Amrix

Description

AMRIX is a skeletal muscle relaxant indicated for the relief of muscle spasms of local origin without impairing muscle function. The active ingredient in AMRIX extended-release capsules is cyclobenzaprine hydrochloride, USP, which is a white, crystalline tricyclic amine salt. The chemical designation of cyclobenzaprine hydrochloride is 3-(5H-dibenzoa,dcyclohepten-5-ylidene)-N,N-dimethyl-1-propanamine hydrochloride, with an empirical formula of C20H21N·HCl and a molecular weight of 311.9 g/mol.

Cyclobenzaprine hydrochloride has a melting point of 217°C and a pKa of 8.47 at 25°C. It 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.

AMRIX extended-release capsules are available for oral administration in strengths of 15 mg and 30 mg. The capsules contain several inactive ingredients, including diethyl phthalate NF, ethylcellulose NF (Ethocel Standard 10 Premium), gelatin, Opadry® Clear YS-1-7006, sugar spheres NF (20-25 mesh), and titanium dioxide. The 15 mg capsules also include D&C yellow #10, FD&C green #3, and FD&C red #40, while the 30 mg capsules contain FD&C blue #1, FD&C blue #2, FD&C red #40, and FD&C yellow #6.

Uses and Indications

AMRIX is a muscle relaxant indicated as an adjunct to rest and physical therapy for the relief of muscle spasm associated with acute, painful musculoskeletal conditions. The therapeutic benefit is characterized by the alleviation of muscle spasm and its associated signs and symptoms, including pain, tenderness, and limitation of motion.

AMRIX is intended for short-term use, specifically for periods not exceeding 2 to 3 weeks. This limitation is based on the lack of adequate evidence supporting the effectiveness of prolonged use, as muscle spasms related to acute, painful musculoskeletal conditions are typically of short duration. Therefore, specific therapy for extended periods is seldom warranted.

It is important to note that AMRIX 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 adult dose for most patients is 15 mg taken once daily. In certain cases, some patients may require an increased dose of 30 mg taken once daily. It is advised that doses be administered at approximately the same time each day to maintain consistent therapeutic levels.

Patients should be instructed to swallow AMRIX capsules intact. Alternatively, if preferred, the contents of the capsules may be sprinkled on a tablespoon of applesauce and swallowed immediately without chewing to ensure proper administration.

Prolonged use beyond 2 or 3 weeks is not recommended, and healthcare professionals should monitor patients accordingly during the treatment period.

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, as this may lead to serious drug interactions.

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

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

Warnings and Precautions

Serotonin syndrome has been reported in patients receiving cyclobenzaprine in conjunction with other serotonergic agents. Healthcare professionals should remain vigilant for symptoms of serotonin syndrome, which may include confusion, hallucination, seizure, extreme changes in blood pressure, increased heart rate, fever, excessive sweating, shivering, blurred vision, muscle spasm or stiffness, and gastrointestinal symptoms.

Cyclobenzaprine is structurally related to tricyclic antidepressants, which are known to potentially cause adverse cardiovascular effects and central nervous system (CNS) depressant effects. Therefore, caution is advised when prescribing cyclobenzaprine, particularly in patients with pre-existing cardiovascular conditions or those who may be sensitive to CNS depressants.

The use of cyclobenzaprine in elderly patients is not recommended due to an increased risk of adverse effects. Similarly, it is contraindicated in individuals with hepatic impairment, as the drug's metabolism may be significantly affected, leading to increased systemic exposure and potential toxicity.

Healthcare professionals should exercise caution when prescribing cyclobenzaprine to patients with a history of urinary retention, angle-closure glaucoma, or increased intraocular pressure. Additionally, patients taking anticholinergic medications may be at heightened risk for adverse effects, and careful monitoring is advised in these cases. Regular assessment of the patient's condition and any relevant laboratory tests should be conducted to ensure safe use of cyclobenzaprine in these populations.

