Cyclobenzaprine hydrochloride

Description

Cyclobenzaprine hydrochloride, USP is a white, crystalline tricyclic amine salt with the molecular 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. 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 in tablet form for oral administration, available in dosages of 5 mg, 7.5 mg, and 10 mg. Each tablet contains cyclobenzaprine hydrochloride along with inactive ingredients, which include croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, silicon dioxide, talc, and titanium dioxide. Additionally, the 5 mg and 10 mg tablets contain D&C Yellow #10 aluminum lake, FD&C Blue #2 aluminum lake, and FD&C Yellow #6 aluminum lake.

Uses and Indications

Cyclobenzaprine hydrochloride tablets, USP are 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 should be utilized for short durations, specifically up to two or three weeks, as there is insufficient evidence to support its effectiveness for prolonged use. Muscle spasms related to acute, painful musculoskeletal conditions are typically of short duration, and extended therapy is rarely necessary.

Cyclobenzaprine hydrochloride tablets 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 dose of Cyclobenzaprine hydrochloride for most patients is 5 mg administered three times a day. Based on individual patient response, the dose may be increased to 10 mg three times a day.

Cyclobenzaprine hydrochloride is not recommended for use beyond two or three weeks. For patients with hepatic impairment or elderly patients, consideration should be given to less frequent dosing to ensure safety and efficacy.

Contraindications

Use of this product is contraindicated in the following situations:

Patients with hypersensitivity to any component of this 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 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 conditions.

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

Warnings and Precautions

The use of Cyclobenzaprine hydrochloride necessitates careful consideration of potential risks and precautions to ensure patient safety.

Warnings

The concomitant use of Cyclobenzaprine hydrochloride with other serotonergic agents, including selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), tramadol, bupropion, meperidine, verapamil, or monoamine oxidase (MAO) inhibitors, may lead to the development of serotonin syndrome, a potentially life-threatening condition. Symptoms of serotonin syndrome may include mental status changes such as confusion, agitation, and hallucinations; autonomic instability characterized by diaphoresis, tachycardia, labile blood pressure, and hyperthermia; neuromuscular abnormalities including tremor, ataxia, hyperreflexia, clonus, and muscle rigidity; and gastrointestinal symptoms such as nausea, vomiting, and diarrhea. In the event of these symptoms, treatment with Cyclobenzaprine hydrochloride and any concomitant serotonergic agents should be discontinued immediately, and supportive symptomatic treatment should be initiated. If the clinical situation necessitates the concurrent use of Cyclobenzaprine hydrochloride with other serotonergic drugs, careful observation is advised, particularly during the initiation of treatment or when increasing doses.

Cyclobenzaprine is structurally related to tricyclic antidepressants, such as amitriptyline and imipramine. In short-term studies involving indications other than muscle spasm associated with acute musculoskeletal conditions, and typically at doses higher than those recommended for muscle spasm, serious central nervous system reactions similar to those observed with tricyclic antidepressants have been reported. Additionally, tricyclic antidepressants are known to cause arrhythmias, sinus tachycardia, and prolongation of conduction time, which may lead to myocardial infarction and stroke. Cyclobenzaprine may also enhance the effects of alcohol, barbiturates, and other central nervous system depressants, necessitating caution in patients using these substances.

General Precautions

Due to its atropine-like properties, Cyclobenzaprine should be administered with caution in patients who have a history of urinary retention, angle-closure glaucoma, or increased intraocular pressure, as well as in those taking anticholinergic medications. Furthermore, the plasma concentration of Cyclobenzaprine is elevated in patients with hepatic impairment, who may be more susceptible to the sedative effects of this medication. In patients with mild hepatic impairment, it is recommended to initiate treatment with a 5 mg dose and to titrate slowly. The use of Cyclobenzaprine is not recommended in patients with moderate to severe hepatic insufficiency due to insufficient data regarding its safety in this population.

In summary, healthcare professionals should remain vigilant regarding the potential for serious adverse effects associated with Cyclobenzaprine hydrochloride, particularly in the context of concurrent medication use and patient-specific factors such as hepatic function.

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, compared to 10% for placebo), dry mouth (21% at 5 mg, 32% at 10 mg, 7% for placebo), fatigue (6% at both 5 mg and 10 mg, 3% for placebo), and headache (5% at both 5 mg and 10 mg, 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.

Postmarketing experience has revealed additional adverse reactions. These include syncope and malaise under the category of body as a whole. Cardiovascular effects may include tachycardia, arrhythmia, vasodilatation, palpitation, and hypotension. Digestive system reactions can involve 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 may manifest as anaphylaxis, angioedema, pruritus, facial edema, urticaria, and rash.

