Cyclobenzaprine Hydrochloride

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

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 )

Embryofetal Toxicity : Based on animal data, TONMYA may cause neural tube defects when used two weeks prior to conception and through the first trimester of pregnancy. Advise females of reproductive potential of the potential risk and to use effective contraception during treatment and for two weeks after the final dose. ( 5.1 , 8.1 , 8.3 ) Serotonin Syndrome: Potentially life-threatening serotonin syndrome has been reported with cyclobenzaprine when used in combination with other drugs. Immediately discontinue concomitant treatment with TONMYA and a serotonergic agent if serotonin syndrome symptoms occur and initiate supportive symptomatic treatment. If concomitant treatment with TONMYA and other serotonergic drugs is clinically warranted, careful observation is advised, particularly during treatment initiation or dosage increases. ( 5.2 ) Tricyclic Antidepressant-like Adverse Reactions: TCAs have been reported to produce arrhythmias, sinus tachycardia, prolongation of the conduction time leading to myocardial infarction and stroke. TCAs lower the seizure threshold, and are associated with serious CNS reactions. If clinically significant CNS symptoms develop, consider discontinuation of TONMYA. ( 5.3 ) Atropine-like Adverse Reactions: Use with caution in patients with a history of urinary retention, angle-closure glaucoma, increased intraocular pressure and in patients taking anticholinergic medications. ( 5.4 ) CNS Depression and Risk of Operating a Motor Vehicle or Hazardous Machinery: TONMYA monotherapy may cause CNS depression. Advise patients not to operate a motor vehicle or other dangerous machinery until they are reasonably certain that TONMYA therapy will not adversely affect their ability to engage in such activities. (5.5) Oral Mucosal Adverse Reactions : In clinical studies, oral mucosal adverse reactions occurred more frequently in TONMYA-treated patients compared to placebo-treated patients. Advise patients to moisten the mouth with sips of water before administration of TONMYA to reduce the risk of oral sensory changes (hypoesthesia). Consider discontinuation of TONMYA if severe reactions occur. ( 5.6 )

5.1 Embryofetal Toxicity Based on data from animal reproduction studies, TONMYA may cause an increased risk of neural tube defects when administered to a pregnant female two 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 TONMYA two weeks prior to conception and through the first trimester of pregnancy. Perform a pregnancy test prior to initiation of treatment with TONMYA to exclude use of TONMYA during the first trimester of pregnancy. Advise females of reproductive potential to use effective contraception during TONMYA treatment and for two weeks after the final dose [see Use in Specific Populations (8.1 , 8.3) ].

5.2 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 (TCAs), tramadol, bupropion, meperidine, verapamil, or MAO inhibitors. The concomitant use of TONMYA with MAO inhibitors is contraindicated [see Contraindications (4) ] . Serotonin syndrome 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). Treatment with TONMYA 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 TONMYA and other serotonergic drugs is clinically warranted, careful observation is advised, particularly during treatment initiation or dosage increases.

5.3 Tricyclic Antidepressant-like Adverse Reactions Cyclobenzaprine is structurally related to tricyclic antidepressants (TCAs). TCAs have been reported to produce arrhythmias, sinus tachycardia, prolongation of the conduction time leading to myocardial infarction and stroke [see Contraindications (4) ] . Some of the more TCA-associated serious central nervous system (CNS) reactions have occurred in short-term studies of oral cyclobenzaprine. If clinically significant CNS symptoms develop, consider discontinuation of TONMYA. Caution should be used when TCAs are given to patients with a history of seizure disorder, because TCAs may lower the seizure threshold. Patients with a history of seizures should be monitored during TCA use to identify recurrence of seizures or increase in frequency of seizures.

5.4 Atropine-like Adverse Reactions Because of its atropine-like action, TONMYA 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. 5.5 CNS Depression and Risk of Operating a Motor Vehicle or Hazardous Machinery TONMYA monotherapy may cause CNS depression and concomitant use of TONMYA with alcohol, barbiturates, or other CNS depressants may increase the risk of CNS depression [see Drug Interactions (7) ]. Symptoms of CNS depression include somnolence. Advise patients not to operate a motor vehicle or dangerous machinery until they are reasonably certain that TONMYA therapy will not adversely affect their ability to engage in such activities.

5.6 Oral Mucosal Adverse Reactions Oral mucosal adverse reactions, including sensory changes (e.g., numbness, tingling), discomfort, pain, irritation, inflammation, and lesions, occurred more frequently in patients treated with TONMYA compared to placebo (43% vs. 8%) [see Adverse Reactions (6.1) ]. 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 TONMYA was discontinued and no treatment was required. Advise patients to moisten the mouth with sips of water before administration of TONMYA 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 TONMYA if severe reactions occur.

