Fexmid

Description

Fexmid® (cyclobenzaprine hydrochloride) is a skeletal muscle relaxant presented as a white, crystalline tricyclic amine salt. It has an empirical formula of C20H21N•HCl and a molecular weight of 311.9 g/mol. The compound exhibits 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.

Chemically, cyclobenzaprine HCl is designated as 3-(5H-dibenzoa,dcyclohepten-5-ylidene)-N,N-dimethyl-1-propanamine hydrochloride. Fexmid® is supplied in a dosage form of 7.5 mg tablets for oral administration. Each tablet contains cyclobenzaprine hydrochloride along with inactive ingredients, including colloidal silicon dioxide, crospovidone, lactose anhydrous, magnesium stearate, microcrystalline cellulose, OPADRY White, pregelatinized starch, and purified water. The OPADRY components consist of hypromellose, polyethylene glycol/macrogol, talc, and titanium dioxide. It is important to note that the FDA-approved dissolution specifications for Fexmid® differ from those established by the USP.

Uses and Indications

Fexmid® is indicated as an adjunct to rest and physical therapy for the relief of muscle spasm associated with acute, painful musculoskeletal conditions. The therapeutic benefits 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.

Fexmid® 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 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.

Fexmid® 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 hydrochloride tablets 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 Fexmid for periods longer than two or three weeks is not recommended. Additionally, 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.

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

The product should not be used in the acute recovery phase of myocardial infarction, or in patients with arrhythmias, heart block, conduction disturbances, or congestive heart failure, as these conditions may exacerbate cardiovascular risks.

Additionally, the product is contraindicated in patients with hyperthyroidism.

Warnings and Precautions

The use of Fexmid® (cyclobenzaprine hydrochloride) necessitates careful consideration of several critical warnings and precautions to ensure patient safety.

Serotonin Syndrome The concomitant use of Fexmid® with serotonergic agents, including selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), tramadol, bupropion, meperidine, verapamil, or monoamine oxidase inhibitors (MAOIs), may lead to the development of serotonin syndrome, a potentially life-threatening condition. The use of Fexmid® with MAO inhibitors is contraindicated. Symptoms of serotonin syndrome may manifest as mental status changes (e.g., confusion, agitation, hallucinations), autonomic instability (e.g., diaphoresis, tachycardia, labile blood pressure, hyperthermia), neuromuscular abnormalities (e.g., tremor, ataxia, hyperreflexia, clonus, muscle rigidity), and gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Should these symptoms occur, immediate discontinuation of Fexmid® and any concomitant serotonergic agents is required, along with the initiation of supportive symptomatic treatment. If the clinical situation necessitates the concurrent use of Fexmid® and other serotonergic drugs, careful monitoring is essential, particularly during the initiation of treatment or when adjusting dosages.

CNS Reactions Fexmid® shares structural similarities with 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 exceeding those recommended for muscle spasm, serious central nervous system reactions similar to those observed with tricyclic antidepressants have been reported. Healthcare professionals should remain vigilant for any CNS-related adverse effects during treatment.

Arrhythmias Tricyclic antidepressants, including Fexmid®, have been associated with the occurrence of arrhythmias, sinus tachycardia, and prolongation of conduction time, which may lead to serious cardiovascular events such as myocardial infarction and stroke. Continuous monitoring of cardiac function is advised for patients receiving Fexmid®.

CNS Depressants Fexmid® may potentiate the effects of alcohol, barbiturates, and other central nervous system depressants. Caution is warranted when prescribing Fexmid® to patients who are concurrently using these substances, as the risk of enhanced CNS depression may increase.

Healthcare professionals are encouraged to conduct appropriate laboratory tests and monitoring as necessary to ensure the safe use of Fexmid® in their patients.

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 reported in 1% to 3% of patients include abdominal pain, acid regurgitation, constipation, diarrhea, dizziness, nausea, irritability, decreased mental acuity, nervousness, upper respiratory infections, 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), as well as vomiting, anorexia, gastrointestinal pain, gastritis, thirst, flatulence, edema of the tongue, abnormal liver function, and rare reports of hepatitis, jaundice, and cholestasis (digestive). Hypersensitivity reactions such as anaphylaxis, angioedema, pruritus, facial edema, urticaria, and rash have also been reported.