Nervous system and psychiatric adverse reactions reported 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, diplopia, and serotonin syndrome. Musculoskeletal reactions may present as local weakness, while skin reactions can include sweating. Special senses may be affected, leading to ageusia and tinnitus, and urogenital issues may involve urinary frequency and/or retention.

Rare adverse reactions, for which a causal relationship is unknown, include chest pain and edema in the body as a whole, hypertension, myocardial infarction, heart block, and stroke in the cardiovascular system. Digestive system reactions may include paralytic ileus, tongue discoloration, stomatitis, and parotid swelling. Endocrine reactions can involve inappropriate ADH syndrome. Hematic and lymphatic reactions may present as purpura, bone marrow depression, leukopenia, eosinophilia, and thrombocytopenia. Metabolic, nutritional, and immune reactions may lead to elevation and 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 present as impaired urination, dilatation of the urinary tract, impotence, testicular swelling, gynecomastia, breast enlargement, and galactorrhea.

In cases of overdosage, the most common effects observed include drowsiness and tachycardia. Less frequent manifestations 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.

Drug Interactions

Cyclobenzaprine has significant drug interactions that warrant careful consideration, particularly with serotonergic agents and central nervous system (CNS) depressants.

Serotonergic Drugs Cyclobenzaprine may interact with monoamine oxidase inhibitors (MAOIs), leading to potentially life-threatening serotonin syndrome. Postmarketing reports indicate that the concurrent use of Cyclobenzaprine hydrochloride with other serotonergic medications, including selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), tramadol, bupropion, meperidine, and verapamil, can precipitate this condition. If the combination of Cyclobenzaprine and other serotonergic drugs is deemed necessary, it is essential to monitor the patient closely, especially during the initiation of therapy or when adjusting dosages.

CNS Depressants Cyclobenzaprine may potentiate the effects of alcohol, barbiturates, and other CNS depressants. Caution is advised when these substances are used concurrently, as the risk of sedation and respiratory depression may be increased.

Tricyclic Antidepressants Tricyclic antidepressants can interfere with the antihypertensive effects of guanethidine and similar agents. Additionally, the use of TCAs may elevate the risk of seizures in patients who are also taking tramadol. Monitoring and potential dosage adjustments may be necessary in these scenarios to mitigate risks.

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 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 may be at an elevated risk for central nervous system (CNS) adverse events, including hallucinations and confusion.

Additionally, elderly patients may be more susceptible to cardiac events, which could lead to falls or other serious complications. It is crucial to monitor these patients closely for any signs of adverse effects.

Furthermore, there is a potential for drug-drug and drug-disease interactions in the geriatric population, which underscores the importance of a thorough medication review prior to initiation of cyclobenzaprine.

Cyclobenzaprine should only be prescribed to elderly patients when clearly indicated. When initiating treatment, it is recommended that cyclobenzaprine hydrochloride be started at a dose of 5 mg, with a gradual titration upward to minimize the risk of adverse effects.

Pregnancy

Pregnancy Category B indicates that 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 due to Cyclobenzaprine. 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 should be used during pregnancy only if clearly needed. Healthcare professionals are advised to weigh the potential benefits against any possible risks when considering the use of this medication in 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, USP 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 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.

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

Although rare, cyclobenzaprine overdosage can lead to fatal outcomes, particularly when multiple drugs, including alcohol, are ingested. The management of such overdoses is complex and subject to change; therefore, it is imperative that healthcare professionals contact a poison control center for the most current treatment recommendations.

Signs and Symptoms

Toxicity from cyclobenzaprine overdose can manifest rapidly, necessitating immediate hospital monitoring. The acute oral LD50 of cyclobenzaprine is approximately 338 mg/kg in mice and 425 mg/kg in rats. Common symptoms of overdose include drowsiness and tachycardia, while less frequent effects may involve tremor, agitation, coma, ataxia, hypertension, slurred speech, confusion, dizziness, nausea, vomiting, and hallucinations. Rare but critical manifestations 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, serve as important indicators of cyclobenzaprine toxicity.

Initial Management

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 essential, and emesis is contraindicated. To protect against severe manifestations, an electrocardiogram (ECG) should be obtained, and cardiac monitoring should commence immediately. It is crucial to maintain the patient's airway, establish an intravenous line, and initiate gastric decontamination. Continuous observation for signs of central nervous system (CNS) or respiratory depression, hypotension, cardiac dysrhythmias, conduction blocks, and seizures is necessary. Extended monitoring is warranted if any signs of toxicity arise during this period. Plasma drug level monitoring should not dictate patient management, and dialysis is likely ineffective due to the low plasma concentrations of cyclobenzaprine.

Advanced Management

A maximal limb-lead QRS duration of ≥ 0.10 seconds may indicate the severity of the overdose. 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. It is important to avoid a pH >7.60 or a pCO2 <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 cases of CNS depression, early intubation is recommended due to the risk of sudden 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 advised unless life-threatening symptoms are unresponsive to other treatments, and even then, only after consulting a poison control center.

