RIZAFILM

1 INDICATIONS AND USAGE RizaFilmTM is indicated for the acute treatment of migraine with or without aura in adults and in pediatric patients 6 to 17 years of age. Limitations of Use RizaFilm should only be used where a clear diagnosis of migraine has been established. If a patient has no response for the first migraine attack treated with RizaFilm, the diagnosis of migraine should be reconsidered before RizaFilm is administered to treat any subsequent attacks. RizaFilm is not indicated for the preventive treatment of migraine. Safety and effectiveness of RizaFilm have not been established for cluster headache. RizaFilm is a serotonin (5-HT) 1B/1D receptor agonist (triptan) indicated for the acute treatment of migraine with or without aura in adults and in pediatric patients 6 to 17 years of age (1) Limitations of Use : Use only after 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)

2 DOSAGE AND ADMINISTRATION RizaFilm is administered on the tongue (2.1) Adults: 10 mg single dose; separate repeat doses by at least two hours; maximum cumulative dosage in a 24-hour period is 30 mg (2.1) Pediatric patients 6 to 17 years of age: 5 mg single dose in patients less than 40 kg (88 lb); 10 mg single dose in patients 40 kg (88 lb) or more. (2.2) 2.1 Dosing Information in Adults The recommended dose of RizaFilm in adults is 10 mg administered on the tongue. The maximum cumulative dose that may be given in 24 hours is 30 mg, with doses separated by at least 2 hours. The safety of treating, on average, more than four headaches in a 30-day period has not been established. 2.2 Dosing Information in Pediatric Patients (6 to 17 Years of Age) Dosing in pediatric patients is based on the patient's body weight. The recommended dose of RizaFilm is 5 mg in patients weighing less than 40 kg (88 lb), and 10 mg in patients weighing 40 kg (88 lb) or more administered on the tongue. The efficacy and safety of treatment with more than one dose of RizaFilm within 24 hours in pediatric patients 6 to 17 years of age have not been established. 2.3 Administration of RizaFilm Oral Films For RizaFilm oral films, administration with liquid is not necessary. Oral films are packaged individually in child-resistant aluminum pouches with a tear notch. To open the pouch, fold on the dotted line and tear open at the notch. Place the oral film on the tongue, where it will disintegrate within approximately two minutes and can be swallowed with saliva.

3 DOSAGE FORMS AND STRENGTHS RizaFilm 10 mg oral films are white to off-white, rectangular strips of 2.2 cm x 2.75 cm with a blue identifier “RIZA10” on one side. RizaFilm 5 mg oral films are white to off-white, rectangular strips of 1.1 cm x 1.375 cm with a blue identifier “RZ5” on one side. Oral film: 5mg and 10 mg rizatripan. (3)

4 CONTRAINDICATIONS RizaFilm is contraindicated in patients with: Ischemic coronary artery disease (angina pectoris, history of myocardial infarction, or documented silent ischemia), or other significant underlying cardiovascular disease [ see Warnings and Precautions (5.1) ]. 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) [ see Warnings and Precautions (5.4) ]. Peripheral vascular disease (PVD) [ see Warnings and Precautions (5.5) ]. Ischemic bowel disease [ see Warnings and Precautions (5.5) ]. Uncontrolled hypertension [ see Warnings and Precautions (5.9) ]. Recent use (i.e., within 24 hours) of another 5-HT 1 agonist, ergotamine-containing medication, or ergot-type medication (such as dihydroergotamine or methysergide) [ see Drug Interactions (7.2 and 7.3) ]. Hemiplegic or basilar migraine. Concurrent administration or recent discontinuation (i.e., within 2 weeks) of a MAO-A inhibitor [see Drug Interactions (7.5) and Clinical Pharmacology (12.3) ] Concurrent administration of propranolol [see Drug Interactions (7.1) and Clinical Pharmacology (12.3) ] Hypersensitivity to rizatriptan or any ingredients in RizaFilm (angioedema and anaphylaxis seen) [see Warnings and Precautions (5.6) ] History of ischemic heart disease or coronary artery vasospasm (4) History of stroke or transient ischemic attack (4) Wolff-Parkinson-White syndrome or other cardiac accessory conduction pathway disorders (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) Hemiplegic or basilar migraine (4) MAO-A inhibitor used in the past 2 weeks (4) Co-administration with propranolol (4) Hypersensitivity to rizatriptan or any of the ingredients of RizaFilm (4)