The following clinically significant reactions are described in greater detail, in other sections of this labeling: Embryofetal Toxicity [see Warnings and Precautions (5.1) ] Serotonin Syndrome [see Warnings and Precautions (5.2) ] Tricyclic Antidepressant-like Adverse Reactions [see Warnings and Precautions (5.3) ] Atropine-like Adverse Reactions [see Warnings and Precautions (5.4) ] CNS Depression [see Warnings and Precautions (5.5) ] Oral Mucosal Adverse Reactions [see Warnings and Precautions (5.6) ] Most common adverse reactions (incidence ≥2% and at a higher incidence in TONMYA-treated patients compared to placebo-treated patients): oral hypoesthesia, oral discomfort, abnormal product taste, somnolence, oral paresthesia, oral pain, fatigue, dry mouth, and aphthous ulcer ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Tonix Medicines, Inc. at 1-888-869-7633 (1-888-TNXPMED) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 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 TONMYA (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 [see Clinical Studies (14) ]. A total of 1,182 patients completed at least 14 weeks of daily treatment, including 580 TONMYA-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 TONMYA-treated patients and at a higher incidence in TONMYA-treated patients compared to placebo-treated patients). Table 1: Adverse Reactions Reported in ≥2% of TONMYA-Treated Patients and a Higher Incidence than Placebo-Treated Patients in Adult Patients with Fibromyalgia (Trials 1, 2, and 3) Adverse Reactions Placebo (N = 739) TONMYA (N = 735) Oral hypoesthesia Oral hypoesthesia includes hypoesthesia and teeth hypoesthesia 0.7% 23% Oral discomfort Oral discomfort includes tongue discomfort 0.7% 9% Abnormal product taste 0.7% 9% Somnolence Somnolence includes hypersomnia, lethargy, and sedation 2% 6% Oral paresthesia Oral paresthesia includes paresthesia and teeth hyperesthesia 0.4% 6% Oral pain Oral pain includes glossodynia 1% 5% Fatigue Fatigue includes asthenia and lethargy 2% 4% Dry mouth Dry mouth includes dry throat 2% 3% Aphthous ulcer 0.5% 2% Oral Mucosal Adverse Reactions in Trials 1, 2, and 3 In Trials 1, 2, and 3, 43% of TONMYA-treated patients compared to 8% of placebo-treated patients experienced at least 1 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 TONMYA-treated patients) experienced severe oral mucosal adverse reactions, including paresthesia, glossitis, hypoesthesia, oral pain, and dry mouth. Most reactions resolved within days after TONMYA was discontinued. Oral mucosal adverse reactions leading to discontinuation occurred more frequently in TONMYA-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 TONMYA once daily (maximum recommended dosage) or placebo, 56 patients were treated with 5.6 mg of TONMYA for at least 1 year. The most common adverse reactions in the TONMYA-treated patients (>5%) were oral hypoesthesia (45%), somnolence (18%), abnormal product taste (7%), and paresthesia oral (7%). In an open-label, long-term 52 week safety trial of adult patients with fibromyalgia previously been exposed to 2.8 mg TONMYA once daily (one half the recommended dosage [see Dosage and Administration (2.1)] ) or placebo (Trial 5), 97 patients were treated for at least 1 year with 2.8 mg of TONMYA once daily. The most common adverse reactions (>5%) in the TONMYA-treated patients were hypoesthesia oral (15%), fatigue (7%), sinusitis (7%), and abnormal product taste (6%).

6.2 Postmarketing Experience The following adverse reactions have been reported in clinical studies or postmarketing experience with cyclobenzaprine immediate-release (IR) products, cyclobenzaprine extended-release (ER) products, or TCAs. 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 IR 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 ER products or cyclobenzaprine IR products, in clinical studies of cyclobenzaprine IR products (incidence <1%), or in postmarketing experience with other TCAs: 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 urinary tract; impotence; testicular swelling; gynecomastia; breast enlargement; galactorrhea.

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 )

Hepatic impairment: The use of TONMYA is not recommended in patients with moderate HI (Child Pugh B) or severe HI (Child Pugh C) ( 2.3 , 8.6 ).

8.1 Pregnancy 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.

8.2 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 TONMYA and any potential adverse effects on the breastfed child from TONMYA or from the underlying maternal condition.

8.3 Females and Males of Reproductive Potential Based on animal data, TONMYA may cause neural tube defects at clinically relevant doses. Females of reproductive potential should avoid use of TONMYA two weeks prior to conception through the first trimester of pregnancy [see Use in Specific Populations (8.1) ]. Pregnancy Testing Pregnancy testing is recommended for females of reproductive potential prior to initiation of treatment with TONMYA. Contraception Females Advise female patients of reproductive potential to use effective contraception during treatment with TONMYA and for two weeks after the final dose.

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

8.5 Geriatric Use 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) ].

8.6 Hepatic Impairment The recommended dosage of TONMYA in patients with mild hepatic impairment (HI) (Child Pugh A) is 2.8 mg once daily at bedtime, lower than the recommended dosage in patients with normal hepatic function [see Dosage and Administration (2.2) ]. The use of TONMYA is not recommended in patients with moderate HI (Child Pugh B) or severe HI (Child Pugh C). Cyclobenzaprine exposure (AUC) was increased in patients with mild HI and moderate HI compared to subjects with normal hepatic function [see Clinical Pharmacology (12.3) ] , which may increase the risk of TONMYA-associated adverse reactions.

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.