RIZAFILM

1 INDICATIONS AND USAGE RizaFilm™ is indicated for the acute treatment of migraine with or without aura in adults and in pediatric patients 12 to 17 years of age weighing 40 kg or more. 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 12 to 17 years of age weighing 40 kg or more (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)

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 10 mg (N=1167) Placebo (N=627) Atypical Sensations 5 4 Paresthesia 4 <2 Pain and other Pressure Sensations 9 3 Chest Pain: tightness/pressure and/or heaviness 3 1 Pain, location unspecified 3 <2 Neck/throat/jaw: pain/tightness/pressure 2 1 Regional Pain: tightness/pressure and/or heaviness 2 0 Digestive 13 8 Nausea 6 4 Dry Mouth 3 1 Neurological 20 11 Dizziness 9 5 Somnolence 8 4 Headache 2 <1 Other Asthenia/fatigue 7 2 The frequencies of adverse reactions in clinical trials did not increase when up to three doses were taken within 24 hours. Adverse reaction frequencies were also unchanged by concomitant use of drugs commonly taken for migraine prophylaxis, oral contraceptives, or analgesics. The incidences of adverse reactions were not affected by age or gender. There were insufficient data to assess the impact of race on the incidence of adverse reactions. Other Events Observed in Association with the Administration of Rizatriptan Benzoate in Adults In the following section, the frequencies of less commonly reported adverse events are presented that were not reported in other sections of the labeling. Because the reports include events observed in open studies, the role of rizatriptan benzoate in their causation cannot be reliably determined. Furthermore, variability associated with adverse event reporting, the terminology used to describe adverse events, limit the value of the quantitative frequency estimates provided. Event frequencies are calculated as the number of patients who used rizatriptan benzoate and reported an event divided by the total number of patients exposed to rizatriptan benzoate (N=3716). All reported events occurred at an incidence ≥1%, or are believed to be reasonably associated with the use of the drug. Events are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse events are those defined as those occurring in at least (>)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 12 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 12-17 years of age), of which 977 (72%) were administered at least one dose of study treatment (rizatriptan benzoate orally disintegrating tablets and/or placebo) [see Clinical Studies (14.2) ]. The incidence of adverse reactions reported for pediatric patients in the acute clinical trial was similar in patients who received rizatriptan benzoate tablets to those who received placebo. The adverse reaction pattern in pediatric patients is expected to be similar to that in adults. Other Events Observed in Association with the Administration of Rizatriptan Benzoate Orally Disintegrating Tablets in Pediatric Patients In the following section, the frequencies of less commonly reported adverse events are presented. Because the reports include events observed in open studies, the role of rizatriptan benzoate orally disintegrating tablets in their causation cannot be reliably determined. Furthermore, variability associated with adverse event reporting, the terminology used to describe adverse events, limit the value of the quantitative frequency estimates provided. Event frequencies are calculated as the number of pediatric patients (including those 12 to 17 years of age) who used rizatriptan benzoate orally disintegrating tablets and reported an event divided by the total number of patients exposed to rizatriptan benzoate orally disintegrating tablets (N=1068). All reported events occurred at an incidence ≥1%, or are believed to be reasonably associated with the use of the drug. Events are further classified within system organ class and enumerated in order of decreasing frequency using the following definitions: frequent adverse events are those occurring in (>)1/100 pediatric patients; infrequent adverse experiences are those occurring in 1/100 to 1/1000 pediatric patients, and rare adverse experiences are those occurring in fewer than 1/1000 patients. General: Frequent was fatigue. Ear and labyrinth disorders: Infrequent was hypoacusis. Gastrointestinal disorders: Frequent was abdominal discomfort. Nervous system disorders: Infrequent were coordination abnormal, disturbance in attention, and presyncope. Psychiatric disorders: Infrequent was hallucination. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of rizatriptan. 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 relationship to drug exposure. Neurological/Psychiatric: Seizure. General: Allergic conditions including anaphylaxis/anaphylactoid reaction, angioedema, wheezing, and toxic epidermal necrolysis [see Contraindications (4) ]. Special Senses: Dysgeusia.