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in more detail in other sections of the labeling: Myocardial Ischemia, Myocardial Infarction, and Prinzmetal's Angina [see Warnings and Precautions (5.1) ]. Arrhythmias [see Warnings and Precautions (5.2) ]. Chest and or 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) ]. Hypersensitivity Reactions [see Warnings and Precautions (5.6) ] Medication Overuse Headache [see Warnings and Precautions (5.7) ]. Serotonin Syndrome [see Warnings and Precautions (5.8) ]. Increase in Blood Pressure [see Warnings and Precautions (5.9) ]. The most common adverse reactions in adults were (incidence ≥5% and greater than placebo): asthenia/fatigue, somnolence, pain/pressure sensation, dizziness, and nausea ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Gensco Pharma at 1-866-608-6284 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. The studies described below were conducted with rizatriptan benzoate tablets; adverse reactions with RizaFilm are expected to be similar to rizatriptan benzoate tablets. Adults Incidence in Controlled Clinical Trials Adverse reactions to rizatriptan benzoate were assessed in controlled clinical trials that included over 3700 adult patients who received single or multiple doses of rizatriptan benzoate tablets. The most common adverse reactions during treatment with rizatriptan benzoate (≥5% in either treatment group and greater than placebo) were asthenia/fatigue, somnolence, pain/pressure sensation, dizziness, and nausea. Table 1 lists the adverse reactions (incidence ≥2% and greater than placebo) after a single dose of rizatriptan benzoate in adults. Table 1: Incidence (≥2% and Greater than Placebo) of Adverse Reactions After a Single Dose of Rizatriptan Benzoate Tablets or Placebo in Adults % of Patients Adverse Reactions Rizatriptan Benzoate 5 mg (N=977) % Rizatriptan Benzoate 10 mg (N=1167) % Placebo (N=627) % Atypical Sensations 4 5 4 Paresthesia 3 4 )1/100 patients; infrequent adverse experiences are those occurring in 1/100 to 1/1000 patients; and rare adverse experiences are those occurring in fewer than 1/1000 patients. General: Infrequent was facial edema. Rare were syncope and edema/swelling. Atypical Sensations: Frequent were warm sensations. Cardiovascular: Frequent was palpitation. Infrequent were tachycardia, cold extremities, and bradycardia. Digestive: Frequent were diarrhea and vomiting. Infrequent were dyspepsia, tongue edema and abdominal distention. Musculoskeletal: Infrequent were muscle weakness, stiffness, myalgia and muscle cramp/spasm. Neurological/Psychiatric: Frequent were hypoesthesia, euphoria and tremor. Infrequent were vertigo, insomnia, confusion/disorientation, gait abnormality, memory impairment, and agitation. Respiratory: Frequent was dyspnea. Infrequent was pharyngeal edema. Special Senses: Infrequent were blurred vision and tinnitus. Rare was eye swelling. Skin and Skin Appendage: Frequent was flushing. Infrequent were sweating, pruritus, rash, and urticaria. Rare was erythema, hot flashes. Pediatric Patients 6 to 17 Years of Age Incidence in Controlled Clinical Trials in Pediatric Patients Adverse reactions to rizatriptan benzoate orally disintegrating tablets were assessed in a controlled clinical trial for the acute treatment of migraine (Study 7) that included a total of 1382 pediatric patients (including those 6-17 years of age), of which 977 (72%) were administered at least one dose of study treatment (rizatriptan benzoate orally disintegrati …

7 DRUG INTERACTIONS 7.1 Propranolol Because propranolol increases the exposure of rizatriptan and dosage adjustment is not possible with RizaFilm, concomitant use of RizaFilm with propranolol is contraindicated [see Contraindications (4) and Clinical Pharmacology (12.3) ] . 7.2 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 RizaFilm within 24 hours is contraindicated [ see Contraindications (4) ]. 7.3 Other 5-HT 1 Agonists Because their vasospastic effects may be additive, co-administration of RizaFilm and other 5-HT 1 agonists within 24 hours of each other is contraindicated [ see Contraindications (4) ]. 7.4 SSRIs/SNRIs and Serotonin Syndrome Cases of serotonin syndrome have been reported during co-administration of triptans and selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs) [see Warnings and Precautions (5.7) ] . 7.5 Monoamine Oxidase Inhibitors Because of an increase in the systemic exposure of rizatriptan and its metabolite, RizaFilm is contraindicated in patients taking MAO-A inhibitors and non-selective MAO inhibitors [see Contraindications (4) and Clinical Pharmacology (12.3) ] .

