Cyclobenzaprine hydrochloride

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. Improvement is manifested by relief of muscle spasm and its associated signs and symptoms, which include pain, tenderness, limitation of motion, and restriction in activities of daily living.

Cyclobenzaprine hydrochloride should be used only for short periods (up to two or three weeks) because adequate evidence of effectiveness for more prolonged use is not available. Muscle spasm associated with acute, painful musculoskeletal conditions is generally of short duration, and specific therapy for longer periods is seldom warranted.

Cyclobenzaprine hydrochloride has not been found effective in the treatment of spasticity associated with cerebral or spinal cord disease, or in children with cerebral palsy.

Limitations of Use

• Cyclobenzaprine hydrochloride should be used only for short periods (up to 2 or 3 weeks).

• It has not been found effective in the treatment of spasticity associated with cerebral or spinal cord disease or in children with cerebral palsy.

Dosage and Administration

For most patients, the recommended dosage of cyclobenzaprine hydrochloride tablets 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. In some cases, a dose of 7.5 mg three times a day may also be considered.

Cyclobenzaprine hydrochloride should not be used for periods longer than two or three weeks. Less frequent dosing should be considered for patients who are elderly or have hepatic impairment.

For the extended-release formulation, the recommended adult dose for most patients is 15 mg taken once daily. Some patients may require an increase to 30 mg taken once daily. It is advised that doses be taken at approximately the same time each day. Patients should be instructed to swallow the extended-release capsules intact or to sprinkle the capsule contents on a tablespoon of applesauce and swallow immediately without chewing.

In all cases, careful monitoring of patient response is essential to ensure optimal therapeutic outcomes.

Contraindications

Patients with hypersensitivity to any component of this product should not use cyclobenzaprine hydrochloride. The concomitant use of monoamine oxidase (MAO) inhibitors or within 14 days after their discontinuation is contraindicated due to the risk of hyperpyretic crisis, seizures, and fatalities associated with this combination.

Cyclobenzaprine is also contraindicated during the acute recovery phase of myocardial infarction, as well as in patients with arrhythmias, heart block, conduction disturbances, or congestive heart failure. Additionally, it should not be used in individuals with hyperthyroidism.

Warnings and Precautions

The development of a potentially life-threatening serotonin syndrome has been reported with cyclobenzaprine hydrochloride when used in combination with other drugs, such as selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), tramadol, bupropion, meperidine, verapamil, or monoamine oxidase (MAO) inhibitors. The concomitant use of cyclobenzaprine hydrochloride with MAO inhibitors is contraindicated. Symptoms of serotonin syndrome may include 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/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Treatment with cyclobenzaprine hydrochloride and any concomitant serotonergic agents should be discontinued immediately if the above reactions occur, and supportive symptomatic treatment should be initiated. If concomitant treatment with cyclobenzaprine hydrochloride and other serotonergic drugs is clinically warranted, careful observation is advised, particularly during treatment initiation or dose increases.

Cyclobenzaprine is closely related to the tricyclic antidepressants, such as amitriptyline and imipramine. In short-term studies for indications other than muscle spasm associated with acute musculoskeletal conditions, and usually at doses somewhat greater than those recommended for skeletal muscle spasm, some of the more serious central nervous system reactions noted with the tricyclic antidepressants have occurred. Tricyclic antidepressants have been reported to produce arrhythmias, sinus tachycardia, and prolongation of the conduction time leading to myocardial infarction and stroke. Cyclobenzaprine hydrochloride may enhance the effects of alcohol, barbiturates, and other CNS depressants.

Because of its atropine-like action, cyclobenzaprine hydrochloride should be used with caution in patients with a history of urinary retention, angle-closure glaucoma, increased intraocular pressure, and in patients taking anticholinergic medication. The plasma concentration of cyclobenzaprine is increased in patients with hepatic impairment. These patients are generally more susceptible to drugs with potentially sedating effects, including cyclobenzaprine. Cyclobenzaprine hydrochloride should be used with caution in subjects with mild hepatic impairment starting with a 5 mg dose and titrating slowly upward. Due to the lack of data in subjects with more severe hepatic insufficiency, the use of cyclobenzaprine hydrochloride in subjects with moderate to severe impairment is not recommended.

Treatment with cyclobenzaprine hydrochloride and any concomitant serotonergic agents should be discontinued immediately if serotonin syndrome symptoms occur.

