ADVERSE REACTIONS SECTION.

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 Unichem Pharmaceuticals (USA) Inc. at 1-866-562-4616 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 Prinzmetals 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)] .. Myocardial Ischemia, Myocardial Infarction, and Prinzmetals 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 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 lists the adverse reactions (incidence >=2% and greater than placebo) after single dose of rizatriptan benzoate in adults. Table 1: Incidence (>=2% and Greater than Placebo) of Adverse Reactions After Single Dose of Rizatriptan Benzoate Tablets or Placebo in Adults of Patients Rizatriptan Rizatriptan Adverse Reactions Benzoate Tablets, Benzoate Tablets, mg 10 mg Placebo (N=977) (N=1167) (N=627) Atypical Sensations 5 Paresthesia 4 <2 Pain and other Pressure Sensations 9 Chest Pain: tightness/pressure and/or heaviness <2 1 Neck/throat/jaw: pain/tightness/pressure <2 1 Regional Pain: tightness/pressure and/or heaviness <1 0 Pain, location unspecified 3 <2 Digestive 13 Dry Mouth 3 Nausea 6 Neurological 14 20 11 Dizziness 9 Headache <2 <1 Somnolence 8 Other Asthenia/fatigue 7 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 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. The adverse reaction profile seen with rizatriptan benzoate Orally Disintegrating Tablets was similar to that seen with rizatriptan benzoate tablets.Pediatric Patients to 17 Years of Age Incidence in Controlled Clinical Trials in Pediatric Patients Adverse reactions to rizatriptan benzoate orally disintegrating tablets were assessed in controlled clinical trial in the acute treatment of migraines (Study 7) that included total of 1382 pediatric patients 6-17 years of age, of which 977 (72%) 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 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 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 section enumerates potentially important adverse events that have occurred in clinical practice and which have been reported spontaneously to various surveillance systems. The events enumerated include all except those already listed in other sections of the labeling or those too general to be informative. Because the reports cite events reported spontaneously from worldwide postmarketing experience, frequency of events and the role of rizatriptan benzoate in their causation cannot be reliably determined. Neurological/Psychiatric: Seizure. General: Allergic conditions including anaphylaxis/anaphylactoid reaction, angioedema, wheezing, and toxic epidermal necrolysis [see Contraindications (4)]. Special Senses: Dysgeusia.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Rizatriptan binds with high affinity to human cloned 5-HT1B/1D receptors. Rizatriptan presumably exerts its therapeutic effects in the treatment of migraine headache by binding to 5-HT1B/1D receptors located on intracranial blood vessels and sensory nerves of the trigeminal system. 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 (Cmax) are reached in approximately 1-1.5 hours (Tmax). The presence of 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 was administered without regard to food. The bioavailability and Cmax 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 rizatriptan benzoate orally disintegrating tablets with Tmax 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.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, metabolite with activity similar to that of parent compound at the 5-HT1B/1D receptor, is formed to minor degree. Plasma concentrations of N-monodesmethyl-rizatriptan are approximately 14% of those of parent compound, and it is eliminated at 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-HT1B/1D receptor. Elimination The total radioactivity of the administered dose recovered over 120 hours in urine and feces was 82% and 12%, respectively, following single 10-mg oral administration of 14C-rizatriptan. Following oral administration of 14C-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. The plasma half-life of rizatriptan in males and females averages 2-3 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 competitive inhibitor (Ki=1400 nM) of cytochrome P450 2D6, but only at high, clinically irrelevant concentrations.Special 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 to 17 years of age. Exposures following single dose administration of mg rizatriptan benzoate orally disintegrating tablets to pediatric patients weighing 20-39 kg (44-87 lb) or 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 AUC0- and Cmax 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.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 control group of subjects with normal hepatic function; plasma concentrations of rizatriptan were approximately 30% greater in patients with moderate hepatic insufficiency. Renal impairment: In patients with renal impairment (creatinine clearance 10-60 mL/min/1.73 m2), the AUC0- 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 [See also Drug Interactions (7).]Monoamine oxidase inhibitors: Rizatriptan is principally metabolized via monoamine oxidase, 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 and B] (e.g., isocarboxazid, phenelzine, tranylcypromine, and pargyline). In drug interaction study, when rizatriptan 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 Cmax 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 study of concurrent administration of propranolol 240 mg/day and 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 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 drug interactions study, effects of multiple doses of nadolol 80 mg or metoprolol 100 mg every 12 hours on the pharmacokinetics of single dose of 10 mg rizatriptan were evaluated in healthy subjects (n=12). No pharmacokinetic interactions were observed. Paroxetine: In study of the interaction between the selective serotonin reuptake inhibitor (SSRI) paroxetine 20 mg/day for two weeks and single dose of rizatriptan 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 study of concurrent administration of an oral contraceptive during 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.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Adults. The efficacy of rizatriptan benzoate tablets, USP was established in four multicenter, randomized, placebo-controlled trials. Patients enrolled in these studies were primarily female (84%) and Caucasian (88%), with mean age of 40 years (range of 18 to 71). Patients were instructed to treat moderate to severe headache. Headache response, defined as reduction of moderate or severe headache pain to no or mild headache pain, was assessed for up to hours (Study 1) or up to hours after dosing (Studies 2, and 4). Associated symptoms of nausea, photophobia, and phonophobia and maintenance of response up to 24 hours post-dose were evaluated. second dose of rizatriptan benzoate tablets, USP was allowed to 24 hours after dosing for treatment of recurrent headache in Studies and 2. Additional analgesics and/or antiemetics were allowed hours after initial treatment for rescue in all four studies. In all studies, the percentage of patients achieving headache response hours after treatment was significantly greater in patients who received either rizatriptan benzoate mg or 10 mg compared to those who received placebo. In separate study, doses of 2.5 mg were not different from 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 Hours Following Treatment of Initial Headache in Studies 1, 2, 3, and Study Placebo Rizatriptan Benzoate Tablets, Rizatriptan Benzoate Tablets, mg 10 mg 35% (n=304) 62% p-value <0.05 in comparison with placebo (n=458) 71%,p-value <0.05 in comparison with mg (n=456) 2Results for initial headache only. 37% (n=82) -- 77% (n=320) 23% (n=80) 63% (n=352) -- 