Rizatriptan Benzoate

RECENT MAJOR CHANGES Dosage and Administration ( 2 ) 09/2020

1 INDICATIONS AND USAGE Rizatriptan benzoate tablets 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 • Rizatriptan benzoate tablets 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 rizatriptan benzoate tablets, the diagnosis of migraine should be reconsidered before rizatriptan benzoate tablets are administered to treat any subsequent attacks. • Rizatriptan benzoate tablets are not indicated for use in the management of hemiplegic or basilar migraine [see Contraindications ( 4 )]. • Rizatriptan benzoate tablets are not indicated for the prevention of migraine attacks. • Safety and effectiveness of rizatriptan benzoate tablets have not been established for cluster headache. Rizatriptan benzoate 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 )

2 DOSAGE AND ADMINISTRATION • Adults: 5 mg 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 tablets 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 tablets 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 tablets within 24 hours in pediatric patients 6 to 17 years of age have not been established. 2.4 Dosage Adjustment for Patients on Propranolol Adult Patients In adult patients taking propranolol, only the 5 mg dose of rizatriptan benzoate tablets 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 tablets is recommended (maximum dose of 5 mg in a 24-hour period). Rizatriptan benzoate tablets 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 )].

3 DOSAGE FORMS AND STRENGTHS Rizatriptan Benzoate Tablets USP • 5 mg tablets are a pale pink-colored, circular, flat, beveled-edge uncoated tablets debossed with ‘X’ on one side and ‘13’ on other side. The tablets may be mottled. • 10 mg tablets are a pale pink-colored, circular, flat, beveled-edge uncoated tablets debossed with ‘X’ on one side and ‘14’ on other side. The tablets may be mottled. • Rizatriptan Benzoate Tablets USP: 5 mg and 10 mg (3)

4 CONTRAINDICATIONS Rizatriptan benzoate tablets are 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) [s ee 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 benzoate tablets or rizatriptan benzoate orally disintegrating tablets 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 )

6 ADVERSE REACTIONS 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 Cipla Ltd. at 1-866-604-3268 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 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 )]. 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 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 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 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 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. % of patients Adverse Reactions Rizatriptan Benzoate Tablets 5 mg (N=977) Rizatriptan Benzoate Tablets 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. The adverse reaction profile seen with rizatriptan benzoate orally disintegrating tablets was similar to that seen with rizatriptan benzoate tablets. Pediatric Patients 6 to 17 Years of Age I …

7 DRUG INTERACTIONS 7.1 Propranolol The dose of rizatriptan benzoate should be adjusted in propranolol-treated patients, as propranolol has been shown to increase the plasma AUC of rizatriptan by 70% [see Dosage and Administration ( 2.4 ) 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 rizatriptan benzoate 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 rizatriptan benzoate 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 Rizatriptan benzoate is contraindicated in patients taking MAO-A inhibitors and non-selective MAO inhibitors. A specific MAO-A inhibitor increased the systemic exposure of rizatriptan and its metabolite [see Contraindications ( 4 ) and Clinical Pharmacology ( 12.3 )] .

Drug Interactions [See also Drug Interactions ( 7 )]. Monoamine oxidase inhibitors: Rizatriptan is principally metabolized via monoamine oxidase, ‘A’ subtype (MAO-A). Plasma concentrations of rizatriptan may be increased by drugs that are selective MAO-A inhibitors (e.g., moclobemide) or nonselective MAO inhibitors [type A and B] (e.g., isocarboxazid, phenelzine, tranylcypromine, and pargyline). In a drug interaction study, when rizatriptan benzoate 10 mg was administered to subjects (n=12) receiving concomitant therapy with the selective, reversible MAO-A inhibitor, moclobemide 150 mg t.i.d., 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. No pharmacokinetic interaction is anticipated in patients receiving selective MAO-B inhibitors [see Contraindications ( 4 ) and Drug Interactions ( 7.5 )] . 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% during propranolol administration, and a four-fold increase was observed in one subject. The AUC of the active N-monodesmethyl metabolite of rizatriptan was not affected by propranolol [see Dosage and Administration ( 2.4 ) and Drug Interactions ( 7.1 )] . 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 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 benzoate (10 to 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 benzoate 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 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 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 benzoate 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 benzoate. Additionally, there was significant loss to follow-up in the prospective pregnancy reports, further complicating this assessment of an association between rizatriptan benzoate 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 drug to the fetus was demonstrated in both species. Oral administration of rizatriptan (0, 2, 10, or 100 mg/kg/day) to female rats prior to and during mating …

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

11 DESCRIPTION Rizatriptan benzoate tablets USP contain rizatriptan benzoate, USP, a selective 5-hydroxytryptamine 1B/1D (5-HT 1B/1D ) receptor agonist. Rizatriptan benzoate, USP 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 molecular formula is C 15 H 19 N 5 •C 7 H 6 O 2 , representing a molecular weight of the free base of 391.47 g/mol. Rizatriptan benzoate, USP is a white to off-white powder that is soluble in methanol; sparingly soluble in water; slightly soluble in acetone and ethanol. Rizatriptan benzoate tablets USP are available for oral administration in strengths of 5 mg and 10 mg (corresponding to 7.265 mg or 14.53 mg of the benzoate salt, respectively). Each compressed tablet contains the following inactive ingredients: colloidal silicon dioxide, ferric oxide red, lactose monohydrate, magnesium stearate, microcrystalline cellulose and pregelatinized corn starch. chemical-structure

10 OVERDOSAGE No overdoses of rizatriptan benzoate tablets were reported during clinical trials in adults. Some adult patients who received 40 mg of rizatriptan benzoate tablets 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 rizatriptan benzoate tablets, 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 tablets, 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 rizatriptan benzoate tablets. 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 Rizatriptan benzoate tablets, USP 5 mg, are white to off-white, capsule-shaped, compressed tablets debossed “ RZT” on one side and “5” on other side. They are supplied as follows: NDC 67877-261-30, bottle of 30 tablets. NDC 67877-261-01, bottle of 100 tablets. NDC 67877-261-05, bottle of 500 tablets. NDC 67877-261-18, carton of 18 tablets NDC 67877-261-25, carton of 12 tablets Rizatriptan benzoate tablets, USP 10 mg, are white to off-white, capsule-shaped, compressed tablets debossed “RZT” on one side and “10” on other side. They are supplied as follows: NDC 67877-262-30, bottle of 30 tablets. NDC 67877-262-01, bottle of 100 tablets. NDC 67877-262-05, bottle of 500 tablets. NDC 67877-262-18, carton of 18 tablets NDC 67877-262-25, carton of 12 tablets Storage Store rizatriptan benzoate tablets, USP at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.