Tosymra

1 INDICATIONS AND USAGE TOSYMRA is indicated for the acute treatment of migraine with or without aura in adults. TOSYMRA is a serotonin (5-HT 1B/1D ) receptor agonist (triptan) indicated for the acute treatment of migraine with or without aura in adults ( 1 ) Limitations of Use : Use only if a clear diagnosis of migraine has been established ( 1 ) Not indicated for the preventive treatment of migraine ( 1 ) Not indicated for the treatment of cluster headache ( 1 ) Limitations of Use : Use only if a clear diagnosis of migraine has been established. If a patient has no response to the first migraine attack treated with TOSYMRA, reconsider the diagnosis before TOSYMRA is administered to treat any subsequent attacks. TOSYMRA is not indicated for the preventive treatment of migraine. TOSYMRA is not indicated for the treatment of cluster headache.

2 DOSAGE AND ADMINISTRATION The recommended dose of TOSYMRA is 10 mg given as a single spray in one nostril. The maximum cumulative dose that may be given in a 24-hour period is 30 mg, with doses of TOSYMRA separated by at least 1 hour. TOSYMRA may also be given at least 1 hour following a dose of another sumatriptan product. Single dose of 10 mg of nasal spray ( 2 ) Maximum dose in a 24-hour period: 30 mg; separate doses by at least one hour ( 2 )

3 DOSAGE FORMS AND STRENGTHS Single-dose nasal spray device delivering 10 mg of sumatriptan. Nasal Spray, 10 mg ( 3 )

4 CONTRAINDICATIONS TOSYMRA is contraindicated in patients with: Ischemic coronary artery disease (CAD) (angina pectoris, history of myocardial infarction, or documented silent ischemia) or coronary artery vasospasm, including Prinzmetal's angina [see Warnings and Precautions (5.1) ] . Wolff-Parkinson-White syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders [see Warnings and Precautions (5.2) ] . History of stroke or transient ischemic attack (TIA) or history of hemiplegic or basilar migraine because these patients are at a higher risk of stroke [see Warnings and Precautions (5.4) ] . Peripheral vascular disease [see Warnings and Precautions (5.5) ] . Ischemic bowel disease [see Warnings and Precautions (5.5) ] . Uncontrolled hypertension [see Warnings and Precautions (5.8) ] . Recent use (i.e., within 24 hours) of ergotamine-containing medication, ergot-type medication (such as dihydroergotamine or methysergide), or another 5-hydroxytryptamine 1 (5-HT 1 ) agonist [see Drug Interactions (7.1 , 7.3) ] . Concurrent administration of a monoamine oxidase (MAO)-A inhibitor or recent (within 2 weeks) use of an MAO-A inhibitor [see Drug Interactions (7.2) and Clinical Pharmacology (12.3) ] . Hypersensitivity to sumatriptan (angioedema and anaphylaxis seen) [see Warnings and Precautions (5.9) ] . Severe hepatic impairment [see Clinical Pharmacology (12.3) ] . History of coronary artery disease or coronary vasospasm ( 4 ) Wolff-Parkinson-White syndrome or other cardiac accessory conduction pathway disorders ( 4 ) History of stroke, transient ischemic attack, or hemiplegic or basilar migraine ( 4 ) Peripheral vascular disease ( 4 ) Ischemic bowel disease ( 4 ) Uncontrolled hypertension ( 4 ) Recent (within 24 hours) use of another 5-HT 1 agonist (e.g., another triptan) or of an ergotamine-containing medication ( 4 ) Concurrent or recent (past 2 weeks) use of monoamine oxidase-A inhibitor ( 4 ) Hypersensitivity to sumatriptan (angioedema and anaphylaxis seen) ( 4 ) Severe hepatic impairment ( 4 )

