Highlights

This article describes the drug label information for cyclobenzaprine HCl sublingual tablets (Tonmya™). For other formulations of cyclobenzaprine hydrochloride, see the DAILYMED database.

See Patient counseling information and medication guide available in the DAILYMED drug label information.

Indications and usage

Cyclobenzaprine HCl is indicated for treatment of fibromyalgia in adults.

Dosage and administration

Recommended dosage

The recommended dosage of cyclobenzaprine HCl is 5.6 mg administered sublingually once daily at bedtime:

Recommended dosage in geriatric patients

The recommended cyclobenzaprine HCl dosage--and the maximum recommended dosage--in geriatric patients is 2.8 mg administered sublingually once daily at bedtime.

Recommended dosage in patients with hepatic impairment

The recommended cyclobenzaprine HCl dosage--and the maximum recommended dosage--in patients with mild hepatic impairment is 2.8 mg administered sublingually once daily at bedtime. Cyclobenzaprine HCl is not recommended in patients with moderate or severe hepatic impairment.

Administration instructions

Cyclobenzaprine HCl is only for sublingual use.

Recommendations regarding missed doses

If you missed a cyclobenzaprine HCl bedtime dose, take cyclobenzaprine HCl the next evening. Do not take a missed dose during the day.

Pregnancy testing prior to administration

Pregnancy testing is recommended in females of reproductive potential prior to initiating treatment with cyclobenzaprine HCl.

Dosage forms and strengths

Sublingual tablets: 2.8 mg of cyclobenzaprine hydrochloride - yellow and round with the letter "T" debossed on one face.

Contraindications

Warnings and precautions

Embryofetal toxicity

Based on data from animal reproduction studies, cyclobenzaprine HCl may cause an increased risk of neural tube defects when administered to a pregnant female 2 weeks prior to conception and during the first trimester of pregnancy. Neural tube defects (splayed vertebral arches and spina bifida occulta) were observed in a rabbit embryofetal development study at the highest maternal dose tested, in the absence of maternal toxicity. Because neural tube development occurs early in pregnancy, often before pregnancy is recognized, advise females of reproductive potential of the potential risk to the fetus and avoid use of cyclobenzaprine HCl 2 weeks prior to conception and through the first trimester of pregnancy.

Perform a pregnancy test prior to initiation of treatment with cyclobenzaprine HCl to exclude use of cyclobenzaprine HCl during the first trimester of pregnancy.

Advise females of reproductive potential to use effective contraception during cyclobenzaprine HCl treatment and for 2 weeks after the final dose.

Serotonin syndrome

The development of a potentially life-threatening serotonin syndrome has been reported with cyclobenzaprine when used in combination with other drugs, such as selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, tramadol, bupropion, meperidine, verapamil, or monoamine oxidase inhibitors. The concomitant use of cyclobenzaprine HCl with monoamine oxidase inhibitors is contraindicated.

Serotonin syndrome symptoms may include mental status changes (eg, confusion, agitation, hallucinations), autonomic instability (eg, diaphoresis, tachycardia, labile blood pressure, hyperthermia), neuromuscular abnormalities (eg, tremor, ataxia, hyperreflexia, clonus, muscle rigidity), and/or gastrointestinal symptoms (eg, nausea, vomiting, diarrhea).

Treatment with cyclobenzaprine HCl and any concomitant serotonergic agents should be discontinued immediately if serotonin syndrome symptoms occur and supportive symptomatic treatment should be initiated. If concomitant treatment with cyclobenzaprine HCl and other serotonergic drugs is clinically warranted, careful observation is advised, particularly during treatment initiation or dosage increases.

Tricyclic antidepressant-like adverse reactions

Cyclobenzaprine is structurally related to tricyclic antidepressants.

Tricyclic antidepressants have been reported to produce arrhythmias, sinus tachycardia, prolongation of the conduction time leading to myocardial infarction and stroke.

Some of the more tricyclic antidepressant-associated serious CNS reactions have occurred in short-term studies of oral cyclobenzaprine. If clinically significant CNS symptoms develop, consider discontinuation of cyclobenzaprine HCl.

