impairment, it is recommended to start with a 5 mg dose and titrate slowly. Due to insufficient data, the use of cyclobenzaprine hydrochloride is not recommended for patients with moderate to severe hepatic insufficiency.

Providers should also communicate that the safety and effectiveness of cyclobenzaprine hydrochloride in pediatric patients under 15 years of age have not been established. In pregnant patients, cyclobenzaprine should only be used if clearly needed, as animal reproduction studies may not accurately predict human responses. Caution is advised when administering this medication to nursing women, as it is not known whether cyclobenzaprine is excreted in human milk.

For most patients, the recommended dosage of cyclobenzaprine hydrochloride is 5 mg three times a day, with the possibility of increasing the dose to 10 mg three times a day based on individual response. Providers should emphasize that the use of cyclobenzaprine hydrochloride for longer than two to three weeks is not recommended.

Storage and Handling

The product is supplied in a tight, light-resistant container as defined in the United States Pharmacopeia (USP). It is essential to store the product at a temperature range of 20°C to 25°C (68°F to 77°F), with permissible excursions between 15°C and 30°C (59°F to 86°F).

When dispensing the contents, a child-resistant closure must be utilized as required. Additionally, it is crucial to keep this and all medications out of the reach of children to ensure safety.

Additional Clinical Information

No additional information found.

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)