Psychiatric Considerations

Given that overdosage is often intentional, there is a risk that patients may attempt suicide by other means during the recovery phase. A psychiatric referral may be appropriate for these individuals.

The management principles for both child and adult overdoses are similar; however, it is strongly recommended that healthcare professionals consult the local poison control center for specific pediatric treatment guidelines.

Nonclinical Toxicology

In nonclinical studies, Cyclobenzaprine was administered to rats for up to 67 weeks at doses ranging from approximately 5 to 40 times the maximum recommended human dose. Observations included pale and occasionally enlarged livers, along with dose-related hepatocyte vacuolation and 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 point. Conversely, at lower doses, these changes were not observed until after 26 weeks of treatment.

In terms of carcinogenic potential, 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, indicating a lack of carcinogenicity.

Regarding reproductive toxicity, Cyclobenzaprine was administered at oral doses of up to 10 times the human dose without adversely affecting the reproductive performance or fertility of both male and female rats.

Additionally, Cyclobenzaprine did not exhibit mutagenic activity in male mice at dose levels of up to 20 times the human dose, suggesting a favorable profile in terms of genetic safety.

Postmarketing Experience

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

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, abnormal liver function, and rare reports of hepatitis, jaundice, and cholestasis.

Hypersensitivity reactions include anaphylaxis, angioedema, pruritus, facial edema, urticaria, and rash. Musculoskeletal reactions reported are local weakness. In the Nervous System and Psychiatric category, 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, diplopia, and serotonin syndrome. 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 under circumstances where a causal relationship could not be established, or reported for other tricyclic drugs, and are listed to serve as alerting information to physicians. These include Body as a Whole reactions such as chest pain and edema. Cardiovascular events include hypertension, myocardial infarction, heart block, and stroke. Digestive reactions consist of paralytic ileus, tongue discoloration, stomatitis, and parotid swelling. Endocrine reactions include inappropriate ADH syndrome.

Hematic and lymphatic reactions reported are purpura, bone marrow depression, leukopenia, eosinophilia, and thrombocytopenia. Metabolic, nutritional, and immune reactions include elevation and lowering of blood sugar levels, as well as weight gain or loss. Musculoskeletal reactions include myalgia. In the Nervous System and Psychiatric category, additional events reported are decreased or increased libido, abnormal gait, delusions, aggressive behavior, paranoia, peripheral neuropathy, Bell's palsy, alteration in EEG patterns, and extrapyramidal symptoms. Respiratory reactions include dyspnea. Skin reactions reported are photosensitization and alopecia. Urogenital reactions include impaired urination, dilatation of the urinary tract, impotence, testicular swelling, gynecomastia, breast enlargement, and galactorrhea.

Patient Counseling

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

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 this population, healthcare providers should recommend initiating treatment with a 5 mg dose of cyclobenzaprine hydrochloride, with a gradual titration to higher doses as appropriate.

Patients should also be cautioned about the potential risk of serotonin syndrome when cyclobenzaprine hydrochloride is used concurrently with other medications, such as selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), tramadol, bupropion, meperidine, verapamil, or monoamine oxidase inhibitors (MAOIs).

Healthcare providers should ensure that patients are aware of the signs and symptoms of serotonin syndrome, and instruct them to seek immediate medical attention if they experience any of these symptoms.

Storage and Handling

The product is supplied in a container that is not intended for household use. It must be dispensed with a child-resistant closure, as required, and stored in a tight, light-resistant container in accordance with the United States Pharmacopeia (USP) standards.

Storage conditions require the product to be maintained 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). Proper adherence to these storage guidelines is essential to ensure the integrity and efficacy of the product.

Additional Clinical Information

Laboratory tests related to Cyclobenzaprine do not provide additional information. Clinicians should be aware that while withdrawal symptoms such as nausea, headache, and malaise may occur with abrupt cessation after prolonged use, these symptoms are not indicative of addiction.

Patient counseling is essential, particularly regarding the potential impairment of mental and physical abilities when Cyclobenzaprine is used in conjunction with alcohol or other CNS depressants. Patients should also be informed about the risk of serotonin syndrome when Cyclobenzaprine is taken with certain medications, including SSRIs, SNRIs, TCAs, tramadol, bupropion, meperidine, verapamil, or MAO inhibitors. They should be educated on the signs and symptoms of serotonin syndrome and advised to seek immediate medical attention if these occur.

In a post-marketing surveillance program involving 7,607 patients with acute musculoskeletal disorders, including 297 patients treated with Cyclobenzaprine hydrochloride 10 mg for 30 days or longer, the overall effectiveness was consistent with findings from controlled studies, while the incidence of adverse effects was lower.

FDA Insert (PDF)

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

View full prescribing information (PDF)