Caution should be used when tricyclic antidepressants are given to patients with a history of seizure disorder, because tricyclic antidepressants may lower the seizure threshold. Patients with a history of seizures should be monitored during tricyclic antidepressant use to identify recurrence of seizures or an increase in frequency of seizures.

Atropine-like adverse reactions

Because of its atropine-like action, cyclobenzaprine HCl should be used with caution in patients with a history of urinary retention, angle-closure glaucoma, increased intraocular pressure, and in patients taking anticholinergic drugs.

CNS depression and risk of operating a motor vehicle or hazardous machinery

Cyclobenzaprine HCl monotherapy may cause CNS depression, and concomitant use of cyclobenzaprine HCl with alcohol, barbiturates, or other CNS depressants may increase the risk of CNS depression.

Symptoms of CNS depression include somnolence. Advise patients not to operate a motor vehicle or dangerous machinery until they are reasonably certain that cyclobenzaprine HCl therapy will not adversely affect their ability to engage in such activities.

Oral mucosal adverse reactions

Oral mucosal adverse reactions, including sensory changes (eg, numbness, tingling), discomfort, pain, irritation, inflammation, and lesions, occurred more frequently in patients treated with cyclobenzaprine HCl compared to placebo (43% vs. 8%). Reactions typically occurred within minutes of administration and most resolved within 60 minutes.

Five patients experienced severe oral mucosal adverse reactions, including sensory changes (paresthesia, hypoesthesia), inflammation (glossitis), oral pain, and dry mouth. Most severe oral mucosal adverse reactions resolved within days after cyclobenzaprine HCl was discontinued, and no treatment was required.

Advise patients to moisten the mouth with sips of water before administration of cyclobenzaprine HCl to reduce the risk of oral sensory changes (hypoesthesia). Advise patients to report severe oral mucosal adverse reactions to their healthcare provider. Consider discontinuation of cyclobenzaprine HCl if severe reactions occur.

Adverse reactions

The following clinically significant reactions are described in greater detail in other sections of this labeling:

Clinical trials experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of sublingual cyclobenzaprine HCl (14 days of 2.8 mg once daily and then 5.6 mg once daily thereafter) is supported by three double-blind, placebo-controlled clinical trials (Trials 1, 2, and 3) in adult patients with fibromyalgia. A total of 1,182 patients completed at least 14 weeks of daily treatment, including 580 cyclobenzaprine HCl-treated patients (14 days of 2.8 mg once daily and then 5.6 mg once daily thereafter) and 602 placebo-treated patients.

Table 1 summarizes the most common adverse reactions in Trials 1, 2, and 3 (≥2% of cyclobenzaprine HCl-treated patients and at a higher incidence in cyclobenzaprine HCl-treated patients compared to placebo-treated patients).

Table 1. Adverse Reactions Reported in ≥2% of Cyclobenzaprine HCl-Treated Patients and a Higher Incidence than Placebo-Treated Patients in Adult Patients with Fibromyalgia (Trials 1, 2, and 3)

Oral mucosal adverse reactions in trials 1, 2, and 3. In Trials 1, 2, and 3, 43% of cyclobenzaprine HCl-treated patients compared to 8% of placebo-treated patients experienced at least one treatment-emergent oral mucosal adverse reaction. The most common oral mucosal adverse reactions included oral hypoesthesia, abnormal product taste, oral paresthesia, tongue discomfort, oral discomfort, glossodynia, oral pain, and aphthous ulcer. The majority (82%) of oral mucosal adverse reactions began within minutes of dosing, and of those, 88% occurred after nearly every dose. Almost two-thirds lasted less than 60 minutes. Of the approximately one-third that lasted longer than 60 minutes, 63% were present the next morning.

Five patients (0.7% of cyclobenzaprine HCl-treated patients) experienced severe oral mucosal adverse reactions, including paresthesia, glossitis, hypoesthesia, oral pain, and dry mouth. Most reactions resolved within days after cyclobenzaprine HCl was discontinued. Oral mucosal adverse reactions leading to discontinuation occurred more frequently in cyclobenzaprine HCl-treated patients compared to placebo-treated patients (4.5% vs. 0.5%).