40% (n=159) 60% (n=164) 67% (n=385) 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 hours following treatment in pooled Studies 1, 2, 3, and is depicted in Figure 1.Figure 1: Estimated Probability of Achieving an Initial Headache Response by Hours in Pooled Studies 1, 2, 3, and 4++ ++ Figure shows the Kaplan-Meier plot of the probability over time of obtaining headache response (no or mild pain) following treatment with rizatriptan benzoate or placebo. The averages displayed are based on pooled data from placebo-controlled, outpatient trials providing evidence of efficacy (Studies 1, 2, 3, and 4). Patients taking additional treatment or not achieving headache response prior to hours were censored at hours.For patients with migraine-associated photophobia, phonophobia, and nausea at baseline, there was decreased incidence of these symptoms following administration of rizatriptan benzoate 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 second dose of study treatment or other medication. The estimated probability of patients taking 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 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 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 hours and those who had no response to the initial dose. Remedication was not allowed within 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.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 and 6). Patients were instructed to treat moderate to severe headache. Patients treated in these studies were primarily female (88%) and Caucasian (95%), with mean age of 42 years (range 18-72).In both studies, the percentage of patients achieving headache response hours after treatment was significantly greater in patients who received either rizatriptan benzoate orally disintegrating tablets mg or 10 mg compared to those who received placebo. The results from Studies and are summarized in Table 3. Table 3: Response Rates Hours Following Treatment of Initial Headache in Studies and Study Placebo Rizatriptan Benzoate orally disintegrating Tablets, Rizatriptan Benzoate orally disintegrating Tablets, mg 10 mg 47% (n=98) 66%p-value <0.01 in comparison with placebo (n=100) 66% (n=113) 28% (n=180) 59% (n=181) 74%, p-value <0.01 in comparison with mg (n=186) The estimated probability of achieving an initial headache response by hours following treatment with rizatriptan benzoate orally disintegrating tablets in pooled Studies and is depicted in Figure 3.Figure 3: Estimated Probability of Achieving an Initial Headache Response with Rizatriptan Benzoate Orally Disintegrating Tablets by Hours in Pooled Studies and Figure 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 placebo-controlled, outpatient trials providing evidence of efficacy (Studies and 6). Patients taking additional treatment or not achieving headache response prior to hours were censored at hours.For patients with migraine-associated photophobia and phonophobia at baseline, there was 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 second dose of study treatment or other medication. The estimated probability of patients taking 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 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 and This Kaplan-Meier plot is based on data obtained in placebo-controlled outpatient clinical trials (Studies and 6). Patients not using additional treatments were censored at 24 hours. The plot includes both patients who had headache response at hours and those who had no response to the initial dose. Remedication was not allowed within hours post-dose.. 14.2 Pediatric Patients to 17 Years of Age. The efficacy of rizatriptan benzoate orally disintegrating tablets in pediatric patients to 17 years was evaluated in multicenter, randomized, double-blind, placebo-controlled, parallel group clinical trial (Study 7). Patients had to have at least 6-month history of migraine attacks (with or without aura) usually lasting hours or more (when untreated). The patient population was historically non-responsive to NSAIDs and acetaminophen therapy. Patients were instructed to treat single migraine attack with headache pain of moderate to severe intensity. The treatment phase of the study had two stages. Stage 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 weight-based dosing strategy, patients 20 kg to <40 kg (44 lb to <88 lb) received rizatriptan benzoate orally disintegrating tablets mg or placebo, and patients >=40 kg (88 lb) received rizatriptan benzoate orally disintegrating tablets 10 mg or placebo. The mean age for the studied patient population was 13 years. 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 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 results are summarized in Table 4. Table 4: Response Rates Hours Following Treatment of Initial Headache in Pediatric Patients to 17 Years of Age in Study n Number of evaluable patients with no headache pain at hours post-dose.m Number of evaluable patients in population. Endpoint Placebo Rizatriptan Benzoate Orally Disintegrating Tablets p-Value No headache pain at hours 24% 33% 0.01 post-dose (n/m 94/388) (n/m 126/382) See FDA-Approved Patient Labeling (Patient Information).Additional patient information leaflets can be obtained by calling Unichem at 1-866-562-4616.Risk of Myocardial Ischemia and/or Infarction, Prinzmetals Angina, Other Vasospasm-Related Events, and Cerebrovascular Events Inform patients that rizatriptan benzoate 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 sign 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 rizatriptan benzoate 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 Inform patients that rizatriptan benzoate should not be used during pregnancy unless the potential benefit justifies the potential risk to the fetus [see Use in Specific Populations (8.1)].LactationAdvise 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 rizatriptan benzoate may cause somnolence and dizziness, instruct patients to evaluate their ability to perform complex tasks during migraine attacks and after administration of rizatriptan benzoate. 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 headache diary) [see Warnings and Precautions (5.6)].Handling of Orally Disintegrating Tablets Packages Instruct patients not to remove the blister from the carton until ready to use the orally disintegrating tablet inside [see Dosage and Administration (2.3)]. The prevalence of the exploratory endpoints of absence of migraine-associated symptoms (nausea, photophobia, and phonophobia) at hours after taking the dose was not statistically significantly different between patients who received rizatriptan benzoate orally disintegrating tablets and those who received placebo.. Figure 1. Figure 2. Figure 3. Figure 4. Figure 5.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. 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-HT1agonist (e.g., another triptan), or of an ergotamine-containing medication (4) Hemiplegic or basilar migraine (4) MAO-A inhibitor used in the past weeks (4) Hypersensitivity to rizatriptan or any of the excipients (4). 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-HT1agonist (e.g., another triptan), or of an ergotamine-containing medication (4). Hemiplegic or basilar migraine (4). MAO-A inhibitor used in the past weeks (4). Hypersensitivity to rizatriptan or any of the excipients (4). 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 Prinzmetals 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-HT1agonist, 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 weeks) of 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)] .. 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 Prinzmetals 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-HT1agonist, 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 weeks) of 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)].