Side Effects

Patients receiving cyclobenzaprine may experience a range of adverse reactions. The most common adverse reactions reported include dry mouth, dizziness, fatigue, constipation, nausea, dyspepsia, and somnolence.

Serious adverse reactions have also been noted, particularly in specific populations. Cyclobenzaprine is structurally related to tricyclic antidepressants, which have been associated with adverse cardiovascular effects and central nervous system (CNS) depressant effects. Therefore, its use is not recommended in elderly patients or those with hepatic impairment. Caution is advised when prescribing cyclobenzaprine to patients with a history of urinary retention, angle-closure glaucoma, increased intraocular pressure, or those taking anticholinergic medications.

Additionally, serotonin syndrome has been reported in patients using cyclobenzaprine in conjunction with other serotonergic drugs, necessitating careful monitoring in such cases.

In the event of an overdose, the most common effects observed include drowsiness and tachycardia. Less frequent symptoms may encompass tremor, agitation, coma, ataxia, hypertension, slurred speech, confusion, dizziness, nausea, vomiting, and hallucinations. Rare but potentially critical symptoms of overdose include cardiac arrest, chest pain, cardiac dysrhythmias, severe hypotension, seizures, neuroleptic malignant syndrome, and rhabdomyolysis. Clinically significant changes in the electrocardiogram, particularly alterations in the QRS axis or width, may indicate cyclobenzaprine toxicity.

Patients who abruptly discontinue treatment after prolonged administration may experience withdrawal symptoms such as nausea, headache, and malaise; however, these symptoms are not indicative of addiction.

Drug Interactions

Life-threatening interactions may occur when this medication is co-administered with monoamine oxidase inhibitors (MAOIs). It is advised that concurrent use of MAOIs be avoided to prevent severe adverse effects.

The combination of this medication with serotonergic drugs has been associated with the development of serotonin syndrome. Clinicians should monitor patients closely for symptoms of serotonin syndrome, which may include agitation, hallucinations, coma, and autonomic instability.

When used in conjunction with central nervous system (CNS) depressants, such as alcohol and barbiturates, the effects of these substances may be significantly enhanced. Caution is recommended, and dosage adjustments may be necessary to mitigate the risk of excessive sedation or respiratory depression.

Co-administration with tramadol may increase the risk of seizures. It is advisable to monitor patients for seizure activity and consider dosage adjustments as appropriate.

Additionally, the antihypertensive effect of guanethidine may be blocked when this medication is used together with it. Clinicians should assess blood pressure regularly and adjust antihypertensive therapy as needed to maintain effective control.

Packaging & NDC

The table below lists all NDC Code configurations of Amrix (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 AMRIX have not been studied in pediatric patients. Therefore, its use in this population is not recommended due to the lack of clinical data supporting its use in children and adolescents.

Geriatric Use

Clinical studies of AMRIX did not include a sufficient number of patients aged 65 and over to determine the safety and efficacy of AMRIX in the geriatric population.

It has been observed that the plasma concentration and half-life of cyclobenzaprine are substantially increased in elderly patients compared to the general patient population. Due to these pharmacokinetic changes, the use of AMRIX is not recommended in geriatric patients.

Healthcare providers should exercise caution when considering treatment options for elderly patients, taking into account the potential for increased drug exposure and the associated risks. Monitoring for adverse effects is advised if AMRIX is considered in this population.

Pregnancy

Available data from case reports with AMRIX use in pregnancy have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. However, it is important to note that the estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies carry a background risk of birth defects, loss, or other adverse outcomes. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Animal studies have provided some insights into the potential effects of cyclobenzaprine during pregnancy. In rats, decreased pup body weight and survival were noted at cyclobenzaprine doses of ≥10 mg/kg/day (approximately ≥3 times the maximum recommended human dose (MRHD) of 30 mg/day) when administered orally during pregnancy and lactation. Additionally, no adverse embryofetal effects were reported following oral administration of cyclobenzaprine during organogenesis to mice and rabbits at maternal doses up to 20 mg/kg/day (approximately 3 and 15 times the MRHD, respectively, on a mg/m² basis). Maternal toxicity, characterized by decreased body weight gain, was observed only in mice at the highest tested dose of 20 mg/kg/day.