Adverse reactions from other trials. In an open-label, long-term 40 to 52-week safety trial (Trial 4) in an unapproved population of patients previously exposed to 5.6 mg cyclobenzaprine HCl once daily (maximum recommended dosage) or placebo, 56 patients were treated with 5.6 mg of cyclobenzaprine HCl for at least 1 year. The most common adverse reactions in the cyclobenzaprine HCl-treated patients (>5%) were oral hypoesthesia (45%), somnolence (18%), abnormal product taste (7%), and oral paresthesia (7%).

In an open-label, long-term 52-week safety trial of adult patients with fibromyalgia previously exposed to 2.8 mg cyclobenzaprine HCl once daily (one half the recommended dosage) or placebo (Trial 5), 97 patients were treated for at least 1 year with 2.8 mg of cyclobenzaprine HCl once daily. The most common adverse reactions (>5%) in the cyclobenzaprine HCl-treated patients were hypoesthesia oral (15%), fatigue (7%), sinusitis (7%), and abnormal product taste (6%).

Postmarketing experience

The following adverse reactions have been reported in clinical studies or postmarketing experience with cyclobenzaprine immediate-release products, cyclobenzaprine extended-release products, or tricyclic antidepressants. Because some of these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

In a postmarketing surveillance program of cyclobenzaprine immediate-release products, the adverse reactions reported most frequently were drowsiness, dry mouth, and dizziness, and adverse reactions reported in 1% to 3% of the patients were: fatigue/tiredness, asthenia, nausea, constipation, dyspepsia, unpleasant taste, blurred vision, headache, nervousness, and confusion.

The following adverse reactions have been reported in postmarketing experience with cyclobenzaprine extended-release products or cyclobenzaprine immediate-release products, in clinical studies of cyclobenzaprine immediate-release products (incidence <1%), or in postmarketing experience with other tricyclic antidepressants:

Body as a whole. Syncope; malaise; chest pain; edema.

Cardiovascular. Tachycardia; arrhythmia; vasodilatation; palpitation; hypotension; hypertension; myocardial infarction; heart block; stroke.

Digestive. Vomiting; anorexia; diarrhea; gastrointestinal pain; gastritis; thirst; flatulence; edema of the tongue; abnormal liver function and rare reports of hepatitis, jaundice, and cholestasis; paralytic ileus, tongue discoloration; stomatitis; parotid swelling.

Endocrine. Inappropriate ADH syndrome.

Hematologic and lymphatic. Purpura; bone marrow depression; leukopenia; eosinophilia; thrombocytopenia.

Hypersensitivity. Anaphylaxis; angioedema; pruritus; facial edema; urticaria; rash.

Metabolic, nutritional, and immune. Elevation and lowering of blood sugar levels; weight gain or loss.

Musculoskeletal. Local weakness; myalgia.

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; neuroleptic malignant syndrome; decreased or increased libido; abnormal gait; delusions; aggressive behavior; paranoia; peripheral neuropathy; Bell's palsy; alteration in EEG patterns; extrapyramidal symptoms.

Respiratory. Dyspnea.

Skin. Sweating; photosensitization; alopecia.

Special senses. Ageusia; tinnitus.

Urogenital. Urinary frequency and/or retention; impaired urination; dilatation of the urinary tract; impotence; testicular swelling; gynecomastia; breast enlargement; galactorrhea.

Drug interactions

Based on its structural similarity to tricyclic antidepressants, concomitant use of cyclobenzaprine HCl with:

Postmarketing cases of serotonin syndrome have been reported with the concomitant use of oral cyclobenzaprine and other drugs, such as SSRIs, SNRIs, tricyclic antidepressants, tramadol, bupropion, meperidine, verapamil, or monoamine oxidase inhibitors.

Use in specific populations

Pregnancy

Risk summary. Based on animal data, cyclobenzaprine HCl may cause fetal harm when administered to a pregnant woman. In rabbits, an increased incidence of neural tube defects (splayed vertebral arches and spina bifida occulta) was observed when pregnant rabbits were treated with oral cyclobenzaprine during embryogenesis with 30 mg/kg/day (approximately 0.2 times the maximum recommended human dose (MRHD) of cyclobenzaprine HCl), in the absence of maternal toxicity. In rats, decreased pup body weight and survival were noted at a cyclobenzaprine dose of ≥10 mg/kg/day (approximately ≥0.8 times the MRHD of cyclobenzaprine HCl), when administered orally during pregnancy and lactation (see Data). The limited amount of available observational data on oral cyclobenzaprine use in pregnancy is of insufficient quality to inform a cyclobenzaprine HCl-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Advise pregnant women about the potential risk to the fetus with maternal exposure to cyclobenzaprine HCl and to avoid use of cyclobenzaprine HCl 2 weeks prior to conception and through the first trimester of pregnancy.