DESCRIPTION SECTION.

11 DESCRIPTION. Rizatriptan benzoate tablets, USP contain rizatriptan benzoate, selective 5-hydroxytryptamine1B/1D (5-HT1B/1D) receptor agonist.Rizatriptan benzoate is described chemically as: N,N-dimethyl-5-(1H-1,2,4-triazol-1-ylmethyl)-1H-indole-3-ethanamine monobenzoate and its structural formula is:Its molecular formula is C15H19N5oC7H6O2, representing molecular weight of the free base of 269.4. Rizatriptan benzoate is white to off-white, crystalline powder that is soluble in water at about 42 mg per mL (expressed as free base) at 25oC. Rizatriptan benzoate tablets, USP are available for oral administration in strengths of mg and 10 mg (corresponding to 7.265 mg or 14.53 mg of the benzoate salt, respectively). Each orally disintegrating tablet contains the following inactive ingredients: lactose monohydrate, microcrystalline cellulose, pregelatinized starch, and magnesium stearate.. Chemical Structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Adults: mg or 10 mg single dose; separate repeat doses by at least two hours; maximum dose in 24-hour period: 30 mg (2.1) Pediatric patients to 17 years: 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). Adults: mg or 10 mg single dose; separate repeat doses by at least two hours; maximum dose in 24-hour period: 30 mg (2.1). Pediatric patients to 17 years: 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 mg or 10 mg for the acute treatment of migraines in adults. The 10-mg dose may provide greater effect than the 5-mg dose, but may have greater risk of adverse reactions [see Clinical Studies (14.1)].Redosing in Adults Although the effectiveness of second dose or subsequent doses has not been established in placebo-controlled trials, if the migraine headache returns, second dose may be administered 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 30-day period has not been established.. 2.2 Dosing Information in Pediatric Patients (Age to 17 Years). Dosing in pediatric patients is based on the patients body weight. The recommended dose of rizatriptan benzoate tablets is 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 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 maximum of 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 single 5-mg dose of rizatriptan benzoate tablets is recommended (maximum dose of mg in 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)].

