Tonmya Drug Information

TONMYA™ is indicated for treatment of fibromyalgia in adults. TONMYA is indicated for the treatment of fibromyalgia in adults.

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.

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.

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.

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.

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.

Pregnancy Testing

Prior to Administration Pregnancy testing is recommended in females of reproductive potential prior to initiating treatment with TONMYA

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. 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 ) 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%).

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 , 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 . 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 Other serotonergic Drugs: Serotonin syndrome has been reported CNS Depressants: CNS depressant effects of alcohol, barbiturates, and other CNS depressants may be enhanced Tramadol: Seizure risk may be enhanced Guanethidine: Antihypertensive effect may be blocked

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.

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

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 Concomitant use of monoamine oxidase (MAO) inhibitors or within 14 days after their discontinuation During acute recovery phase of myocardial infarction and in patients with arrhythmias, heart block or conduction disturbances, or congestive heart failure Hyperthyroidism

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 . 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.