The background risk of major birth defects and miscarriage for pregnant women with fibromyalgia is unknown. All pregnancies have a background risk of birth defects, 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.

Report Pregnancies to the Tonix Medicines, Inc., Adverse Event reporting line at 1-888-869-7633 (1-888-TNXPMED).

Data.

Animal data. Oral administration of cyclobenzaprine during organogenesis to rabbits at the highest maternal dose of 30 mg/kg/day (approximately 0.2 times the MRHD of 5.6 mg/day of cyclobenzaprine HCl on an AUC basis) increased the incidence of neural tube defects (splayed vertebral arches and spina bifida occulta) in the absence of maternal toxicity. The no effect level for embryo-fetal development in rabbits was 10 mg/kg/day (approximately 0.05 times the MRHD of cyclobenzaprine HCl on an AUC basis).

In another study, no adverse embryofetal effects were reported following oral administration of cyclobenzaprine during organogenesis to rabbits at maternal doses up to 20 mg/kg/day (approximately 0.1 times the MRHD of cyclobenzaprine HCl on an estimated AUC basis).

No adverse embryofetal effects were reported following oral administration of cyclobenzaprine during organogenesis to rats at doses up to 25 mg/kg/day (approximately 9.2 times the MRHD of cyclobenzaprine HCl, on an AUC basis). Maternal toxicity, characterized by decreased body weight gain, was observed in rats at this dose of 25 mg/kg/day.

No adverse embryofetal effects were reported following oral administration of cyclobenzaprine during organogenesis to mice at maternal doses up to 20 mg/kg/day (approximately 17 times the MRHD of cyclobenzaprine HCl on a mg/m2 basis). Maternal toxicity, characterized by decreased body weight gain, was observed at the highest tested dose of 20 mg/kg/day.

Decreased pup body weight and survival were reported in a prenatal and postnatal study where pregnant rats were treated orally with cyclobenzaprine during pregnancy and lactation with maternal doses of 10 and 20 mg/kg/day (approximately 0.8 and 1.7 times the MRHD of cyclobenzaprine HCl on an estimated AUC basis). Maternal toxicity, characterized by decreased body weight gain, was observed only at the highest tested dose of 20 mg/kg/day.

In another prenatal and postnatal study where pregnant rats were treated orally with cyclobenzaprine during pregnancy and lactation with maternal doses up to 10 mg/kg/day (approximately 0.8 times the MRHD of cyclobenzaprine HCl on an AUC basis) no adverse effects were reported in maternal animals and offspring.

Lactation

Risk summary. A small number of published cases report the transfer of cyclobenzaprine into human milk in low amounts, but these data cannot be confirmed. There are no data on the effects of cyclobenzaprine on a breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for cyclobenzaprine HCl and any potential adverse effects on the breastfed child from cyclobenzaprine HCl or from the underlying maternal condition.

Females and males of reproductive potential

Based on animal data, cyclobenzaprine HCl may cause neural tube defects at clinically relevant doses. Females of reproductive potential should avoid use of cyclobenzaprine HCl 2 weeks prior to conception through the first trimester of pregnancy.

Pregnancy testing. Pregnancy testing is recommended for females of reproductive potential prior to initiation of treatment with cyclobenzaprine HCl.

Contraception.

Females. Advise female patients of reproductive potential to use effective contraception during treatment with cyclobenzaprine HCl and for 2 weeks after the final dose.

Pediatric use

The safety and effectiveness of cyclobenzaprine HCl have not been established in pediatric patients.

Geriatric use

Of the total number of cyclobenzaprine HCl-treated patients in the clinical trials in adult patients with fibromyalgia (Trials 1, 2, and 3), none were 65 years of age or older. Clinical trials of cyclobenzaprine HCl did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger adult patients.