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)

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 10 mg strength (equivalent to 14.53 mg rizatriptan benzoate). 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

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 12 to 17 years of age weighing 40 kg or more: 10 mg single dose (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 (12 to 17 Years of Age) The recommended dose of RizaFilm in patients weighing 40 kg or more is 10 mg administered on the tongue. The efficacy and safety of treatment with more than one dose of RizaFilm within 24 hours in pediatric patients 12 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.

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.

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) ] .

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Rizatriptan binds with high affinity to human cloned 5-HT 1B/1D receptors. RizaFilm presumably exerts its therapeutic effects in the treatment of migraine headache by binding to 5-HT 1B/1D receptors located on intracranial blood vessels and sensory nerves of the trigeminal system. 12.2 Pharmacodynamics Blood Pressure: Significant elevation in blood pressure, including hypertensive crisis, has been reported in patients treated with rizatriptan, with and without a history of hypertension [see Warnings and Precautions (5.9) ]. 12.3 Pharmacokinetics Absorption Rizatriptan is completely absorbed following oral administration. The mean oral absolute bioavailability of the rizatriptan benzoate tablet is about 45% and mean peak plasma concentrations (C max ) are reached in approximately 1-1.5 hours (T max ). The presence of a migraine headache did not appear to affect the absorption or pharmacokinetics of rizatriptan. Food has no significant effect on the bioavailability of rizatriptan but delays the time to reach peak concentration by an hour. In clinical trials, rizatriptan benzoate tablets were administered without regard to food. The bioavailability and C max of rizatriptan were similar following administration of rizatriptan benzoate tablets and rizatriptan benzoate orally disintegrating tablets, but the rate of absorption is somewhat slower with the orally disintegrating tablets, with T max delayed by up to 0.7 hour. AUC of rizatriptan is approximately 30% higher in females than in males. No accumulation occurred on multiple dosing. Following a single dose of 10mg RizaFilm, the mean C max and AUC inf of rizatriptan were 23.79 (± 8.36) ng/mL and 84.54 (± 18.65) ng·hr/mL, respectively; the maximum peak plasma concentrations were achieved in 1.4 hours. Distribution The mean volume of distribution is approximately 140 liters in male subjects and 110 liters in female subjects. Rizatriptan is minimally bound (14%) to plasma proteins. Metabolism The primary route of rizatriptan metabolism is via oxidative deamination by monoamine oxidase-A (MAO-A) to the indole acetic acid metabolite, which is not active at the 5-HT1B/1D receptor. N-monodesmethyl-rizatriptan, a metabolite with activity similar to that of parent compound at the 5-HT 1B/1D receptor, is formed to a minor degree. Plasma concentrations of N-monodesmethyl-rizatriptan are approximately 14% of those of parent compound, and it is eliminated at a similar rate. Other minor metabolites, the N-oxide, the 6-hydroxy compound, and the sulfate conjugate of the 6-hydroxy metabolite are not active at the 5-HT 1B/1D receptor. Elimination The total radioactivity of the administered dose recovered over 120 hours in urine and feces was 82% and 12%, respectively, following a single 10-mg oral administration of 14 C-rizatriptan. Following oral administration of 14 C-rizatriptan, rizatriptan accounted for about 17% of circulating plasma radioactivity. Approximately 14% of an oral dose is excreted in urine as unchanged rizatriptan while 51% is excreted as indole acetic acid metabolite, indicating substantial first-pass metabolism. Following administration of RizaFilm, the mean plasma half-life of rizatriptan is 2 hours. Cytochrome P450 Isoforms Rizatriptan is not an inhibitor of the activities of human liver cytochrome P450 isoforms 3A4/5, 1A2, 2C9, 2C19, or 2E1; rizatriptan is a competitive inhibitor (Ki =1400 nM) of cytochrome P450 2D6, but only at high, clinically irrelevant concentrations. Specific Populations Geriatric: Rizatriptan pharmacokinetics in healthy elderly non-migraineur volunteers (age 65-77 years) were similar to those in younger non-migraineur volunteers (age 18-45 years). Pediatric : The pharmacokinetics of rizatriptan was determined in pediatric migraineurs 12 to 17 years of age. Exposures following single-dose administration of 10 mg rizatriptan benzoate orally disintegrating tablets to pediatric patients weighing ≥40 kg (88 lb) were similar to those observed following single-dose administration of 10 mg rizatriptan benzoate orally disintegrating tablets to adults. Gender: The mean AUC 0-∞ and C max of rizatriptan (10 mg orally) were about 30% and 11% higher in females as compared to males, respectively, while Tmax occurred at approximately the same time. Patients with Hepatic Impairment: Following oral administration in patients with hepatic impairment caused by mild to moderate alcoholic cirrhosis of the liver, plasma concentrations of rizatriptan were similar in patients with mild hepatic insufficiency compared to a control group of subjects with normal hepatic function; plasma concentrations of rizatriptan were approximately 30% greater in patients with moderate hepatic insufficiency. Patients with Renal Impairment: In patients with renal impairment (creatinine clearance 10-60 mL/min/1.73 m 2 ), the AUC 0-∞ of rizatriptan was not significantly different from that in subjects with normal renal function. In hemodialysis patients, (creatinine clearance <2 mL/min/1.73 m2), however, the AUC for rizatriptan was approximately 44% greater than that in patients with normal renal function. Race: Pharmacokinetic data revealed no significant differences between African American and Caucasian subjects. 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.