Given these findings, healthcare professionals should weigh the potential benefits and risks of AMRIX use in pregnant patients, particularly at higher doses, and consider monitoring for any adverse outcomes.

Lactation

There are no data on the presence of cyclobenzaprine in either human or animal milk, nor are there any known effects on a breastfed infant or on milk production.

The developmental and health benefits of breastfeeding should be weighed against the clinical need for AMRIX in lactating mothers, as well as any potential adverse effects on the breastfed child from AMRIX or from the underlying maternal condition.

Renal Impairment

Patients with renal impairment should be closely monitored due to the potential for altered pharmacokinetics. Dosing adjustments may be necessary based on the degree of renal function decline. It is essential to assess renal function prior to initiating treatment and periodically during therapy to ensure appropriate dosing and minimize the risk of adverse effects. Caution is advised when prescribing to this population, and alternative therapies should be considered if significant renal impairment is present.

Hepatic Impairment

Use in patients with hepatic impairment is not recommended. Due to the potential for altered pharmacokinetics and the risk of adverse effects, it is advised that these patients avoid the use of this medication. Monitoring of liver function is essential in patients with compromised liver function, and alternative therapeutic options should be considered to ensure patient safety.

Overdosage

In cases of overdosage with AMRIX, although rare, fatalities may occur. It is important to note that deliberate cyclobenzaprine 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 Overdosage

Toxicity symptoms can manifest rapidly following cyclobenzaprine overdose, necessitating immediate hospital monitoring. 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.

Critical symptoms, although rare, can include cardiac arrest, chest pain, cardiac dysrhythmias, severe hypotension, seizures, neuroleptic malignant syndrome, and rhabdomyolysis. Clinically significant changes in the electrocardiogram, particularly alterations in the QRS axis or width, serve as important indicators of cyclobenzaprine toxicity. Additionally, any symptoms listed under Adverse Reactions may also be present.

Management Procedures

To mitigate the risk of severe symptoms, it is essential to obtain an electrocardiogram (ECG) and initiate cardiac monitoring without delay. The patient's airway should be protected, an intravenous line established, and gastric decontamination commenced. All patients suspected of an AMRIX 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.

Continuous observation with cardiac monitoring is necessary to detect signs of central nervous system (CNS) or respiratory depression, hypotension, cardiac dysrhythmias or conduction blocks, and seizures. Extended monitoring is warranted if any signs of toxicity arise during this period. It is important to note that monitoring plasma drug levels should not dictate patient management, and dialysis is likely ineffective due to the low plasma concentrations of the drug.

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. 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, and 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 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. A psychiatric referral may be appropriate in such cases. The management principles for both child and adult overdosage are similar; therefore, it is strongly recommended that physicians consult the local poison control center for specific pediatric treatment guidance.

Nonclinical Toxicology

Long-term studies were conducted in CD-1 mice and Sprague-Dawley rats to evaluate the carcinogenic potential of cyclobenzaprine. In an 81-week carcinogenicity study, metastatic hemangiosarcoma was observed in 3 of 21 male mice at a dose of 10 mg/kg/day, which is approximately twice the maximum recommended human dose (MRHD) of 30 mg/day on a mg/m² basis. In a separate 105-week carcinogenicity study, malignant astrocytoma was noted in 3 of 50 male rats at the same dose of 10 mg/kg/day, approximately three times the MRHD on a mg/m² basis. No tumor findings were reported in female mice or rats.

Cyclobenzaprine HCl was evaluated for mutagenic and clastogenic potential and was found to be non-mutagenic in several assays, including an in vitro Ames bacterial mutation assay, an in vitro Chinese hamster ovary (CHO) cell chromosomal aberration test, and an in vivo mouse bone marrow micronucleus assay.