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Rizatriptan Benzoate Tablets, USP: mg and 10 mg (3). Rizatriptan Benzoate Tablets, USP: mg and 10 mg (3). Rizatriptan Benzoate Tablets, USP5 mg Tablet White to off white, round shaped tablets debossed with 316 on one side of tablet and U on other side of tablets.10 mg Tablet White to off white, round shaped tablets debossed with 317 on one side of tablet and U on other side of tablets. mg Tablet White to off white, round shaped tablets debossed with 316 on one side of tablet and U on other side of tablets.. 10 mg Tablet White to off white, round shaped tablets debossed with 317 on one side of tablet and U on other side of tablets.

DRUG INTERACTIONS SECTION.

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-HT1 Agonists. Because their vasospastic effects may be additive, co-administration of rizatriptan benzoate and other 5-HT1 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. specific MAO-A inhibitor increased the systemic exposure of rizatriptan and its metabolite [see Contraindications (4) and Clinical Pharmacology (12.3)].

GERIATRIC USE SECTION.

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. Although the pharmacokinetics of rizatriptan were similar in elderly (aged >=65 years) and in younger adults (n=17), in general, dose selection for an elderly patient should be cautious, starting at the low end of the dosing range. This reflects the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.Geriatric patients who have other cardiovascular risk factors (e.g., diabetes, hypertension, smoking, obesity, strong family history of coronary artery disease) should have cardiovascular evaluation prior to receiving rizatriptan benzoate [see Warnings and Precautions (5.1)].

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. Rizatriptan Benzoate Tablets, USP mg are White to off white, round shaped tablets debossed with 316 on one side of tablet and U on other side of tablets.Unit-of-use blister package of 12 (NDC 29300-316-21)Unit-of-use blister package of 18 (NDC 29300-316-81)Rizatriptan Benzoate Tablets, USP 10 mg are White to off white, round shaped tablets debossed with 317 on one side of tablet and U on other side of tablets.Unit-of-use blister package of 12 (NDC 29300-317-21)Unit-of-use blister package of 18 (NDC 29300-317-81)Storage Store rizatriptan benzoate tablets at 20o to 25oC (68o to 77oF) [see USP Controlled Room Temperature]. Protect from light and moisture.PHARMACIST: Dispense Patient Information Leaflet with each prescription.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. Rizatriptan benzoate is 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 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). 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). Rizatriptan benzoate tablets are indicated for the acute treatment of migraine with or without aura in adults and in pediatric patients to 17 years old.Limitations of Use Rizatriptan benzoate tablets should only be used where clear diagnosis of migraine has been established. If 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 tablets should only be used where clear diagnosis of migraine has been established. If 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.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. See FDA-Approved Patient Labeling (Patient Information).Additional patient information leaflets can be obtained by calling Unichem at 1-866-562-4616.Risk of Myocardial Ischemia and/or Infarction, Prinzmetals Angina, Other Vasospasm-Related Events, and Cerebrovascular EventsInform patients that rizatriptan benzoate 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 sign 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 rizatriptan benzoate 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 Inform patients that rizatriptan benzoate should not be used during pregnancy unless the potential benefit justifies the potential risk to the fetus [see Use in Specific Populations (8.1)].LactationAdvise 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 rizatriptan benzoate may cause somnolence and dizziness, instruct patients to evaluate their ability to perform complex tasks during migraine attacks and after administration of rizatriptan benzoate.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 headache diary) [see Warnings and Precautions (5.6)].Manufactured by: UNICHEM LABORATORIES LTD. Pilerne Ind. Estate, Pilerne, Bardez, Goa 403 511, India Manufactured for:East Brunswick, NJ 0881605-R-04/202013012734. Company Logo.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Rizatriptan binds with high affinity to human cloned 5-HT1B/1D receptors. Rizatriptan presumably exerts its therapeutic effects in the treatment of migraine headache by binding to 5-HT1B/1D receptors located on intracranial blood vessels and sensory nerves of the trigeminal system.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.3 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisOral carcinogenicity studies of rizatriptan were conducted in mice (100 weeks) and rats (106 weeks) at doses of up to 125 mg/kg/day. There was no evidence of an increase in tumor incidence related to rizatriptan in either species. Plasma exposures (AUC) at the highest dose tested were approximately 150 (mice) and 240 times (rats) that in humans at the maximum recommended human dose (MRHD) of 30 mg/day. MutagenesisRizatriptan was neither mutagenic nor clastogenic in 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 FertilityOral administration of rizatriptan (0, 2, 10, or 100 mg/kg/day) to female rats prior to and during mating and continuing throughout gestation and lactation resulted in no effect on fertility; however, altered estrous cyclicity and delays in time to mating were observed at the highest dose tested. Plasma exposure at the no-effect dose (10 mg/kg/day) for reproductive toxicity was approximately 15 times that in humans at the MRHD.Oral administration of rizatriptan (0, 5, 35, or 250 mg/kg/day) to male rats prior to and during mating resulted in no impairment of fertility or reproductive performance. Plasma exposure (AUC) at the highest dose tested was approximately 550 times that in humans at the MRHD.