20240110

4

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. Oral film: 10 mg rizatripan. (3)

RIZAFILM rizatriptan benzoate SUCRALOSE LEVOMENTHOL TRIACETIN AMMONIUM GLYCYRRHIZATE COPOVIDONE HYDROXYPROPYL CELLULOSE (90000 WAMW) TITANIUM DIOXIDE BUTYLATED HYDROXYTOLUENE ISOPROPYL ALCOHOL METHYL ETHYL KETONE ETHYLCELLULOSE, UNSPECIFIED SODIUM ACETATE FD&C BLUE NO. 1 CUPRIC CHLORIDE RIZATRIPTAN BENZOATE RIZATRIPTAN RIZA10

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Oral carcinogenicity studies were conducted in mice (100 weeks) and rats (106 weeks) at doses of up to 125 mg/kg/day. Plasma exposures (AUC) at the highest dose tested were approximately 150 (mice) and 240 times (rats) that in humans at the maximum recommended daily dose (MRDD) of 30 mg/day. There was no evidence of an increase in tumor incidence related to rizatriptan in either species. Mutagenesis Rizatriptan was neither mutagenic nor clastogenic in a battery of in vitro and in vivo genetic toxicity studies, including the microbial mutagenesis (Ames) assay, in vitro mammalian cell mutagenesis and chromosomal aberration assays, and the in vivo chromosomal aberration assay in mouse. Impairment of Fertility In a fertility study in rats, altered estrus cyclicity and delays in time to mating were observed in females treated orally with 100 mg/kg/day rizatriptan. The no-effect dose was 10 mg/kg/day (approximately 15 times the human exposure at the MRDD). There were no other fertility-related effects in the female rats. There was no impairment of fertility or reproductive performance in male rats treated with up to 250 mg/kg/day (approximately 550 times the human exposure at the MRDD).

NDA205394

RIZAFILM

rizatriptan benzoate

35781-0600

HUMAN PRESCRIPTION DRUG

ORAL

PRINCIPAL DISPLAY PANEL - 1 pouch and carton box with 18 pouches NDC 35781-0600-1 RizaFilm [rizatriptan] oral film 10 mg 1 Film Rx only Gensco Pharma NDC 35781-0600-8 18 Films RizaFilm [rizatriptan] oral film 10 mg Rx only Contains 10mg rizatriptan equivalent to 14.53mg rizatriptan benzoate Gensco Pharma Pouch of 1 film Carton of 18 films