Side Effects

Common adverse reactions associated with cyclobenzaprine hydrochloride, occurring in more than 3% of patients, include:

• Drowsiness: 29% (5 mg), 38% (10 mg), 10% (Placebo)

• Dry Mouth: 21% (5 mg), 32% (10 mg), 7% (Placebo)

• Fatigue: 6% (5 mg), 6% (10 mg), 3% (Placebo)

• Headache: 5% (5 mg), 5% (10 mg), 8% (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 infection

• Pharyngitis

• Fatigue/Tiredness

• Asthenia

• Dyspepsia

• Unpleasant taste

• Blurred vision

• Confusion

Less frequent adverse reactions (incidence < 1%) include:

• Body as a Whole: Syncope; malaise.

• Cardiovascular: Tachycardia; arrhythmia; vasodilatation; palpitation; hypotension.

• Digestive: Vomiting; anorexia; 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.

Causal Relationship Unknown

The following adverse reactions have been reported, but a causal relationship is unknown:

• 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.

Warnings

The development of a potentially life-threatening serotonin syndrome has been reported with cyclobenzaprine hydrochloride when used in combination with other drugs, such as selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), tramadol, bupropion, meperidine, verapamil, or MAO inhibitors. Symptoms may include 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/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).

Overdosage

Common effects associated with cyclobenzaprine overdose include drowsiness and tachycardia. Less frequent manifestations include 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. Changes in the electrocardiogram, particularly in QRS axis or width, are clinically significant indicators of cyclobenzaprine toxicity.

Drug Interactions

Cyclobenzaprine hydrochloride has several significant drug interactions that warrant careful consideration.

MAO Inhibitors

Cyclobenzaprine may have life-threatening interactions with monoamine oxidase (MAO) inhibitors. The concomitant use of cyclobenzaprine and MAO inhibitors is contraindicated due to the risk of severe adverse effects.

Serotonergic Drugs

Postmarketing cases of serotonin syndrome have been reported when cyclobenzaprine is used in combination with other serotonergic agents, including selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), tramadol, bupropion, meperidine, and verapamil. If the combination of cyclobenzaprine with these serotonergic drugs is clinically warranted, careful observation is advised, particularly during treatment initiation or dose increases.

CNS Depressants

Cyclobenzaprine hydrochloride may enhance the effects of alcohol, barbiturates, and other central nervous system (CNS) depressants. This interaction can lead to increased sedation and respiratory depression, necessitating caution when these substances are used concurrently.

Tricyclic Antidepressants

Tricyclic antidepressants may block the antihypertensive action of guanethidine and similarly acting compounds. Additionally, the use of tricyclic antidepressants in patients taking tramadol may enhance the risk of seizures.

Monitoring Recommendations

Due to the potential for serious interactions, it is recommended that healthcare providers closely monitor patients who are prescribed cyclobenzaprine, especially when it is used in conjunction with the aforementioned drug classes.

Pediatric Use

Safety and effectiveness of cyclobenzaprine hydrochloride, including its tablet, film-coated, and extended-release capsule forms, have not been established in pediatric patients below 15 years of age. Additionally, the safety and effectiveness of AMRIX and TONMYA have not been studied in pediatric patients. Therefore, caution is advised when considering the use of these medications in this population.

Geriatric Use

The plasma concentration of cyclobenzaprine is significantly increased in elderly patients, with pharmacokinetic studies indicating that mean steady-state AUC values are approximately 1.7-fold higher in individuals aged 65 years and older compared to younger adults. Elderly male subjects exhibit the highest observed mean increase, approximately 2.4-fold, while elderly females show a lesser increase of about 1.2-fold.

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. There is also a potential for drug-drug and drug-disease interactions in this population. Therefore, cyclobenzaprine should be used in elderly patients only if clearly needed.

When initiating therapy with cyclobenzaprine hydrochloride in elderly patients, it is recommended to start with a 5 mg dose, which should be titrated slowly upward based on clinical response and tolerability. Additionally, less frequent dosing may be considered to mitigate the risk of adverse effects. The use of cyclobenzaprine hydrochloride extended-release capsules is not recommended in elderly patients due to insufficient safety and efficacy data in this age group, as well as the significantly increased plasma concentration and half-life observed in older adults.

Pregnancy

Pregnancy Category B. Reproduction studies have been conducted in rats, mice, and rabbits at doses up to 20 times the human dose, revealing no evidence of impaired fertility or harm to the fetus due to cyclobenzaprine hydrochloride. However, there are no adequate and well-controlled studies in pregnant women. Therefore, cyclobenzaprine should be used during pregnancy only if clearly needed, as animal reproduction studies are not always predictive of human response.

Available data from case reports regarding the use of cyclobenzaprine hydrochloride extended-release capsules in pregnancy have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Nonetheless, in animal studies, decreased pup body weight and survival were noted at cyclobenzaprine doses of ≥10 mg/kg/day (approximately ≥3 times the maximum recommended human dose of 30 mg/day) when administered orally during pregnancy and lactation.