6 ADVERSE REACTIONS The following serious adverse reactions are described below and elsewhere in the labeling: Myocardial Ischemia, Myocardial Infarction, and Prinzmetal's Angina [see Warnings and Precautions (5.1) ] Arrhythmias [see Warnings and Precautions (5.2) ] Chest, Throat, Neck, and/or Jaw Pain/Tightness/Pressure [see Warnings and Precautions (5.3) ] Cerebrovascular Events [see Warnings and Precautions (5.4) ] Other Vasospasm Reactions [see Warnings and Precautions (5.5) ] Medication Overuse Headache [see Warnings and Precautions (5.6) ] Serotonin Syndrome [see Warnings and Precautions (5.7) ] Increase in Blood Pressure [see Warnings and Precautions (5.8) ] Hypersensitivity Reactions [see Contraindications (4) , Warnings and Precautions (5.9) ] Seizures [see Warnings and Precautions (5.10) ] Local Irritation [see Warnings and Precautions (5.11) ] Most common adverse reactions (≥5% and > placebo) with sumatriptan injection were tingling, dizziness/vertigo, warm/hot sensation, burning sensation, feeling of heaviness, pressure sensation, flushing, feeling of tightness, and numbness ( 6.1 ) Additional common adverse reactions with TOSYMRA include application site reactions, dysgeusia, and throat irritation. ( 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 with rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse Reactions in Placebo-Controlled Trials with Sumatriptan Injection Table 1 lists adverse reactions that occurred in 2 placebo-controlled clinical trials in patients with migraine (Studies 2 and 3) following either a single 6 mg dose of sumatriptan injection or placebo. Only reactions that occurred at a frequency of 2% or more in groups treated with sumatriptan injection 6 mg and that occurred at a frequency greater than the placebo group are included in Table 1. Table 1: Adverse Reactions in Pooled Placebo-Controlled Trials in Patients with Migraine (Studies 2 and 3) Adverse Reaction Sumatriptan Injection 6 mg Subcutaneous (n = 547) % Placebo (n = 370) % Atypical sensations 42 9 Tingling 14 3 Warm/hot sensation 11 4 Burning sensation 7 <1 Feeling of heaviness 7 1 Pressure sensation 7 2 Feeling of tightness 5 <1 Numbness 5 2 Feeling strange 2 <1 Tight feeling in head 2 <1 Cardiovascular Flushing 7 2 Chest discomfort 5 1 Tightness in chest 3 <1 Pressure in chest 2 <1 Ear, nose, and throat Throat discomfort 3 <1 Discomfort: nasal cavity/sinuses 2 <1 Miscellaneous Jaw discomfort 2 0 Musculoskeletal Weakness 5 <1 Neck pain/stiffness 5 <1 Myalgia 2 <1 Neurological Dizziness/vertigo 12 4 Drowsiness/sedation 3 2 Headache 2 <1 Skin Sweating 2 1 The incidence of adverse reactions in controlled clinical trials was not affected by gender or age of the patients. There were insufficient data to assess the impact of race on the incidence of adverse reactions. Adverse Reactions in Studies with TOSYMRA In an open-label study that was designed to evaluate the local tolerability of TOSYMRA, repeated use of TOSYMRA was allowed over the course of 6 months. In this study, local irritative symptoms were reported in approximately 46% of patients treated with TOSYMRA, the most common of which were application site reactions (e.g., burning sensations in the nose), dysgeusia, and throat irritation [see Warnings and Precautions (5.11) ] . 6.2 Post-marketing Experience The following adverse reactions have been identified during post-approval use of sumatriptan tablets, sumatriptan nasal spray, and sumatriptan injection. Because 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 rela …

7 DRUG INTERACTIONS 7.1 Ergot-Containing Drugs Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because these effects may be additive, use of ergotamine-containing or ergot-type medications (like dihydroergotamine or methysergide) and TOSYMRA within 24 hours of each other is contraindicated. 7.2 Monoamine Oxidase-A Inhibitors MAO-A inhibitors increase systemic exposure by 2-fold. Therefore, the use of TOSYMRA in patients receiving MAO-A inhibitors is contraindicated [see Clinical Pharmacology (12.3) ] . 7.3 Other 5-HT 1 Agonists Because their vasospastic effects may be additive, coadministration of TOSYMRA and other 5-HT 1 agonists (e.g., triptans) within 24 hours of each other is contraindicated. 7.4 Selective Serotonin Reuptake Inhibitors/Serotonin Norepinephrine Reuptake Inhibitors and Serotonin Syndrome Cases of serotonin syndrome have been reported during co-administration of triptans and SSRIs, SNRIs, TCAs, and MAO inhibitors [see Warnings and Precautions (5.7) ] .