After administration of cyclobenzaprine extended-release capsules, the plasma concentration and half-life of cyclobenzaprine were substantially increased in the subjects 65 years of age and older compared to those under 65 years of age. Given the higher cyclobenzaprine exposure in patients 65 years of age and older, the recommended cyclobenzaprine HCl dosage in patients 65 years of age and older is 2.8 mg once daily at bedtime, lower than the recommended dosage in younger adult patients.

Hepatic impairment

The recommended dosage of cyclobenzaprine HCl in patients with mild hepatic impairment (Child Pugh A) is 2.8 mg once daily at bedtime, lower than the recommended dosage in patients with normal hepatic function. The use of cyclobenzaprine HCl is not recommended in patients with moderate hepatic impairment (Child Pugh B) or severe hepatic impairment (Child Pugh C).

Cyclobenzaprine exposure (AUC) was increased in patients with mild hepatic impairment and moderate hepatic impairment compared to subjects with normal hepatic function, which may increase the risk of cyclobenzaprine HCl-associated adverse reactions.

Drug abuse and dependence

Controlled substance

Cyclobenzaprine HCl contains cyclobenzaprine, which is not a controlled substance.

Dependence

Given the pharmacologic similarities among the tricyclic antidepressants, consider withdrawal symptoms when stopping cyclobenzaprine HCl. Abrupt cessation of cyclobenzaprine HCl treatment after prolonged administration may produce nausea, headache, and malaise. These are not indicative of addiction.

Overdosage

Overdose signs, symptoms, and complications of cyclobenzaprine overdose

Changes in the electrocardiogram, particularly in QRS axis or width, are clinically significant indicators of cyclobenzaprine toxicity. Other potential cyclobenzaprine overdosage adverse reactions include any of the adverse reactions listed under Adverse reactions.

Multiple drug ingestion (including alcohol) is common in deliberate cyclobenzaprine overdose.

Treatment of cyclobenzaprine overdose

Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdose management recommendations.

Signs and symptoms of toxicity may develop rapidly after cyclobenzaprine overdose; therefore, hospital monitoring is recommended as soon as possible. To reduce the risk of rare but potentially critical cyclobenzaprine overdose manifestations, obtain an ECG and immediately initiate cardiac monitoring. Protect the patient's airway and establish an intravenous line. Recommend observation with cardiac monitoring and observation for signs of CNS or respiratory depression, hypotension, cardiac dysrhythmias and/or conduction blocks, and seizures.

Monitoring of plasma cyclobenzaprine levels should not guide overdose management of the patient. Dialysis is probably of no value because of low plasma concentrations of cyclobenzaprine.

Treatment of cardiovascular overdosage complications. A maximal limb-lead QRS duration of 0.1 seconds may be the best indication of the severity of the cyclobenzaprine 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 >7.6 or a pCO2 <20 mmHg is undesirable. Dysrhythmias unresponsive to sodium bicarbonate therapy/hyperventilation may respond to lidocaine or phenytoin. Type 1A and 1C antiarrhythmics (eg, quinidine, disopyramide, and procainamide) are generally contraindicated in the setting of a cyclobenzaprine overdose.

Treatment of CNS overdosage complications. In patients with CNS depression associated with a cyclobenzaprine overdose, early intubation is advised because of the potential for abrupt deterioration. Seizures should be controlled with benzodiazepines or, if these are ineffective, other anticonvulsants (eg, phenobarbital, 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 center.

Clinical pharmacology

Mechanism of action

The mechanism of action of cyclobenzaprine for the treatment of fibromyalgia in adults is unknown. In in vitro pharmacology studies, cyclobenzaprine demonstrated functional antagonism of 5-HT_2A, α₁-adrenergic, H₁-histaminergic, and M₁-muscarinic acetylcholine receptors. In addition, pharmacological studies in animals demonstrated a similarity between the effects of cyclobenzaprine and the structurally related tricyclic antidepressants, including reserpine antagonism, norepinephrine potentiation, potent peripheral and central anticholinergic effects, and sedation.

Pharmacodynamics

The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of cyclobenzaprine have not been fully characterized.

Pharmacokinetics

Following single-dose sublingual administration of 2.8 mg and 5.6 mg of cyclobenzaprine HCl in healthy adult subjects (n=16), C_max, AUC_0-tau, and AUC_0-inf of cyclobenzaprine increased in an approximately dose-proportional manner.