In studies assessing fertility, cyclobenzaprine HCl was administered to male and female rats at doses up to 20 mg/kg/day, approximately 6.5 times the MRHD on a mg/m² basis, for 70 and 14 days prior to mating, respectively. No effects on fertility or reproductive performance were observed.

In a 67-week study involving rats receiving oral doses of cyclobenzaprine at 10, 20, or 40 mg/kg/day (3 to 15 times the MRHD on a mg/m² basis), liver findings included midzonal vacuolation with lipidosis in males and midzonal and centrilobular hepatocytic enlargement in females. Additionally, centrilobular coagulative necrosis was noted. These microscopic changes were evident in higher dose groups after 26 weeks and earlier in rats that died prior to this time; lower doses did not show these changes until after 26 weeks.

A 26-week study with Cynomolgus monkeys receiving cyclobenzaprine at oral doses of 2.5, 5, 10, or 20 mg/kg/day revealed that one monkey at the highest dose of 20 mg/kg/day (15 times the MRHD on a mg/m² basis) was euthanized in week 17 due to morbidity attributed to chronic pancreatitis, cholecystitis, cholangitis, and focal liver necrosis.

Postmarketing Experience

Postmarketing experience with AMRIX has identified several serious side effects, including the potential for serotonin syndrome, particularly when used in conjunction with certain other medications. Symptoms indicative of serotonin syndrome may include agitation, hallucinations, coma, or other alterations in mental status, as well as coordination issues, muscle twitching, rapid heartbeat, fluctuations in blood pressure, excessive sweating or fever, gastrointestinal disturbances such as nausea, vomiting, or diarrhea, and muscle stiffness or tightness.

Additionally, AMRIX may be associated with serious cardiovascular events that could lead to heart attack or stroke. Healthcare providers should be contacted immediately if patients experience irregular or abnormal heartbeats (arrhythmias) or tachycardia.

Commonly reported side effects of AMRIX include dry mouth, dizziness, fatigue, constipation, nausea, upset stomach, and drowsiness. It is important to note that these are not exhaustive lists of possible side effects. Patients are encouraged to seek medical advice regarding any side effects and may report adverse events to the FDA at 1-800-FDA-1088.

Patient Counseling

Patients should be instructed to swallow AMRIX capsules intact. Alternatively, they may sprinkle the contents of the capsule on a tablespoon of applesauce and swallow it immediately without chewing.

It is important to advise patients to discontinue AMRIX and notify their physician immediately if they experience any symptoms of an allergic reaction, which may include difficulty breathing, hives, swelling of the face or tongue, or itching.

Patients should be informed that AMRIX must not be taken in conjunction with MAO inhibitors or within 14 days following their discontinuation. Additionally, caution should be exercised regarding the risk of serotonin syndrome when AMRIX is used alongside other medications such as SSRIs, SNRIs, TCAs, tramadol, bupropion, meperidine, verapamil, or MAO inhibitors. Patients should be made aware of the signs and symptoms of serotonin syndrome and instructed to seek medical attention immediately if they experience these symptoms.

Patients should also be advised to stop taking AMRIX and contact their physician right away if they experience arrhythmias or tachycardia. Furthermore, it is essential to inform patients that AMRIX may enhance the impairment effects of alcohol, and similar effects may occur when taken with other CNS depressants.

Patients should be cautioned about operating an automobile or other hazardous machinery until it is reasonably certain that AMRIX therapy will not adversely affect their ability to perform such activities. Lastly, patients should be encouraged to take AMRIX at approximately the same time each day to maintain consistent therapeutic levels.

Storage and Handling

The product is supplied in a tight, light-resistant container as defined in the USP/NF. It should be stored at a temperature of 25°C (77°F), with permissible excursions between 15°C and 30°C (59°F to 86°F) in accordance with USP Controlled Room Temperature guidelines. Proper handling and storage conditions are essential to maintain the integrity of the product.

Additional Clinical Information

No further data are available.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Amrix as submitted by Cephalon, LLC. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)