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information) . Administration Instructions Advise patients to fold the pouch on the dotted line and tear open at the notch. Inform patients that administration with liquids is not necessary. Direct patients to place RizaFilm oral film on the tongue, where it will disintegrate and be swallowed with saliva [see Dosage and Administration (2.3) ]. Risk of Myocardial Ischemia and/or Infarction, Prinzmetal's Angina, Other Vasospasm-Related Events, and Cerebrovascular Events Inform patients that RizaFilm may cause serious cardiovascular side effects such as myocardial infarction or stroke. Although serious cardiovascular events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and should ask for medical advice when observing any indicative signs or symptoms. Patients should be apprised of the importance of this follow-up [see Warnings and Precautions (5.1 , 5.2 , 5.4 , 5.5 ) ]. Serotonin Syndrome Patients should be cautioned about the risk of serotonin syndrome with the use of RizaFilm or other triptans, particularly during combined use with selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs) [ see Warnings and Precautions (5.7) , Drug Interactions (7.4) , and Clinical Pharmacology (12.3) ]. Pregnancy Advise patients to notify their healthcare provider if they become pregnant during treatment or plan to become pregnant [ see Use in Specific Populations (8.1) ]. Lactation Advise patients to notify their healthcare provider if they are breastfeeding or plan to breastfeed [see Use in Specific Populations (8.2) ]. Ability To Perform Complex Tasks Since migraines or treatment with RizaFilm may cause somnolence and dizziness, instruct patients to evaluate their ability to perform complex tasks during migraine attacks and after administration of RizaFilm. Hypersensitivity Reactions Inform patients that hypersensitivity reactions, including angioedema and anaphylaxis, have occurred in patients receiving rizatriptan. Inform patients that such reactions can be life threatening or fatal and to seek immediate medical attention if they have anaphylactic symptoms [see Warnings and Precautions (5.6) ]. Medication Overuse Headache Inform patients that use of acute migraine drugs for 10 or more days per month may lead to an exacerbation of headache and encourage patients to record headache frequency and drug use (e.g., by keeping a headache diary) [ see Warnings and Precautions (5.7) ].