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

There are also adverse reactions with an unknown causal relationship, reported rarely. These include chest pain and edema (body as a whole), hypertension, myocardial infarction, heart block, and stroke (cardiovascular), as well as paralytic ileus, tongue discoloration, stomatitis, and parotid swelling (digestive). Endocrine reactions such as inappropriate ADH syndrome, hematologic reactions like purpura, bone marrow depression, leukopenia, eosinophilia, and thrombocytopenia, and metabolic changes including elevation and lowering of blood sugar levels, weight gain or loss have been noted. Musculoskeletal reactions include myalgia, while nervous system and psychiatric reactions may 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 such as dyspnea, skin reactions like photosensitization and alopecia, and urogenital issues including impaired urination, dilatation of the urinary tract, impotence, testicular swelling, gynecomastia, breast enlargement, and galactorrhea have also been reported.

A serious warning regarding serotonin syndrome is pertinent, as this potentially life-threatening condition has been observed when the medication is used in conjunction with other drugs, including selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), tramadol, bupropion, meperidine, verapamil, or MAO inhibitors. Symptoms may manifest as mental status changes (e.g., confusion, agitation, hallucinations), autonomic instability (e.g., diaphoresis, tachycardia, labile blood pressure, hyperthermia), neuromuscular abnormalities (e.g., tremor, ataxia, hyperreflexia, clonus, muscle rigidity), and gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).

In cases of overdosage, common effects include drowsiness and tachycardia, while less frequent manifestations may involve tremor, agitation, coma, ataxia, hypertension, slurred speech, confusion, dizziness, nausea, vomiting, and hallucinations. Rare but potentially critical manifestations include cardiac arrest, chest pain, cardiac dysrhythmias, severe hypotension, seizures, and neuroleptic malignant syndrome.

Drug Interactions

Fexmid has the potential to cause life-threatening interactions when administered concurrently with monoamine oxidase (MAO) inhibitors. The combination of cyclobenzaprine hydrochloride, the active ingredient in Fexmid, with other serotonergic agents, including selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), tramadol, bupropion, meperidine, verapamil, or MAO inhibitors, has been associated with postmarketing reports of serotonin syndrome. Clinicians should exercise caution and consider alternative therapies when prescribing these combinations.

Additionally, Fexmid may potentiate the effects of alcohol, barbiturates, and other central nervous system (CNS) depressants, necessitating careful monitoring of patients for increased sedation and respiratory depression.

Tricyclic antidepressants may interfere with the antihypertensive effects of guanethidine and similar agents, which may require dosage adjustments or alternative treatments to maintain blood pressure control. Furthermore, the use of tricyclic antidepressants in conjunction with tramadol may elevate the risk of seizures, warranting close observation and potential modification of tramadol dosing in patients receiving both medications.

Packaging & NDC

The table below lists all NDC Code configurations of Fexmid (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 Fexmid 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 population.

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 than their younger counterparts, while elderly females showed a lesser increase of about 1.2 times.

Due to these pharmacokinetic differences, it is recommended that cyclobenzaprine hydrochloride be initiated at a lower dose of 5 mg in geriatric patients, with a gradual titration to achieve the desired therapeutic effect. Additionally, less frequent dosing should be considered to mitigate the risk of adverse effects.

Elderly patients 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 potential for drug-drug and drug-disease interactions is heightened in this population. Therefore, cyclobenzaprine should only be prescribed to elderly patients when clearly indicated, and close monitoring for adverse effects is essential throughout the treatment course.

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. 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 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 of treatment in nursing women.

Renal Impairment

There is no specific information available regarding dosage adjustments, special monitoring, or safety considerations for patients with renal impairment. Healthcare professionals should exercise caution when prescribing to patients with reduced kidney function, as the absence of detailed guidance necessitates careful clinical judgment. Regular monitoring of renal function may be advisable in 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 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 Fexmid® can lead to serious health consequences, including fatalities, although such occurrences are rare. It is important to note that deliberate overdoses often involve the ingestion of multiple substances, including alcohol.