In a multiple-dose study of 5.6 mg of cyclobenzaprine HCl administered sublingually once daily for 20 days in healthy subjects (n=26), approximately 2.5-fold accumulation of plasma cyclobenzaprine exposure was observed at steady-state.

Absorption. The median time to peak plasma cyclobenzaprine concentration (T_max) was approximately 4.3 hours for the 2.8 mg and 5.6 mg once daily cyclobenzaprine HCl dosages.

Food effect. A food effect study was conducted in healthy adult subjects (n=16) with a single sublingual 5.6 mg cyclobenzaprine HCl dose. When cyclobenzaprine HCl was administered with food, there was approximately a 10% decrease in peak plasma concentration (C_max) compared to the fasted state, with no effect on exposure (AUC_0-tau and AUC_0-inf). These changes are not clinically significant.

Elimination. Cyclobenzaprine HCl has a single dose elimination half-life of approximately 36 hours (range 28-59 hours; n=16).

Metabolism. Cyclobenzaprine is extensively metabolized. Cytochromes P-450 3A4, 1A2, and, to a lesser extent, 2D6 mediate N-demethylation, one of the oxidative pathways for cyclobenzaprine metabolism.

Excretion. Cyclobenzaprine is excreted primarily as glucuronides via the kidney.

Specific populations.

Geriatric patients. After cyclobenzaprine extended-release capsules dosing, the plasma cyclobenzaprine AUC was increased by 40% and the half-life of cyclobenzaprine was prolonged in geriatric subjects greater than 65 years of age compared to younger adult subjects 18 to 45 years of age (50 hours vs. 32 hours, respectively). There were no notable differences in C_max or T_max in this study.

Hepatic impairment. In a pharmacokinetic study of immediate-release cyclobenzaprine tablets in 15 patients with mild hepatic impairment (Child-Pugh A) and one patient with moderate hepatic impairment(Child-Pugh B), both AUC and C_max were approximately double the values seen in subjects with normal hepatic function. The pharmacokinetics of cyclobenzaprine in patients with moderate hepatic impairment (one patient only) and severe hepatic impairment is not known.

How supplied/storage and handling

Carcinogenesis, mutagenesis, and impairment of fertility

Carcinogenesis. Long-term studies were conducted in CD-1 mice and Sprague-Dawley rats with oral cyclobenzaprine to evaluate its carcinogenic potential. In an 81-week carcinogenicity study, metastatic hemangiosarcoma was seen in three of 21 male mice at 10 mg/kg/day (approximately nine times the maximum recommended human dose (MRHD) of 5.6 mg of cyclobenzaprine HCl on a mg/m2 basis). In a 105-week carcinogenicity study, malignant astrocytoma was seen in three of 50 male rats at 10 mg/kg/day (approximately 0.3 times the MRHD on an estimated AUC basis). There were no tumor findings in female mice or rats.

Mutagenesis. Cyclobenzaprine was not mutagenic or clastogenic in the following assays: in vitro Ames bacterial mutation assays, an in vitro Chinese hamster ovary (CHO) cell chromosomal aberration test, an in vitro CHO cell micronucleus test, and in vivo mouse bone marrow micronucleus assays.

Impairment of fertility. Cyclobenzaprine HCl, when administered 70 and 14 days prior to mating to male and female rats, respectively, had no effects on fertility or reproductive performance at oral doses up to 20 mg/kg/day (approximately 1.1 and 3.8 times in males and females, respectively, the MRHD on an estimated AUC basis).

Animal toxicology and pharmacology

In a 67-week study with rats that received cyclobenzaprine at oral doses of 10, 20, or 40 mg/kg/day (approximately 0.3 to 4.3 times and 1.2 to 12.4 times in males and females, respectively, the maximum recommended human dose (MRHD) of 5.6 mg of cyclobenzaprine HCl on an estimated AUC basis), there were findings in the liver consisting of midzonal vacuolation with lipidosis for males and midzonal and centrilobular hepatocytic enlargement for females. In addition, there were findings of centrilobular coagulative necrosis. In the higher dose groups, these microscopic changes were seen 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.