14 CLINICAL STUDIES The studies described below establishing effectiveness for the acute treatment of migraine with or without aura were conducted with rizatriptan benzoate tablets. The efficacy of RizaFilm is based on a relative bioavailability study comparing RizaFilm 10 mg oral film to rizatriptan benzoate 10 mg tablets [see Clinical Pharmacology (12.3) ]. 14.1 Adults The efficacy of rizatriptan benzoate tablets was established in four multicenter, randomized, placebo-controlled trials. Patients enrolled in these studies were primarily female (84%) and Caucasian (88%), with a mean age of 40 years (range of 18 to 71). Patients were instructed to treat a moderate to severe headache. Headache response, defined as a reduction of moderate or severe headache pain to no or mild headache pain, was assessed for up to 2 hours (Study 1) or up to 4 hours after dosing (Studies 2, 3, and 4). Associated symptoms of nausea, photophobia, and phonophobia and maintenance of response up to 24 hours post-dose were evaluated. A second dose of rizatriptan benzoate tablets was allowed 2 to 24 hours after dosing for treatment of recurrent headache in Studies 1 and 2. Additional analgesics and/or antiemetics were allowed 2 hours after initial treatment for rescue in all four studies. In all studies, the percentage of patients achieving headache response 2 hours after treatment was significantly greater in patients who received rizatriptan 10 mg compared to those who received placebo. Doses greater than 10 mg were associated with an increased incidence of adverse effects. The results from the four controlled studies are summarized in Table 2. Table 2: Response Rates 2 Hours Following Treatment of Initial Headaches in Studies 1, 2, 3, and 4 Study Placebo Rizatriptan tablets 10mg 1 35% (n=304) 71% *(n=456) 2** 37% (n=82) 77% *(n=320) 3 23% (n=80) - 4 40% (n=159) 67%*(n=385) * p-value <0.05 in comparison with placebo. **Results for initial headache only. Comparisons of drug performance based upon results obtained in different clinical trials may not be reliable. Because studies are conducted at different times, with different samples of patients, by different investigators, employing different criteria and/or different interpretations of the same criteria, under different conditions (dose, dosing regimen, etc.), quantitative estimates of treatment response and the timing of response may be expected to vary considerably from study to study. The estimated probability of achieving an initial headache response within 2 hours following treatment in pooled Studies 1, 2, 3, and 4 is depicted in Figure 1. Figure 1: Estimated Probability of Achieving an Initial Headache Response by 2 Hours in Pooled Studies 1, 2, 3, and 4* * Figure 1 shows the Kaplan-Meier plot of the probability over time of obtaining headache response (no or mild pain) following treatment with rizatriptan benzoate tablets or placebo. The averages displayed are based on pooled data from 4 placebo-controlled, outpatient trials providing evidence of efficacy (Studies 1, 2, 3, and 4). Patients taking additional treatment or not achieving headache response before 2 hours were censored at 2 hours. For patients with migraine-associated photophobia, phonophobia, and nausea at baseline, there was a decreased incidence of these symptoms following administration of rizatriptan benzoate tablets compared to placebo. Two to 24 hours following the initial dose of study treatment, patients were allowed to use additional treatment for pain response in the form of a second dose of study treatment or other medication. The estimated probability of patients taking a second dose or other medication for migraine over the 24 hours following the initial dose of study treatment is summarized in Figure 2. Figure 2: Estimated Probability of Patients Taking a Second Dose of Rizatriptan Benzoate Tablets or Other Medication for Migraines Over the 24 Hours Following the Initial Dose of Study Treatment in Pooled Studies 1, 2, 3, and 4* * This Kaplan-Meier plot is based on data obtained in 4 placebo-controlled outpatient clinical trials (Studies 1, 2, 3, and 4). Patients not using additional treatments were censored at 24 hours. The plot includes both patients who had headache response at 2 hours and those who had no response to the initial dose. Remedication was not allowed within 2 hours post-dose. Efficacy was unaffected by the presence of aura; by the gender, or age of the patient; or by concomitant use of common migraine prophylactic drugs (e.g., beta-blockers, calcium channel blockers, tricyclic antidepressants) or oral contraceptives. In two additional similar studies, efficacy was unaffected by relationship to menses. There were insufficient data to assess the impact of race on efficacy. figure1 figure2 Rizatriptan Benzoate Orally Disintegrating Tablets The efficacy of rizatriptan benzoate orally disintegrating tablets was established in two multicenter, randomized, placebo-controlled trials that were similar in design to the trials of rizatriptan benzoate tablets (Studies 5 and 6). Patients were instructed to treat a moderate to severe headache. Patients treated in these studies were primarily female (88%) and Caucasian (95%), with