The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies carry a background risk of birth defect, loss, or other adverse outcomes. In the U.S. 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.

In rabbits, an increased incidence of neural tube defects was observed when treated with oral cyclobenzaprine during embryogenesis at a dose of 30 mg/kg/day (approximately 0.2 times the maximum recommended human dose). Additionally, decreased pup body weight and survival were reported in a prenatal and postnatal study where pregnant rats were treated with cyclobenzaprine during pregnancy and lactation at doses of 10 and 20 mg/kg/day (approximately 3 and 6 times the maximum recommended human dose).

Given these findings, it is advised that pregnant women be informed of the potential risks to the fetus associated with maternal exposure to cyclobenzaprine. Women who are pregnant or planning to become pregnant should avoid using cyclobenzaprine, particularly during the first trimester.

Lactation

It is not known whether cyclobenzaprine hydrochloride is excreted in human milk. Given its structural similarity to tricyclic antidepressants, which are known to be excreted in breast milk, caution is advised when administering cyclobenzaprine to lactating mothers.

There are no available data regarding the presence of cyclobenzaprine in either human or animal milk, nor are there studies on its effects on breastfed infants or on milk production. Some published cases suggest that cyclobenzaprine may transfer into human milk in low amounts, but these findings remain unconfirmed.

The developmental and health benefits of breastfeeding should be weighed against the mother's clinical need for cyclobenzaprine and any potential adverse effects on the breastfed child. In animal studies, decreased pup body weight and survival were observed at doses significantly higher than the maximum recommended human dose, indicating potential risks that should be considered when prescribing this medication to nursing women.

Renal Impairment

Patients with renal impairment have not been specifically addressed in the available labeling for Cyclobenzaprine Hydrochloride, which is offered in various forms including tablets, film-coated tablets, and extended-release capsules. The labeling does not provide any information regarding dosage adjustments, special monitoring, or safety considerations for this patient population.

As such, healthcare professionals should exercise caution when prescribing Cyclobenzaprine to patients with reduced kidney function, given the absence of guidance on its use in this context. It is advisable to monitor these patients closely for any potential adverse effects, considering the lack of specific recommendations in the product information.

Hepatic Impairment

Use in patients with hepatic impairment is not recommended for Cyclobenzaprine Hydrochloride, particularly in the extended-release capsule form. There is no specific information regarding dosage adjustments, special monitoring, or precautions for patients with liver problems in the available data for other formulations, including tablets and film-coated tablets.

For the medication Tonmya, the recommended dosage in patients with mild hepatic impairment (Child Pugh A) is 2.8 mg once daily at bedtime, which is lower than the dosage recommended for patients with normal hepatic function. However, the use of Tonmya is not recommended in patients with moderate (Child Pugh B) or severe hepatic impairment (Child Pugh C). It is noted that Cyclobenzaprine exposure (AUC) may be increased in patients with mild and moderate hepatic impairment compared to those with normal hepatic function, potentially raising the risk of associated adverse reactions.

Monitoring parameters specific to hepatic function are not detailed in the provided information.

Overdosage

Although rare, deaths may occur from overdosage with cyclobenzaprine hydrochloride. Multiple drug ingestion, including alcohol, is common in deliberate cyclobenzaprine overdose. Management of overdose is complex and evolving; therefore, it is recommended that the physician contact a poison control center for current information on treatment.

Signs and symptoms of toxicity may develop rapidly after cyclobenzaprine overdose, necessitating immediate hospital monitoring. The acute oral LD50 of cyclobenzaprine is approximately 338 mg/kg in mice and 425 mg/kg in rats. The most common effects associated with cyclobenzaprine overdose include drowsiness and tachycardia. Less frequent manifestations may include tremor, agitation, coma, ataxia, hypertension, slurred speech, confusion, dizziness, nausea, vomiting, and hallucinations. Rare but potentially critical manifestations of overdose include cardiac arrest, chest pain, cardiac dysrhythmias, severe hypotension, seizures, and neuroleptic malignant syndrome. Changes in the electrocardiogram, particularly in QRS axis or width, are clinically significant indicators of cyclobenzaprine toxicity.