In a 26-week study with Cynomolgus monkeys that received cyclobenzaprine at oral of doses of 2.5, 5, 10, or 20 mg/kg/day, one monkey at 20 mg/kg/day (69 times the MRHD on mg/m2 basis) was euthanized in week 17. Morbidity for this animal was attributed to findings of chronic pancreatitis, cholecystitis, cholangitis, and focal liver necrosis.

Clinical studies

The efficacy of cyclobenzaprine HCl for the treatment of fibromyalgia was assessed in three randomized, two-arm, parallel-group, double-blind, placebo-controlled multicenter trials (Trial 1 [NCT04172831], Trial 2 [|}WebSite:NCT04508621}{WebURL:https://clinicaltrials.gov/study/NCT04172831?cond=NCT04508621}|], and Trial 3 [NCT05273749]). The trials enrolled 1,474 patients aged 18 to 65 (735 cyclobenzaprine HCl-treated patients and 739 placebo-treated patients) who met the 2016 American College of Rheumatology (ACR) criteria for diagnosis of fibromyalgia (including generalized pain, defined as pain in at least four of five regions; symptoms that had been present at a similar level for at least 3 months; and widespread pain index (WPI) ≥7 and symptom severity scale (SSS) score ≥5, OR WPI between 4 to 6 and SSS scale score ≥9). In the trials, 95% of patients were female, 83% of patients were not Hispanic or Latino, and the percentages of White, Black, and Asian patients were 86%, 9%, and 1%, respectively. The mean age was 49 years (range 18 to 65 years), and the mean duration of fibromyalgia was 9 years (range 0 to 49 years).

Patients were randomized to receive bedtime sublingual treatment of either:

The primary endpoint in all three trials was the change from baseline to Week 14 in the weekly average of daily 24-hour recall pain intensity scores.

As measured by the 11-point (0-10) numeric rating scale (NRS), the minimum mean baseline pain score required for enrollment was 4. Within each trial, at baseline, the cyclobenzaprine HCl and placebo groups had similar mean weekly averages of daily diary pain scores.

The least squares (LS) mean change from baseline in the weekly average of daily 24-hour recall pain intensity scores at Week 14 in adult patients with fibromyalgia for the cyclobenzaprine HCl and placebo groups in Trial 1 and Trial 3 are presented in Table 2 (available in the Clinical studies section of the DAILYMED drug label information). The LS mean change from baseline in the weekly average of daily 24-hour recall pain intensity scores over the weeks of the study in adult patients with fibromyalgia in Trials 1 and 3 are presented in Figure 1 (available in the Clinical studies section of the DAILYMED drug label information).

Figure 2 (available in the Clinical studies section of the DAILYMED drug label information) shows the percentage of patients in Trials 1 and 3 who achieved various degrees of improvement in the change from baseline to Week 14 in the weekly averages of daily diary pain scores. The figures are cumulative so that patients whose change from baseline is, for example, 50%, are also included at every level of improvement below 50%. Patients who did not complete the trial were assigned 0% improvement. For example, in Trial 1 and Trial 3, the percentage of cyclobenzaprine HCl-treated patients who achieved at least a 30% improvement from baseline in their weekly average of daily 24-hour recall pain intensity score at Week 14 was 47% and 46%, respectively.

How supplied/storage and handling

How Supplied

Cyclobenzaprine HCl (cyclobenzaprine hydrochloride sublingual) tablets are supplied as 2.8 mg sublingual tablets and are round, yellow, debossed "T" on one side, and packaged in 30 cc high-density polyethylene bottles with a 28 mm polypropylene child-resistant cap with induction seal. Each bottle contains polyester coil and a desiccant canister.

Storage and handling

Cyclobenzaprine HCl (cyclobenzaprine hydrochloride sublingual) tablets are labeled for storage at USP controlled room temperature (20°C to 25°C [68°F to 77°F]) with excursions permitted between 15°C to 30°C (59°F to 86°F).

Store and dispense in the original container and protect from moisture. Remove the polyester coil on first use and discard. Keep the desiccant canister in the bottle for the entire period of use.

Patient counseling information

Acknowledgement

This article was excerpted from U.S. FDA Drug Labeling information available on the DailyMed website.