a mean age of 42 years (range 18-72). In both studies, the percentage of patients achieving headache response 2 hours after treatment was significantly greater in patients who received rizatriptan benzoate orally disintegrating tablets 10 mg compared to those who received placebo. The results from Studies 5 and 6 are summarized in Table 3. Table 3: Response Rates 2 Hours Following Treatment of Initial Headache in Studies 5 and 6 Study Placebo Rizatriptan orally disintegrating tablets 10mg 5 47% (n=98) 66%*(n=113) 6 28% (n=180) 74%*(n=186) *p-value <0.01 in comparison with placebo The estimated probability of achieving an initial headache response by 2 hours following treatment with rizatriptan benzoate orally disintegrating tablets in pooled Studies 5 and 6 is depicted in Figure 3. Figure 3: Estimated Probability of Achieving an Initial Headache Response with Rizatriptan Benzoate Orally Disintegrating Tablets by 2 Hours in pooled Studies 5 and 6* * Figure 3 shows the Kaplan-Meier plot of the probability over time of obtaining headache response (no or mild pain) following treatment with rizatriptan benzoate orally disintegrating tablets or placebo. The averages displayed are based on pooled data from 2 placebo-controlled, outpatient trials providing evidence of efficacy (Studies 5 and 6). Patients taking additional treatment or not achieving headache response before 2 hours were censored at 2 hours. For patients with migraine-associated photophobia and phonophobia at baseline, there was a decreased incidence of these symptoms following administration of rizatriptan benzoate orally disintegrating tablets as compared to placebo. Two to 24 hours following the initial dose of study treatment, patients were allowed to use additional treatment for pain response in the form of a second dose of study treatment or other medication. The estimated probability of patients taking a second dose or other medication for migraine over the 24 hours following the initial dose of study treatment is summarized in Figure 4. Figure 4: Estimated Probability of Patients Taking a Second Dose of Rizatriptan Benzoate Orally Disintegrating Tablets or Other Medication for Migraines Over the 24 Hours Following the Initial Dose of Study Treatment in Pooled Studies 5 and 6* * This Kaplan-Meier plot is based on data obtained in 2 placebo-controlled outpatient clinical trials (Studies 5 and 6). Patients not using additional treatments were censored at 24 hours. The plot includes both patients who had headache response at 2 hours and those who had no response to the initial dose. Remedication was not allowed within 2 hours post-dose. figure3 figure4 14.2 Pediatric Patients 12 to 17 Years of Age The efficacy of rizatriptan benzoate orally disintegrating tablets in pediatric patients 12 to 17 years of age was evaluated in a multicenter, randomized, double-blind, placebo-controlled, parallel-group clinical trial (Study 7). Patients had to have at least a 6-month history of migraine attacks (with or without aura) usually lasting 3 hours or more (when untreated). The patient population was historically non-responsive to NSAIDs and acetaminophen therapy. Patients were instructed to treat a single migraine attack with headache pain of moderate to severe intensity. The treatment phase of the study had two stages. Stage 1 was used to identify placebo non-responders, who then entered into Stage 2, in which patients were randomized to rizatriptan benzoate orally disintegrating tablets or placebo. Using a weight-based dosing strategy, patients 12 to 17 years of age and weighing greater than or equal to 40 kg received rizatriptan benzoate orally disintegrating tablets 10 mg or placebo. Of the total pediatric population in Study 7, including those weighing 40 kg or more, sixty-one percent of the patients were Caucasian, and fifty-six percent of the patients were female. The percentage of patients achieving the primary efficacy endpoint of no headache pain at 2 hours after treatment was significantly greater in patients who received rizatriptan benzoate orally disintegrating tablets, compared with those who received placebo (33% vs. 24%). Study 7 results are summarized in Table 4. Table 4: Response Rates 2 Hours Following Treatment of Initial Headache in Pediatric Patients (including 12 to 17 Years of Age) in Study 7 Endpoint Placebo Rizatriptan orally disintegrating tablets p-Value No headache pain at 2 hours post-dose 24% (n/m = 94/388) 33% (n/m = 126/382) 0.01 n = Numbr of evaluable patients with no headache pain at 2 hours post dose.m = Number of evaluable patients in population. The observed percentage of pediatric patients achieving no headache pain within 2 hours following initial treatment with rizatriptan benzoate orally disintegrating tablets is shown in Figure 5. Figure 5: Observed Percentage of Patients Reporting No Headache Pain by 2 Hours Post Dose in Study 7 The prevalence of the exploratory endpoints of absence of migraine-associated symptoms (nausea, photophobia, and phonophobia) at 2 hours after taking the dose was not statistically significantly different between patients who received rizatriptan benzoate orally disintegrating tablets and those who received placebo. figure5

