Rizatriptan

1 INDICATIONS AND USAGE MAXALT ® and MAXALT-MLT ® are indicated for the acute treatment of migraine with or without aura in adults and in pediatric patients 6 to 17 years old. Limitations of Use MAXALT 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 MAXALT, the diagnosis of migraine should be reconsidered before MAXALT is administered to treat any subsequent attacks. MAXALT is not indicated for use in the management of hemiplegic or basilar migraine [see Contraindications (4) ] . MAXALT is not indicated for the prevention of migraine attacks. Safety and effectiveness of MAXALT have not been established for cluster headache. MAXALT 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 clear diagnosis of migraine has been established ( 1 ) Not indicated for the prophylactic therapy of migraine ( 1 ) Not indicated for the treatment of cluster headache ( 1 )

12.1 Mechanism of Action Rizatriptan binds with high affinity to human cloned 5-HT 1B/1D receptors. MAXALT 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.

2 DOSAGE AND ADMINISTRATION Although rizatriptan benzoate 5 mg tablets and orally disintegrating tablets are available in the marketplace, MAXALT Tablets and MAXALT-MLT Orally Disintegrating Tablets are no longer marketed in the 5 mg strength. Adults: 5 or 10 mg single dose; separate repeat doses by at least two hours; maximum dose in a 24-hour period: 30 mg ( 2.1 ) Pediatric patients 6 to 17 years: 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 ) Adjust dose if co-administered with propranolol ( 2.4 ) 2.1 Dosing Information in Adults The recommended starting dose of rizatriptan benzoate is either 5 mg or 10 mg for the acute treatment of migraines in adults. The 10-mg dose may provide a greater effect than the 5-mg dose, but may have a greater risk of adverse reactions [see Clinical Studies (14.1) ] . Redosing in Adults Although the effectiveness of a second dose or subsequent doses has not been established in placebo-controlled trials, if the migraine headache returns, a second dose may be administered 2 hours after the first dose. The maximum daily dose should not exceed 30 mg in any 24-hour period. 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 (Age 6 to 17 Years) Dosing in pediatric patients is based on the patient's body weight. The recommended dose of rizatriptan benzoate is 5 mg in patients weighing less than 40 kg (88 lb), and 10 mg in patients weighing 40 kg (88 lb) or more. The efficacy and safety of treatment with more than one dose of rizatriptan benzoate within 24 hours in pediatric patients 6 to 17 years of age have not been established. 2.3 Administration of MAXALT-MLT Orally Disintegrating Tablets For MAXALT-MLT Orally Disintegrating Tablets, administration with liquid is not necessary. Orally disintegrating tablets are packaged in a blister within an outer aluminum pouch and patients should not remove the blister from the outer pouch until just prior to dosing. The blister pack should then be peeled open with dry hands and the orally disintegrating tablet placed on the tongue, where it will dissolve and be swallowed with the saliva. 2.4 Dosage Adjustment for Patients on Propranolol Adult Patients In adult patients taking propranolol, only the 5-mg dose of rizatriptan benzoate is recommended, up to a maximum of 3 doses in any 24-hour period (15 mg) [see Drug Interactions (7.1) and Clinical Pharmacology (12.3) ]. Pediatric Patients For pediatric patients weighing 40 kg (88 lb) or more, taking propranolol, only a single 5-mg dose of rizatriptan benzoate is recommended (maximum dose of 5 mg in a 24-hour period). Rizatriptan benzoate should not be prescribed to propranolol-treated pediatric patients who weigh less than 40 kg (88 lb) [see Drug Interactions (7.1) and Clinical Pharmacology (12.3) ].

6 ADVERSE REACTIONS The following 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, 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) ] . The most common adverse reactions in adults were (incidence ≥5% and greater than placebo): asthenia/fatigue, somnolence, pain/pressure sensation and dizziness ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Organon LLC, a subsidiary of Organon & Co., at 1-844-674-3200 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. Adults Incidence in Controlled Clinical Trials Adverse reactions to MAXALT were assessed in controlled clinical trials that included over 3700 adult patients who received single or multiple doses of MAXALT Tablets. The most common adverse reactions during treatment with MAXALT (≥5% in either treatment group and greater than placebo) were asthenia/fatigue, somnolence, pain/pressure sensation and dizziness. These adverse reactions appeared to be dose related. Table 1 lists the adverse reactions (incidence ≥2% and greater than placebo) after a single dose of MAXALT in adults. Table 1: Incidence (≥2% and Greater than Placebo) of Adverse Reactions After a Single Dose of MAXALT Tablets or Placebo in Adults % of Patients Adverse Reactions MAXALT 5 mg (N=977) MAXALT 10 mg (N=1167) Placebo (N=627) Atypical Sensations 4 5 4 Paresthesia 3 4 <2 Pain and other Pressure Sensations 6 9 3 Chest Pain: tightness/pressure and/or heaviness <2 3 1 Neck/throat/jaw: pain/tightness/pressure <2 2 1 Regional Pain: tightness/pressure and/or heaviness <1 2 0 Pain, location unspecified 3 3 <2 Digestive 9 13 8 Dry Mouth 3 3 1 Nausea 4 6 4 Neurological 14 20 11 Dizziness 4 9 5 Headache <2 2 <1 Somnolence 4 8 4 Other Asthenia/fatigue 4 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 (including propranolol), 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 MAXALT 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 MAXALT 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 MAXALT and reported an event divided by the total number of patients exposed to MAXALT (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 a