Signs and Symptoms

The onset of toxicity symptoms may occur rapidly following an overdose of Fexmid®. Common manifestations include drowsiness and tachycardia. Other less frequent symptoms may present as tremor, agitation, coma, ataxia, hypertension, slurred speech, confusion, dizziness, nausea, vomiting, and hallucinations. In rare cases, critical symptoms such as cardiac arrest, chest pain, cardiac dysrhythmias, severe hypotension, seizures, and neuroleptic malignant syndrome may arise. Clinically significant changes in the electrocardiogram, particularly alterations in the QRS axis or width, are important indicators of cyclobenzaprine toxicity.

Management Recommendations

Immediate hospital monitoring is essential for all patients suspected of an overdose. Gastrointestinal decontamination should be initiated, which includes large volume gastric lavage followed by the administration of activated charcoal. If the patient's consciousness is impaired, securing the airway is crucial prior to performing lavage, and emesis is contraindicated.

A maximal limb-lead QRS duration of ≥0.10 seconds may serve as a key indicator of overdose severity. For patients exhibiting dysrhythmias and/or QRS widening, serum alkalinization to a pH of 7.45 to 7.55 should be achieved using intravenous sodium bicarbonate, with hyperventilation as necessary. In cases where dysrhythmias do not respond to sodium bicarbonate therapy or hyperventilation, alternative treatments such as lidocaine, bretylium, or phenytoin may be effective.

In instances of central nervous system (CNS) depression, early intubation is recommended due to the risk of sudden deterioration. Seizures should be managed with benzodiazepines; if these are ineffective, other anticonvulsants such as phenobarbital or phenytoin may be utilized.

Physostigmine is not advised except in life-threatening situations that do not respond to other treatments, and its use should only occur in close consultation with a poison control center. Given the similarities in management principles for both child and adult overdoses, it is strongly recommended that physicians contact the local poison control center for specific pediatric treatment guidance.

Due to the complexity and evolving nature of overdose management, healthcare professionals are encouraged to consult a poison control center for the most current treatment information.

Nonclinical Toxicology

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 teratogenic effects associated with cyclobenzaprine hydrochloride. Additionally, cyclobenzaprine did not adversely affect the reproductive performance or fertility of male or female rats. Furthermore, mutagenicity assessments indicated that cyclobenzaprine did not demonstrate mutagenic activity in male mice at dose levels up to 20 times the human dose.

In long-term studies involving rats treated with cyclobenzaprine hydrochloride for up to 67 weeks at doses 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 noted after 26 weeks, with earlier occurrences in rats that died prior to this time. At lower doses, such changes were not observed until after 26 weeks of treatment. Importantly, cyclobenzaprine did not affect the onset, incidence, or distribution of neoplasia in an 81-week study in mice or a 105-week study in rats.

Animal studies indicate that cyclobenzaprine does not act at the neuromuscular junction or directly on skeletal muscle. Instead, it primarily exerts its effects within the central nervous system, particularly at the brain stem, although some action at spinal cord levels may contribute to its overall skeletal muscle relaxant activity. Evidence suggests that the net effect of cyclobenzaprine is a reduction in tonic somatic motor activity, influencing both gamma (γ) and alpha (α) motor systems. Pharmacological studies in animals have demonstrated similarities between the effects of cyclobenzaprine and those of structurally related tricyclic antidepressants, including reserpine antagonism, norepinephrine potentiation, potent peripheral and central anticholinergic effects, and sedation.