NURSING MOTHERS SECTION.

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 on milk production.Rizatriptan was excreted in rat milk, with levels in milk approximately times those in maternal plasma.The developmental and health benefits of breastfeeding should be considered along with themothers clinical need for rizatriptan benzoate tablets or rizatriptan benzoate orally disintegrating tablets and any potential adverse effects on the breastfed infant from rizatriptan benzoate tablets or rizatriptan benzoate orally disintegrating tablets or from the underlying maternal condition.DataFollowing oral administration of rizatriptan to lactating rats at dose of 100 mg/kg/day, drug concentrations of rizatriptan in milk samples exceeded maternal plasma drug concentrations by approximately 6-fold.

OVERDOSAGE SECTION.

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 single dose or as two doses with 2-hour interdose interval had dizziness and somnolence. In 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 24-hour period. Adverse reactions for 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 rizatriptan benzoate. 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.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL. Carton Rizatriptan Benzoate Tablets mg.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. Safety and effectiveness in pediatric patients under years of age have not been established. The efficacy and safety of rizatriptan benzoate in the acute treatment of migraine in patients aged to 17 years was established in an adequate and well-controlled study [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 to those who received placebo. The adverse reaction pattern in pediatric patients is expected to be similar to that in adults.

PHARMACOKINETICS SECTION.

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 (Cmax) are reached in approximately 1-1.5 hours (Tmax). The presence of 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 was administered without regard to food. The bioavailability and Cmax 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 rizatriptan benzoate orally disintegrating tablets with Tmax 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.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, metabolite with activity similar to that of parent compound at the 5-HT1B/1D receptor, is formed to minor degree. Plasma concentrations of N-monodesmethyl-rizatriptan are approximately 14% of those of parent compound, and it is eliminated at 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-HT1B/1D receptor. Elimination The total radioactivity of the administered dose recovered over 120 hours in urine and feces was 82% and 12%, respectively, following single 10-mg oral administration of 14C-rizatriptan. Following oral administration of 14C-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. The plasma half-life of rizatriptan in males and females averages 2-3 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 competitive inhibitor (Ki=1400 nM) of cytochrome P450 2D6, but only at high, clinically irrelevant concentrations.Special 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 to 17 years of age. Exposures following single dose administration of mg rizatriptan benzoate orally disintegrating tablets to pediatric patients weighing 20-39 kg (44-87 lb) or 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 AUC0- and Cmax 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.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 control group of subjects with normal hepatic function; plasma concentrations of rizatriptan were approximately 30% greater in patients with moderate hepatic insufficiency. Renal impairment: In patients with renal impairment (creatinine clearance 10-60 mL/min/1.73 m2), the AUC0- 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 [See also Drug Interactions (7).]Monoamine oxidase inhibitors: Rizatriptan is principally metabolized via monoamine oxidase, 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 and B] (e.g., isocarboxazid, phenelzine, tranylcypromine, and pargyline). In drug interaction study, when rizatriptan 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 Cmax 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 study of concurrent administration of propranolol 240 mg/day and 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 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 drug interactions study, effects of multiple doses of nadolol 80 mg or metoprolol 100 mg every 12 hours on the pharmacokinetics of single dose of 10 mg rizatriptan were evaluated in healthy subjects (n=12). No pharmacokinetic interactions were observed. Paroxetine: In study of the interaction between the selective serotonin reuptake inhibitor (SSRI) paroxetine 20 mg/day for two weeks and single dose of rizatriptan 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 study of concurrent administration of an oral contraceptive during 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.