8 USE IN SPECIFIC POPULATIONS Pregnancy: Based on animal data, may cause fetal harm ( 8.1 ) 8.1 Pregnancy Risk Summary Data from a prospective pregnancy exposure registry and epidemiological studies of pregnant women have not detected an increased frequency of birth defects or a consistent pattern of birth defects among women exposed to sumatriptan compared with the general population (see Data ) . In developmental toxicity studies in rats and rabbits, oral administration of sumatriptan to pregnant animals was associated with embryo lethality, fetal abnormalities, and pup mortality. When administered by the intravenous route to pregnant rabbits, sumatriptan was embryo lethal (see Data ) . In the U.S. general population, the estimated background risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. The reported rate of major birth defects among deliveries to women with migraine ranged from 2.2% to 2.9% and the reported rate of miscarriage was 17%, which were similar to rates reported in women without migraine. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk: Several studies have suggested that women with migraine may be at increased risk of preeclampsia during pregnancy. Data Human Data The Sumatriptan/Naratriptan/Treximet (sumatriptan and naproxen sodium) Pregnancy Registry, a population-based international prospective study, collected data for sumatriptan from January 1996 to September 2012. The Registry documented outcomes of 626 infants and fetuses exposed to sumatriptan during pregnancy (528 with earliest exposure during the first trimester, 78 during the second trimester, 16 during the third trimester, and 4 unknown). The occurrence of major birth defects (excluding fetal deaths and induced abortions without reported defects and all spontaneous pregnancy losses) during first-trimester exposure to sumatriptan was 4.2% (20/478 [95% CI: 2.6% to 6.5%]) and during any trimester of exposure was 4.2% (24/576 [95% CI: 2.7% to 6.2%]). The sample size in this study had 80% power to detect at least a 1.73- to 1.91-fold increase in the rate of major malformations. The number of exposed pregnancy outcomes accumulated during the registry was insufficient to support definitive conclusions about overall malformation risk or for making comparisons of the frequencies of specific birth defects. Of the 20 infants with reported birth defects after exposure to sumatriptan in the first trimester, 4 infants had ventricular septal defects, including one infant who was exposed to both sumatriptan and naratriptan, and 3 infants had pyloric stenosis. No other birth defect was reported for more than 2 infants in this group. In a study using data from the Swedish Medical Birth Register, live births to women who reported using triptans or ergots during pregnancy were compared with those of women who did not. Of the 2,257 births with first-trimester exposure to sumatriptan, 107 infants were born with malformations (relative risk 0.99 [95% CI: 0.91 to 1.21]). A study using linked data from the Medical Birth Registry of Norway to the Norwegian Prescription Database compared pregnancy outcomes in women who redeemed prescriptions for triptans during pregnancy, as well as a migraine disease comparison group who redeemed prescriptions for sumatriptan before pregnancy only, compared with a population control group. Of the 415 women who redeemed prescriptions for sumatriptan during the first trimester, 15 had infants with major congenital malformations (OR 1.16 [95% CI: 0.69 to 1.94]) while for the 364 women who redeemed prescriptions for sumatriptan before, but not during, pregnancy, 20 had infants with major congenital malformations (OR 1.83 [95% CI: 1.17 to 2.88]), each compared with the population comparison group. Additional smaller observational studies evaluating use of sumatriptan during pregnancy have not suggested an increased risk of teratogenicity. A …

12.1 Mechanism of Action Sumatriptan binds with high affinity to human cloned 5-HT 1B/1D receptors. Sumatriptan presumably exerts its therapeutic effects in the treatment of migraine headache through agonist effects at the 5-HT 1B/1D receptors on intracranial blood vessels and sensory nerves of the trigeminal system, which result in cranial vessel constriction and inhibition of pro-inflammatory neuropeptide release.

11 DESCRIPTION TOSYMRA contains sumatriptan, a selective 5-HT 1B/1D receptor agonist. Sumatriptan is chemically designated as 1-[3-[2-(dimethylamino)ethyl]-1H-indol-5-yl]- N -methylmethanesulfonamide, and it has the following structure: The empirical formula is C 14 H 21 N 3 O 2 S, representing a molecular weight of 295.40. Sumatriptan is a white to pale yellow powder that is very slightly soluble in water. TOSYMRA nasal spray is a clear, pale yellow to yellow colored liquid. Each 100 uL of TOSYMRA contains 10 mg of sumatriptan in single-dose aqueous buffered solution containing citric acid monohydrate, n-Dodecyl beta-D-maltoside, potassium phosphate monobasic, sodium chloride, and sodium phosphate dibasic anhydrous in water for injection. The pH range of solution is approximately 5.0 to 6.0 and the osmolality is between 270 to 330 mOsmol. Chemical Structure

10 OVERDOSAGE Coronary vasospasm was observed after intravenous administration of sumatriptan injection [see Contraindications (4) ] . Overdoses would be expected from animal data (dogs at 0.1 g/kg, rats at 2 g/kg) to possibly cause convulsions, tremor, inactivity, erythema of the extremities, reduced respiratory rate, cyanosis, ataxia, mydriasis, injection site reactions (desquamation, hair loss, and scab formation), and paralysis. The elimination half-life of sumatriptan is about 2 hours [see Clinical Pharmacology (12.3) ] , and therefore monitoring of patients after overdose with TOSYMRA should continue for at least 10 hours or while symptoms or signs persist. It is unknown what effect hemodialysis or peritoneal dialysis has on the serum concentrations of sumatriptan.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied TOSYMRA ® 10 mg (NDC 0245-0812-89) contains sumatriptan and is supplied as a ready-to-use, single-dose, disposable unit. Each carton contains 6 units (NDC 0245-0812-61) and a Patient Information and Instructions for Use leaflet. 16.2 Storage and Handling Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F). Do not store in the refrigerator or freezer. Do not test before use.