Cyclobenzaprine Hydrochloride

TONMYA ® is indicated for treatment of fibromyalgia in adults. TONMYA is indicated for the treatment of fibromyalgia in adults ( 1 ).

Recommended dosage of TONMYA is 5.6 mg administered sublingually once daily at bedtime ( 2.1 ): Starting dose: Days 1 to 14, administer 2.8 mg (1 sublingual tablet) once daily at bedtime. Target dose: Days 15 and thereafter, administer 5.6 mg (2 sublingual tablets) once daily at bedtime. Maximum recommended dosage: 5.6 mg once daily. Ensure mouth is moist with sips of water before sublingual administration ( 2.4 , 5.6 , 6.1 ) Do not swallow whole, cut, crush, or chew ( 2.4 ) Geriatric patients: Recommended dosage is 2.8 mg administered sublingually once daily at bedtime ( 2.2 , 8.5 ) Hepatic impairment (HI): Recommended dosage in patients with mild HI is 2.8 mg administered sublingually once daily at bedtime. Use not recommended in patients with moderate HI or severe HI ( 2.3 , 8.6 ). See important administration instructions in the Full Prescribing Information ( 2.4 , 2.5 , 2.6 ).

2.1 Recommended Dosage The recommended dosage of TONMYA is 5.6 mg administered sublingually once daily at bedtime: Starting dose: Days 1 to 14, administer 2.8 mg (1 sublingual tablet) once daily at bedtime. Target dose: Days 15 and thereafter, administer 5.6 mg (2 sublingual tablets) once daily at bedtime. Maximum recommended dosage: 5.6 mg once daily.

2.2 Recommended Dosage in Geriatric Patients The recommended TONMYA dosage―and the maximum recommended dosage―in geriatric patients is 2.8 mg administered sublingually once daily at bedtime [see Use in Specific Populations (8.5) ].

2.3 Recommended Dosage in Patients with Hepatic Impairment The recommended TONMYA dosage―and the maximum recommended dosage―in patients with mild hepatic impairment is 2.8 mg administered sublingually once daily at bedtime . TONMYA is not recommended in patients with moderate or severe hepatic impairment [see Use in Specific Populations (8.6) ].

2.4 Administration Instructions TONMYA is only for sublingual use. Administer after brushing teeth and finishing other oral care and ensure a moist mouth/sublingual area by drinking a few sips of water prior to administration. Place the sublingual tablet(s) under the tongue until dissolved. Do not swallow whole, cut, crush, or chew. Avoid eating or drinking for at least 15 minutes after the sublingual tablet(s) has/have completely dissolved at bedtime and preferably avoid any hot, cold, or acidic beverages until the morning. Avoid talking for at least 5 minutes after administration.

2.5 Recommendations Regarding Missed Dose(s) If you missed a TONMYA bedtime dose, take TONMYA the next evening. Do not take a missed dose during the day.

2.6 Pregnancy Testing Prior to Administration Pregnancy testing is recommended in females of reproductive potential prior to initiating treatment with TONMYA [see Warnings and Precautions (5.1) , and Use in Specific Populations (8.1 , 8.3) ]

Sublingual tablets: 2.8 mg of cyclobenzaprine hydrochloride - yellow and round with the letter "T" debossed on one face. Sublingual tablets: 2.8 mg of cyclobenzaprine hydrochloride ( 3 ).

Hypersensitivity to cyclobenzaprine or any inactive ingredient in TONMYA. Hypersensitivity reactions may manifest as an anaphylactic reaction, urticaria, facial and/or tongue swelling, or pruritus. Discontinue TONMYA if a hypersensitivity reaction is suspected. Concomitant use of monoamine oxidase (MAO) inhibitors or within 14 days after discontinuation of a MAO inhibitor. Hyperpyretic crisis seizures and deaths have occurred in patients who received cyclobenzaprine (or structurally similar tricyclic antidepressants) concomitantly with MAO inhibitors drugs. During the acute recovery phase of myocardial infarction, and in patients with arrhythmias, heart block or conduction disturbances, or congestive heart failure. Hyperthyroidism. Hypersensitivity to cyclobenzaprine or any inactive ingredient in TONMYA ( 4 ) Concomitant use of monoamine oxidase (MAO) inhibitors or within 14 days after their discontinuation ( 4 ) During acute recovery phase of myocardial infarction and in patients with arrhythmias, heart block or conduction disturbances, or congestive heart failure ( 4 ) Hyperthyroidism ( 4 )