Drug Interactions Monoamine Oxidase Inhibitors: In a drug interaction study, when rizatriptan benzoate 10 mg tablets were administered to subjects (n=12) receiving concomitant therapy with the selective, reversible MAO-A inhibitor, moclobemide 150 mg three times a day, there were mean increases in rizatriptan AUC and C max of 119% and 41%, respectively; and the AUC of the active N-monodesmethyl metabolite of rizatriptan was increased more than 400%. The interaction would be expected to be greater with irreversible MAO inhibitors [see Contraindications (4) and Drug Interactions (7.5) ]. No pharmacokinetic interaction is anticipated in patients receiving selective MAO-B inhibitors. Propranolol: In a study of concurrent administration of propranolol 240 mg/day and a single dose of rizatriptan 10 mg in healthy adult subjects (n=11), mean plasma AUC for rizatriptan was increased by 70%, and a four-fold increase was observed in one subject [see Contraindications (4) and Drug Interactions (7.1) ]. The AUC of the active N-monodesmethyl metabolite of rizatriptan was not affected by propranolol. Nadolol/Metoprolol: In a drug interactions study, effects of multiple doses of nadolol 80 mg or metoprolol 100 mg every 12 hours on the pharmacokinetics of a single dose of 10 mg rizatriptan were evaluated in healthy subjects (n=12). No pharmacokinetic interactions were observed. Paroxetine: In a study of the interaction between the selective serotonin reuptake inhibitor (SSRI) paroxetine 20 mg/day for two weeks and a single dose of rizatriptan benzoate tablet 10 mg in healthy subjects (n=12), neither the plasma concentrations of rizatriptan nor its safety profile were affected by paroxetine [see Warnings and Precautions (5.7) , Drug Interactions (7.4) , and Patient Counseling Information (17) ]. Oral Contraceptives: In a study of concurrent administration of an oral contraceptive during 6 days of administration of rizatriptan (10-30 mg/day) in healthy female volunteers (n=18), rizatriptan did not affect plasma concentrations of ethinyl estradiol or norethindrone.

8 USE IN SPECIFIC POPULATIONS Pregnancy: Based on animal data, may cause fetal harm (8.1) 8.1 Pregnancy Risk Summary Available human data on the use of rizatriptan in pregnant women are not sufficient to draw conclusions about drug-associated risk for major birth defects and miscarriage. In animal studies, developmental toxicity was observed following oral administration of rizatriptan during pregnancy (decreased fetal body weight in rats) or throughout pregnancy and lactation (increased mortality, decreased body weight, and neurobehavioral impairment in rat offspring) at maternal plasma exposures greater than that expected at therapeutic doses in humans [see Animal Data]. 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. The reported rate of major birth defects among deliveries to women with migraine range from 2.2% to 2.9% and the reported rate of miscarriage was 17%, which are similar to rates reported in women without migraine. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk In women with migraine, there is an increased risk of adverse perinatal outcomes in the mother, including pre-eclampsia and gestational hypertension. Data Human Data The Pregnancy Registry for rizatriptan did not identify any pattern of congenital anomalies or other adverse birth outcomes over the period of 1998 to 2018. However, the lack of identification of any pattern should be viewed with caution, as the number of prospective reports with outcome information was low and did not provide sufficient power to detect an increased risk of individual birth defects associated with the use of rizatriptan. Additionally, there was significant loss to follow-up in the prospective pregnancy reports, further complicating this assessment of an association between rizatriptan and any pattern of congenital anomalies or other adverse birth outcomes. 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 157 births with first-trimester exposure to rizatriptan, 7 infants were born with malformations (relative risk 1.01 [95% CI: 0.40 to 2.08]). 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 triptans before pregnancy only, compared with a population control group. Of the 310 women who redeemed prescriptions for rizatriptan during the first trimester, 10 had infants with major congenital malformations (OR 1.03 [95% CI: 0.55 to 1.93]), while for the 271 women who redeemed prescriptions for rizatriptan before but not during pregnancy, 12 had infants with major congenital malformations (OR 1.48 [95% CI: 0.83 to 2.64]), each compared with the population comparison group. Animal Data When rizatriptan (0, 2, 10, or 100 mg/kg/day) was administered orally to pregnant rats throughout organogenesis, a decrease in fetal body weight was observed at the highest doses tested. At the mid-dose (10 mg/kg/day), which was a no-effect dose for adverse effects on embryofetal development, plasma exposure (AUC) was approximately 15 times that in humans at the maximum recommended human dose (MRHD) of 30 mg/day. When rizatriptan (0, 5, 10, or 50 mg/kg/day) was administered orally to pregnant rabbits throughout organogenesis, no adverse fetal effects were observed. Plasma exposure (AUC) at the highest dose tested was 115 times that in humans at the MRHD. Placental transfer of the drug to the fetus was demonstrated in both species. Oral administration of rizatriptan (0, 2, 10, or 100 mg/kg/day) to female rats before and during mating and continuing throughout gestation and lact …