8.5 Geriatric Use Clinical studies of rizatriptan benzoate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. The pharmacokinetics of rizatriptan were similar in elderly (aged ≥65 years) and younger adults (n=17) [see Clinical Pharmacology (12.3) ]. Geriatric patients who have cardiovascular risk factors (e.g., diabetes, hypertension, smoking, obesity, strong family history of coronary artery disease) should have a cardiovascular evaluation before receiving RizaFilm [see Warnings and Precautions (5.1) ].

8.2 Lactation Risk Summary There are no data on the presence of rizatriptan or any active metabolites in human milk or on the effects of rizatriptan on the breastfed infant, or milk production. Rizatriptan was excreted in rat milk, with levels in milk approximately 6 times those in maternal plasma. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for RizaFilm and any potential adverse effects on the breastfed infant from RizaFilm or the underlying maternal condition. Data Following oral administration of rizatriptan to lactating rats at a dose of 100 mg/kg/day, the drug concentrations of rizatriptan in milk samples exceeded maternal plasma drug concentrations by approximately 6-fold.

8.4 Pediatric Use The safety and effectiveness of RizaFilm for the acute treatment of migraine have been established in pediatric patients 12 years of age and older weighing 40 kg or more based on an adequate and well-controlled study with rizatriptan benzoate tablets [see Clinical Studies (14.2) ]. The incidence of adverse reactions reported for pediatric patients in the acute clinical trial was similar in patients who received rizatriptan benzoate tablets to those who received placebo. The adverse reaction pattern in pediatric patients is expected to be similar to that in adults. Safety and effectiveness of RizaFilm in pediatric patients under 12 years of age and weighing less than 40 kg have not been established.

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 lactation resulted in reduced body weight in offspring from birth and throughout lactation at all but the lowest dose tested (2 mg/kg/day). Plasma exposure (AUC) at the no-effect dose (2 mg/kg/day) for adverse effects on postnatal development was similar to that in humans at the MRHD. Oral administration of rizatriptan (0, 5, 100, or 250 mg/kg/day) throughout organogenesis and lactation resulted in neonatal mortality, reduced body weight (which persisted into adulthood), and impaired neurobehavioral function in offspring at all but the lowest dose tested. Plasma exposure (AUC) at the no-effect dose for adverse effects on postnatal development (5 mg/kg/day) was approximately 8 times that in humans at the MRHD.

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 lactation resulted in reduced body weight in offspring from birth and throughout lactation at all but the lowest dose tested (2 mg/kg/day). Plasma exposure (AUC) at the no-effect dose (2 mg/kg/day) for adverse effects on postnatal development was similar to that in humans at the MRHD. Oral administration of rizatriptan (0, 5, 100, or 250 mg/kg/day) throughout organogenesis and lactation resulted in neonatal mortality, reduced body weight (which persisted into adulthood), and impaired neurobehavioral function in offspring at all but the lowest dose tested. Plasma exposure (AUC) at the no-effect dose for adverse effects on postnatal development (5 mg/kg/day) was approximately 8 times that in humans at the MRHD. 8.2 Lactation Risk Summary There are no data on the presence of rizatriptan or any active metabolites in human milk or on the effects of rizatriptan on the breastfed infant, or milk production. Rizatriptan was excreted in rat milk, with levels in milk approximately 6 times those in maternal plasma. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for RizaFilm and any potential adverse effects on the breastfed infant from RizaFilm or the underlying maternal condition. Data Following oral administration of rizatriptan to lactating rats at a dose of 100 mg/kg/day, the drug concentrations of rizatriptan in milk samples exceeded maternal plasma drug concentrations by approximately 6-fold. 8.4 Pediatric Use The safety and effectiveness of RizaFilm for the acute treatment of migraine have been established in pediatric patients 12 years of age and older weighing 40 kg or more based on an adequate and well-controlled study with rizatriptan benzoate tablets [see Clinical Studies (14.2) ]. The incidence of adverse reactions reported for pediatric patients in the acute clinical trial was similar in patients who received rizatriptan benzoate tablets to those who received placebo. The adverse reaction pattern in pediatric patients is expected to be similar to that in adults. Safety and effectiveness of RizaFilm in pediatric patients under 12 years of age and weighing less than 40 kg have not been established. 8.5 Geriatric Use Clinical studies of rizatriptan benzoate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. The pharmacokinetics of rizatriptan were similar in elderly (aged ≥65 years) and younger adults (n=17) [see Clinical Pharmacology (12.3) ]. Geriatric patients who have cardiovascular risk factors (e.g., diabetes, hypertension, smoking, obesity, strong family history of coronary artery disease) should have a cardiovascular evaluation before receiving RizaFilm [see Warnings and Precautions (5.1) ].

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. 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.