Based on its structural similarity to TCAs, concomitant use of TONMYA with: MAO inhibitors may be life-threatening [see Contraindications (4) ] , Alcohol, barbiturates, and other CNS depressants may increase the risk of adverse reactions associated with these drugs, Tramadol may increase the seizure risk, Guanethidine or other similar acting drugs may block the antihypertensive action of these drugs. Postmarketing cases of serotonin syndrome have been reported with the concomitant use of oral cyclobenzaprine and other drugs, such as SSRIs, SNRIs, TCAs, tramadol, bupropion, meperidine, verapamil, or MAO inhibitors [see Warnings and Precautions (5.2) ] . The concomitant use of TONMYA with MAO inhibitors is contraindicated. If serotonin syndrome symptoms occur with the use of other serotonergic drugs, immediately discontinue TONMYA. If concomitant treatment with TONMYA and other serotonergic drugs (besides MAO inhibitors) is clinically warranted, careful observation is advised, particularly during dosage increases. MAO Inhibitors: Life-threatening interactions may occur ( 4 , 7 ) Other serotonergic Drugs: Serotonin syndrome has been reported ( 5.2 , 7 ) CNS Depressants: CNS depressant effects of alcohol, barbiturates, and other CNS depressants may be enhanced ( 5.5 , 7 ) Tramadol: Seizure risk may be enhanced ( 7 ) Guanethidine: Antihypertensive effect may be blocked ( 7 )

Overdose Signs, Symptoms, and Complications of Cyclobenzaprine Overdose The most common adverse reactions associated with cyclobenzaprine overdose are drowsiness and tachycardia. Less frequent overdose manifestations include tremor, agitation, coma, ataxia, hypertension, slurred speech, confusion, dizziness, nausea, vomiting, and hallucinations. Rare but potentially critical overdose manifestations that have been reported are cardiac arrest, chest pain, cardiac dysrhythmias, severe hypotension, seizures, cases of neuroleptic malignant syndrome and rhabdomyolysis, and death. 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 (6) . 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 pCO 2 <20 mmHg is undesirable. Dysrhythmias unresponsive to sodium bicarbonate therapy/hyperventilation may respond to lidocaine or phenytoin. Type 1A and 1C antiarrhythmics (e.g., 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 (e.g., 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.

9.1 Controlled Substance TONMYA contains cyclobenzaprine, which is not a controlled substance.

9.3 Dependence Given the pharmacologic similarities among the TCAs, consider withdrawal symptoms when stopping TONMYA. Abrupt cessation of TONMYA treatment after prolonged administration may produce nausea, headache, and malaise. These are not indicative of addiction.

Risk Summary Based on animal data, TONMYA 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 TONMYA), 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 TONMYA), 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 TONMYA-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 TONMYA and to avoid use of TONMYA two 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 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. 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 TONMYA 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 TONMYA 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 TONMYA 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 TONMYA, 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 TONMYA on a mg/m 2 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 TONMYA on an estimated AUC basis). Maternal toxicity, characterized by a 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 TONMYA on an AUC basis) no adverse effects were reported in maternal animals and offspring.

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

Of the total number of TONMYA-treated patients in the clinical trials in adult patients with fibromyalgia (Trials 1, 2, and 3) [see Clinical Studies (14) ], none were 65 years of age and older. Clinical trials of TONMYA 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 [see Clinical Pharmacology (12.3) ]. Given the higher cyclobenzaprine exposure in patients 65 years of age and older, the recommended TONMYA 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 [see Dosage and Administration (2.2) ].

Cyclobenzaprine hydrochloride, USP is a white to off-white crystalline tricyclic amine salt powder, 1-Propanamine, 3-(5H-dibenzo[a,d] cyclohepten-5-ylidene)-N,N-dimethyl-, hydrochloride. The molecular formula is C 20 H 21 N ∙ HCl and the molecular weight is 311.85 g/mol, and it has a pK of 6.8. It is freely soluble in water and pH independent. Cyclobenzaprine hydrochloride has the following chemical structure: Each sublingual tablet contains 2.8 mg of cyclobenzaprine hydrochloride (equivalent to 2.47 mg cyclobenzaprine) and the following inactive ingredients: colloidal silicon dioxide, corn starch, crospovidone (Type A), D&C Yellow No.10, dibasic potassium phosphate, mannitol, and sodium stearyl fumarate. Chemical Structure

12.1 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 , α 1 -adrenergic, H 1 -histaminergic, and M 1 -muscarinic acetylcholine receptors. In addition, pharmacological studies in animals demonstrated a similarity between the effects of cyclobenzaprine and the structurally related TCAs, including reserpine antagonism, norepinephrine potentiation, potent peripheral and central anticholinergic effects, and sedation.