11 DESCRIPTION RizaFilm contains rizatriptan benzoate, a selective 5-hydroxytryptamine 1B/1D (5-HT 1B/1D ) receptor agonist. Rizatriptan benzoate is described chemically as: N,N -dimethyl-5-(1 H -1,2,4-triazol-1-ylmethyl)-1 H- indole-3-ethanamine monobenzoate and its structural formula is: Its empirical formula is C 15 H 19 N 5 •C 7 H 6 O 2 , representing a molecular weight of the free base of 269.4. Rizatriptan benzoate is a white to off-white, crystalline solid that is soluble in water at about 42 mg per mL (expressed as free base) at 25°C. RizaFilm oral film is available for oral administration in a 5 mg and 10 mg strength (equivalent to 7.265 mg and 14.53 mg rizatriptan benzoate respectively). Each oral film contains the following inactive ingredients: ammonium glycyrrhizate, butylated hydroxytoluene, copovidone, cupric chloride, ethylcellulose, FD&C Blue No. 1, hydroxypropyl cellulose, isopropyl alcohol, levomenthol, methyl ethyl ketone, sodium acetate, sucralose, titanium dioxide, and triacetin. structure

10 OVERDOSAGE No overdoses of rizatriptan benzoate were reported during clinical trials in adults. Some adult patients who received 40 mg of rizatriptan benzoate either in a single dose or as two doses with a 2-hour interdose interval had dizziness and somnolence. In a clinical pharmacology study in which 12 adult subjects received rizatriptan benzoate, at total cumulative doses of 80 mg (given within four hours), two of the subjects experienced syncope, dizziness, bradycardia including third degree AV block, vomiting, and/or incontinence. In the long-term, open label study, involving 606 treated pediatric migraineurs 12 to 17 years of age (of which 432 were treated for at least 12 months), 151 patients (25%) took two 10-mg doses of Rizatriptan Benzoate Orally Disintegrating Tablets within a 24-hour period. Adverse reactions for 3 of these patients included abdominal discomfort, fatigue, and dyspnea. In addition, based on the pharmacology of rizatriptan benzoate, hypertension or myocardial ischemia could occur after overdosage. Gastrointestinal decontamination, (i.e., gastric lavage followed by activated charcoal) should be considered in patients suspected of an overdose with RizaFilm. Clinical and electrocardiographic monitoring should be continued for at least 12 hours, even if clinical symptoms are not observed. The effects of hemo- or peritoneal dialysis on serum concentrations of rizatriptan are unknown.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied RizaFilm oral film, 10 mg is a white flexible rectangular strip of 2.2 cm × 2.75 cm with an imprint "RIZA10" in edible blue ink on one side. Each oral film is individually packaged in an aluminum laminate pouch. It is supplied as follows: NDC 35781-0600-8. 1 carton of 18 individually packaged films. RizaFilm oral film, 5 mg is a white flexible rectangular strip of 1.1 cm × 1.375 cm with an imprint "RZ5" in edible blue ink on one side. Each oral film is individually packaged in an aluminum laminate pouch. It is supplied as follows: NDC 35781-0605-8. 1 carton of 18 individually packaged films. 16.2 Storage and Handling Store RizaFilm at room temperature, 20°C to 25°C (68°F to 77°F); excursions permitted from 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Keep product in pouch until ready to use.