Postmarketing Experience

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

Body as a Whole: Syncope; malaise. Cardiovascular: Tachycardia; arrhythmia; vasodilatation; palpitation; hypotension. Digestive: Vomiting; anorexia; diarrhea; gastrointestinal pain; gastritis; thirst; flatulence; edema of the tongue; abnormal liver function; rare reports of hepatitis, jaundice, and cholestasis. Hypersensitivity: Anaphylaxis; angioedema; pruritus; facial edema; urticaria; rash. Musculoskeletal: Local weakness. Nervous System and Psychiatric: 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; serotonin syndrome. Skin: Sweating. Special Senses: Ageusia; tinnitus. Urogenital: 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:

Body as a Whole: Chest pain; edema. Cardiovascular: Hypertension; myocardial infarction; heart block; stroke. Digestive: Paralytic ileus; tongue discoloration; stomatitis; parotid swelling. Endocrine: Inappropriate ADH syndrome. Hematic and Lymphatic: Purpura; bone marrow depression; leukopenia; eosinophilia; thrombocytopenia. Metabolic, Nutritional and Immune: Elevation and lowering of blood sugar levels; weight gain or loss. Musculoskeletal: Myalgia. Nervous System and Psychiatric: Decreased or increased libido; abnormal gait; delusions; aggressive behavior; paranoia; peripheral neuropathy; Bell's palsy; alteration in EEG patterns; extrapyramidal symptoms. Respiratory: Dyspnea. Skin: Photosensitization; alopecia. Urogenital: Impaired urination; dilatation of urinary tract; impotence; testicular swelling; gynecomastia; breast enlargement; galactorrhea.

Patient Counseling

Patients should be cautioned about the risk of serotonin syndrome when using cyclobenzaprine hydrochloride in conjunction with other medications, including SSRIs, SNRIs, TCAs, tramadol, bupropion, meperidine, verapamil, or MAO inhibitors. Healthcare providers should advise patients to be aware of the signs and symptoms of serotonin syndrome, which may include changes in mental status, autonomic instability, and neuromuscular abnormalities. Patients should be instructed to seek medical care immediately if they experience any of these symptoms.

It is important to inform patients that Fexmid, particularly when used with alcohol or other central nervous system (CNS) depressants, may impair their mental and/or physical abilities necessary for performing hazardous tasks, such as operating machinery or driving a motor vehicle. Healthcare providers should emphasize the need for caution in these situations.

In elderly patients, the frequency and severity of adverse events associated with the use of cyclobenzaprine may be increased, whether or not other medications are being taken concurrently. Therefore, Fexmid should be initiated at a lower dose of 5 mg in this population, with a gradual titration to assess tolerance and effectiveness.

Patients should also be informed that therapy with cyclobenzaprine hydrochloride is intended for short-term use only, typically up to two or three weeks, as there is insufficient evidence to support the effectiveness of prolonged use. Additionally, patients should be cautioned about the potential for drowsiness and advised not to drive or operate heavy machinery until they are aware of how Fexmid affects them.

Storage and Handling

The product is supplied in a tight, light-resistant container that complies with the standards set forth by the United States Pharmacopeia (USP) and features a child-resistant closure.

Storage conditions require the product to be maintained 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) as outlined by USP Controlled Room Temperature guidelines.

Additional Clinical Information

Laboratory tests specific to Fexmid have not been detailed. Clinicians should be aware that while withdrawal symptoms have not been reported with Fexmid, abrupt cessation after prolonged use may lead to nausea, headache, and malaise, which are not indicative of addiction. The recommended dosage for most patients is 5 mg three times daily, with the possibility of increasing to 10 mg three times daily based on individual response. Prolonged use beyond two to three weeks is not advised.

Patients should be counseled on the potential for impaired mental and physical abilities when Fexmid is used in conjunction with alcohol or other CNS depressants, particularly regarding tasks such as operating machinery or driving. Additionally, there is a risk of serotonin syndrome when Fexmid is used with certain medications, including SSRIs, SNRIs, TCAs, tramadol, bupropion, meperidine, verapamil, or MAO inhibitors. Patients should be informed of the signs and symptoms of serotonin syndrome and instructed to seek immediate medical attention if they occur. A post-marketing surveillance program involving 7,607 patients indicated that the effectiveness of cyclobenzaprine hydrochloride was consistent with controlled studies, with a lower incidence of adverse effects noted.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Fexmid as submitted by Rising Pharma Holdings, Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)