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

12.3 Pharmacokinetics Following single-dose sublingual administration of 2.8 mg and 5.6 mg of TONMYA 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 TONMYA 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 TONMYA dosages. Food Effect: A food effect study was conducted in healthy adult subjects (n=16) with a single sublingual 5.6 mg TONMYA dose. When TONMYA was administered with food, there was approximately 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 TONMYA 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) [see Use in Specific Populations (8.5) ]. 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 (HI) (Child-Pugh A) and 1 patient with moderate HI (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 HI (1 patient only) and severe HI is not known [see Use in Specific Populations (8.6) ] .

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 , α 1 -adrenergic, H 1 -histaminergic, and M 1 -muscarinic acetylcholine receptors. In addition, pharmacological studies in animals demonstrated a similarity between the effects of cyclobenzaprine and the structurally related TCAs, including reserpine antagonism, norepinephrine potentiation, potent peripheral and central anticholinergic effects, and sedation.

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

Following single-dose sublingual administration of 2.8 mg and 5.6 mg of TONMYA 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 TONMYA 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 TONMYA dosages. Food Effect: A food effect study was conducted in healthy adult subjects (n=16) with a single sublingual 5.6 mg TONMYA dose. When TONMYA was administered with food, there was approximately 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 TONMYA 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) [see Use in Specific Populations (8.5) ]. 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 (HI) (Child-Pugh A) and 1 patient with moderate HI (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 HI (1 patient only) and severe HI is not known [see Use in Specific Populations (8.6) ] .

, Mutagenesis, 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 3 of 21 male mice at 10 mg/kg/day (approximately 9 times the maximum recommended human dose (MRHD) of 5.6 mg of TONMYA on a mg/m 2 basis). In a 105-week carcinogenicity study, malignant astrocytoma was seen in 3 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).

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Advise patients to not swallow whole, cut, crush, or chew TONMYA. Advise patients to moisten mouth with sips of water before administration of TONMYA to reduce the risk of oral numbness. Advise patients that if a dose is missed, take the next dose at the regularly scheduled time the following evening. Patients should not take two doses to make up for a missed dose. Advise patients to stop taking TONMYA and to notify their health care provider right away if they experience symptoms of an allergic reaction, such as difficulty breathing, hives, swelling of face or tongue, or itching. Advise patients that TONMYA should not be taken with MAO inhibitors or within 14 days after discontinuation of a MAO inhibitor. Caution patients about the risk of serotonin syndrome with concomitant use of TONMYA and other drugs, such as SSRIs, SNRIs, TCAs, tramadol, bupropion, meperidine, verapamil, or MAO inhibitors. Advise patients of the signs and symptoms of serotonin syndrome [see Warnings and Precautions (5.1) ] and instruct patients to seek medical care immediately if they experience these symptoms. Advise patients to stop taking TONMYA and to notify their health care provider right away if they experience symptoms of arrhythmias or tachycardia. Advise patients that TONMYA may enhance the impairment effects of alcohol. These effects may also be seen if TONMYA is taken with other CNS depressants. Advise patients to report severe oral mucosal adverse reactions to their health care provider. Caution patients about operating a motor vehicle or hazardous machinery until it is reasonably certain that TONMYA therapy will not adversely affect their ability to engage in such activities. Advise patients to take TONMYA at approximately the same time each night. Inform female patients of reproductive potential that TONMYA may cause fetal harm and to inform their healthcare providers of a known or suspected pregnancy [see Use in Specific Populations (8.1) ] . Advise female patients of reproductive potential to use effective contraception during treatment with TONMYA and for two weeks after the final dose [see Use in Specific Populations (8.3) ]. Advise patients who are exposed to TONMYA during pregnancy to contact Tonix Medicines, Inc., at 1-888-869-7633 (1-888-TNXPMED).

TONMYA (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) [see USP Controlled Room Temperature]. Store and dispense in 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.