All patients suspected of an overdose with cyclobenzaprine should receive gastrointestinal decontamination, which includes large volume gastric lavage followed by activated charcoal. If consciousness is impaired, the airway should be secured prior to lavage, and emesis is contraindicated. A maximal limb-lead QRS duration of ≥0.10 seconds may indicate the severity of the overdose. Serum alkalinization, to a pH of 7.45 to 7.55, using intravenous sodium bicarbonate and hyperventilation (as needed), should be instituted for patients with dysrhythmias and/or QRS widening. A pH >7.60 or a pCO2 <20 mmHg is undesirable. Dysrhythmias unresponsive to sodium bicarbonate therapy or hyperventilation may respond to lidocaine, bretylium, or phenytoin. Type 1A and 1C antiarrhythmics are generally contraindicated (e.g., quinidine, disopyramide, and procainamide).

In patients with CNS depression, early intubation is advised due to the potential for abrupt deterioration. Seizures should be controlled with benzodiazepines or, if these are ineffective, other anticonvulsants such as phenobarbital or phenytoin. Physostigmine is not recommended except to treat life-threatening symptoms that have been unresponsive to other therapies, and then only in close consultation with a poison control center.

Since overdosage is often deliberate, patients may attempt suicide by other means during the recovery phase; psychiatric referral may be appropriate. The principles of management of child and adult overdosages are similar, and it is strongly recommended that the physician contact the local poison control center for specific pediatric treatment.

Nonclinical Toxicology

Teratogenic Effects

Reproduction studies have been performed in rats, mice, and rabbits at doses up to 20 times the human dose, revealing no evidence of impaired fertility or harm to the fetus due to cyclobenzaprine hydrochloride. However, there are no adequate and well-controlled studies in pregnant women. Therefore, this drug should be used during pregnancy only if clearly needed, as animal reproduction studies are not always predictive of human response.

Non-Teratogenic Effects

At oral doses of up to 10 times the human dose, cyclobenzaprine did not adversely affect the reproductive performance or fertility of male or female rats. Additionally, cyclobenzaprine did not demonstrate mutagenic activity in the male mouse at dose levels of up to 20 times the human dose.

Nonclinical Toxicology

In long-term studies conducted in CD-1 mice and Sprague-Dawley rats, cyclobenzaprine hydrochloride was evaluated for its carcinogenic potential. In an 81-week carcinogenicity study, metastatic hemangiosarcoma was observed in 3 of 21 male mice at a dose of 10 mg/kg/day (approximately 2 times the maximum recommended human dose (MRHD) of 30 mg/day on a mg/m² basis). In a 105-week carcinogenicity study, malignant astrocytoma was noted in 3 of 50 male rats at the same dose level (approximately 3 times the MRHD on a mg/m² basis). No tumor findings were reported in female mice or rats.

In a 67-week study with rats treated with cyclobenzaprine hydrochloride at doses of approximately 5 to 40 times the MRHD, pale, sometimes enlarged livers were noted, along with a dose-related hepatocyte vacuolation with lipidosis. In higher dose groups, these microscopic changes were observed after 26 weeks and even earlier in rats that died prior to 26 weeks; at lower doses, these changes were not seen until after 26 weeks.

Cyclobenzaprine did not affect the onset, incidence, or distribution of neoplasia in the aforementioned studies. Furthermore, cyclobenzaprine hydrochloride was not mutagenic or clastogenic in various assays, including the in vitro Ames bacterial mutation assay, in vitro Chinese hamster ovary (CHO) cell chromosomal aberration test, and in vivo mouse bone marrow micronucleus assay.

Animal Pharmacology and Toxicology

Pharmacological studies indicate that cyclobenzaprine reduces or abolishes skeletal muscle hyperactivity in several animal models. It does not act at the neuromuscular junction or directly on skeletal muscle but primarily exerts its effects within the central nervous system at brain stem levels, although its action on spinal cord levels may contribute to its overall skeletal muscle relaxant activity. Evidence suggests that the net effect of cyclobenzaprine is a reduction of tonic somatic motor activity, influencing both gamma (γ) and alpha (α) motor systems.

Additionally, cyclobenzaprine has shown a similarity in effects to those of structurally related tricyclic antidepressants, including reserpine antagonism, norepinephrine potentiation, potent peripheral and central anticholinergic effects, and sedation. Cyclobenzaprine also caused a slight to moderate increase in heart rate in animal studies.

Storage and Handling

Cyclobenzaprine Hydrochloride is supplied in various forms, including tablets and capsules, with specific packaging configurations. The tablets are available as film-coated tablets and standard tablets, while the capsules are offered in an extended-release formulation.

The product should be stored 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 defined by USP Controlled Room Temperature.

For packaging, the tablets and capsules must be dispensed in a tight, light-resistant container as defined in the USP/NF, utilizing a child-resistant closure. This ensures the safety and integrity of the medication.

It is important to keep this and all medications out of the reach of children.