5 WARNINGS AND PRECAUTIONS Myocardial ischemia, myocardial infarction, and Prinzmetal's angina: Perform cardiac evaluation in patients with multiple cardiovascular risk factors ( 5.1 ) Arrhythmias: Discontinue dosing if occurs ( 5.2 ) Chest/throat/neck/jaw pain, tightness, pressure, or heaviness; Generally not associated with myocardial ischemia; Evaluate patients at high risk ( 5.3 ) Cerebral hemorrhage, subarachnoid hemorrhage, and stroke: Discontinue dosing if occurs ( 5.4 ) Gastrointestinal ischemic events, peripheral vasospastic reactions: Discontinue dosing if occurs ( 5.5 ) Medication overuse headache: Detoxification may be necessary ( 5.6 ) Serotonin syndrome: Discontinue dosing if occurs ( 5.7 ) 5.1 Myocardial Ischemia, Myocardial Infarction, and Prinzmetal's Angina MAXALT should not be given to patients with ischemic or vasospastic coronary artery disease. There have been rare reports of serious cardiac adverse reactions, including acute myocardial infarction, occurring within a few hours following administration of MAXALT. Some of these reactions occurred in patients without known coronary artery disease (CAD). 5-HT 1 agonists, including MAXALT may cause coronary artery vasospasm (Prinzmetal's Angina), even in patients without a history of CAD. Triptan-naïve patients who have multiple cardiovascular risk factors (e.g., increased age, diabetes, hypertension, smoking, obesity, strong family history of CAD) should have a cardiovascular evaluation prior to receiving MAXALT. If there is evidence of CAD or coronary artery vasospasm, MAXALT should not be administered [see Contraindications (4) ]. For patients who have a negative cardiovascular evaluation, consideration should be given to administration of the first MAXALT dose in a medically-supervised setting and performing an electrocardiogram (ECG) immediately following MAXALT administration. Periodic cardiovascular evaluation should be considered in intermittent long-term users of MAXALT who have cardiovascular risk factors. 5.2 Arrhythmias Life-threatening disturbances of cardiac rhythm, including ventricular tachycardia and ventricular fibrillation leading to death, have been reported within a few hours following the administration of 5-HT 1 agonists. Discontinue MAXALT if these disturbances occur. 5.3 Chest, Throat, Neck and/or Jaw Pain/Tightness/Pressure As with other 5-HT 1 agonists, sensations of tightness, pain, pressure, and heaviness in the precordium, throat, neck and jaw commonly occur after treatment with MAXALT and are usually non-cardiac in origin. However, if a cardiac origin is suspected, patients should be evaluated. Patients shown to have CAD and those with Prinzmetal's variant angina should not receive 5-HT 1 agonists. 5.4 Cerebrovascular Events Cerebral hemorrhage, subarachnoid hemorrhage, and stroke have occurred in patients treated with 5-HT 1 agonists, and some have resulted in fatalities. In a number of cases, it appears possible that the cerebrovascular events were primary, the 5-HT 1 agonist having been administered in the incorrect belief that the symptoms experienced were a consequence of migraine, when they were not. Also, patients with migraine may be at increased risk of certain cerebrovascular events (e.g., stroke, hemorrhage, transient ischemic attack). Discontinue MAXALT if a cerebrovascular event occurs. As with other acute migraine therapies, before treating headaches in patients not previously diagnosed as migraineurs, and in migraineurs who present with atypical symptoms, care should be taken to exclude other potentially serious neurological conditions. MAXALT should not be administered to patients with a history of stroke or transient ischemic attack [see Contraindications (4) ] . 5.5 Other Vasospasm Reactions 5-HT 1 agonists, including MAXALT, may cause non-coronary vasospastic reactions, such as peripheral vascular ischemia, gastrointestinal vascular ischemia and infarction (presenting with abdominal pain and bloody diarrhea), s

4 CONTRAINDICATIONS MAXALT 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) ] . 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 (5.8) ] . 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 [see Indications and Usage (1) ] . 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) ] . Hypersensitivity to rizatriptan or any of the excipients (angioedema and anaphylaxis seen) [see Adverse Reactions (6.2) ] . History of ischemic heart disease or coronary artery vasospasm ( 4 ) History of stroke or transient ischemic attack ( 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 ) Hypersensitivity to rizatriptan or any of the excipients ( 4 )

10 OVERDOSAGE No overdoses of MAXALT were reported during clinical trials in adults. Some adult patients who received 40 mg of MAXALT either 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 MAXALT, 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 MAXALT-MLT 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 MAXALT, 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 MAXALT. 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.