Cyclobenzaprine for Neuromuscular Disorders

INDICATIONS AND USAGE Cyclobenzaprine hydrochloride extended-release capsules are indicated as an adjunct to rest and physical therapy for relief of muscle spasm associated with acute, painful musculoskeletal conditions. Improvement is manifested by relief of muscle spasm and its associated signs and symptoms, namely, pain, tenderness, and limitation of motion. Limitations of Use: • Cyclobenzaprine hydrochloride extended-release capsules 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 and because muscle spasm associated with acute, painful musculoskeletal conditions is generally of short duration and specific therapy for longer periods is seldom warranted. • Cyclobenzaprine hydrochloride extended-release capsules have not been found effective in the treatment of spasticity associated with cerebral or spinal cord disease or in children with cerebral palsy. Cyclobenzaprine hydrochloride extended-release capsules are a muscle relaxant indicated as an adjunct to rest and physical therapy for relief of muscle spasm associated with acute, painful musculoskeletal conditions. Improvement is manifested by relief of muscle spasm and its associated signs and symptoms, namely, pain, tenderness, and limitation of motion. ( 1 ) Limitations of Use: • Cyclobenzaprine hydrochloride extended-release capsules should be used only for short periods (up to 2 or 3 weeks) because adequate evidence of effectiveness for more prolonged use is not available and because muscle spasm associated with acute, painful musculoskeletal conditions is generally of short duration and specific therapy for longer periods is seldom warranted. ( 1 ) • Cyclobenzaprine hydrochloride extended-release capsules have not been found effective in the treatment of spasticity associated with cerebral or spinal cord disease or in children with cerebral palsy. ( 1 )

DOSAGE AND ADMINISTRATION 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) ]

WARNINGS AND PRECAUTIONS 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.

Drug Interactions Cyclobenzaprine may have life-threatening interactions with MAO inhibitors (see CONTRAINDICATIONS ). Postmarketing cases of serotonin syndrome have been reported during combined use of cyclobenzaprine hydrochloride and other drugs, such as SSRIs, SNRIs, TCAs, tramadol, bupropion, meperidine, verapamil, or MAO inhibitors. If concomitant treatment with cyclobenzaprine hydrochloride and other serotonergic drugs is clinically warranted, careful observation is advised, particularly during treatment initiation or dose increases (see WARNINGS ). Cyclobenzaprine may enhance the effects of alcohol, barbiturates, and other CNS depressants. Tricyclic antidepressants may block the antihypertensive action of guanethidine and similarly acting compounds. Tricyclic antidepressants may enhance the seizure risk in patients taking tramadol. Carcinogenesis, mutagenesis, impairment of fertility In rats treated with cyclobenzaprine hydrochloride for up to 67 weeks at doses of approximately 5 to 40 times the maximum recommended human dose, pale, sometimes enlarged, livers were noted and there was a dose-related hepatocyte vacuolation with lipidosis. In the higher dose groups this microscopic change was seen after 26 weeks and even earlier in rats which died prior to 26 weeks; at lower doses, the change was not seen until after 26 weeks. Cyclobenzaprine did not affect the onset, incidence or distribution of neoplasia in an 81-week study in the mouse or in a 105-week study in the rat. 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. Cyclobenzaprine did not demonstrate mutagenic activity in the male mouse at dose levels of up to 20 times the human dose. Pregnancy Teratogenic Effects. Pregnancy Category B Reproduction studies have been performed in rats, mice and rabbits at doses up to 20 times the human dose, and have revealed no evidence of impaired fertility or harm to the fetus due to cyclobenzaprine. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Nursing Mothers It is not known whether this drug is excreted in human milk. Because cyclobenzaprine is closely related to the tricyclic antidepressants, some of which are known to be excreted in human milk, caution should be exercised when cyclobenzaprine hydrochloride is administered to a nursing woman. Pediatric Use Safety and effectiveness of cyclobenzaprine in pediatric patients below 15 years of age have not been established. Use in the Elderly The plasma concentration of cyclobenzaprine is increased in the elderly (see CLINICAL PHARMACOLOGY: Pharmacokinetics: Elderly .) The elderly may also be more at risk for CNS adverse events such as hallucinations and confusion, cardiac events resulting in falls or other sequelae, drug-drug and drug-disease interactions. For these reasons, in the elderly, cyclobenzaprine should be used only if clearly needed. In such patients cyclobenzaprine hydrochloride should be initiated with a 5 mg dose and titrated slowly upward.

ADVERSE REACTIONS 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.