PREGNANCY SECTION.

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 ConsiderationsDisease-Associated Maternal and/or Embryo/Fetal RiskIn women with migraine, there is an increased risk of adverse perinatal outcomes in the mother, including pre-eclampsia and gestational hypertension.DataHuman DataThe 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 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, infants were born with malformations (relative risk 1.01 [95% CI: 0.40 to 2.08]). 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 migraine disease comparison group who redeemed prescriptions for triptans before pregnancy only, compared with 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 DataWhen rizatriptan (0, 2, 10, or 100 mg/kg/day) was administered orally to pregnant rats throughout organogenesis, decrease in fetal body weight was observed at the highest doses tested. At the mid dose (10 mg/kg/day), which was 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 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 times that in humans at the MRHD.

SPL UNCLASSIFIED SECTION.

Rizatriptan benzoate tablets are indicated for the acute treatment of migraine with or without aura in adults and in pediatric patients to 17 years old.Limitations of Use Rizatriptan benzoate tablets should only be used where clear diagnosis of migraine has been established. If 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 tablets should only be used where clear diagnosis of migraine has been established. If 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.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Pregnancy: Based on animal data, may cause fetal harm (8.1). 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 ConsiderationsDisease-Associated Maternal and/or Embryo/Fetal RiskIn women with migraine, there is an increased risk of adverse perinatal outcomes in the mother, including pre-eclampsia and gestational hypertension.DataHuman DataThe 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 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, infants were born with malformations (relative risk 1.01 [95% CI: 0.40 to 2.08]). 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 migraine disease comparison group who redeemed prescriptions for triptans before pregnancy only, compared with 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 DataWhen rizatriptan (0, 2, 10, or 100 mg/kg/day) was administered orally to pregnant rats throughout organogenesis, decrease in fetal body weight was observed at the highest doses tested. At the mid dose (10 mg/kg/day), which was 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 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 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 on milk production.Rizatriptan was excreted in rat milk, with levels in milk approximately times those in maternal plasma.The developmental and health benefits of breastfeeding should be considered along with themothers clinical need for rizatriptan benzoate tablets or rizatriptan benzoate orally disintegrating tablets and any potential adverse effects on the breastfed infant from rizatriptan benzoate tablets or rizatriptan benzoate orally disintegrating tablets or from the underlying maternal condition.DataFollowing oral administration of rizatriptan to lactating rats at dose of 100 mg/kg/day, drug concentrations of rizatriptan in milk samples exceeded maternal plasma drug concentrations by approximately 6-fold.. 8.4 Pediatric Use. Safety and effectiveness in pediatric patients under years of age have not been established. The efficacy and safety of rizatriptan benzoate in the acute treatment of migraine in patients aged to 17 years was established in an adequate and well-controlled study [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 to those who received placebo. The adverse reaction pattern in pediatric patients is expected to be similar to that in adults.. 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. Although the pharmacokinetics of rizatriptan were similar in elderly (aged >=65 years) and in younger adults (n=17), in general, dose selection for an elderly patient should be cautious, starting at the low end of the dosing range. This reflects the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.Geriatric patients who have other cardiovascular risk factors (e.g., diabetes, hypertension, smoking, obesity, strong family history of coronary artery disease) should have cardiovascular evaluation prior to receiving rizatriptan benzoate [see Warnings and Precautions (5.1)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Myocardial ischemia, myocardial infarction, and Prinzmetals 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). Myocardial ischemia, myocardial infarction, and Prinzmetals 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 Prinzmetals Angina. Keep rizatriptan benzoate orally disintegrating tablets and all medicines out of the reach of children.General Information about the safe and effective use of rizatriptan benzoate orally disintegrating tablets. Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use rizatriptan benzoate for condition for which it was not prescribed. Do not give rizatriptan benzoate orally disintegrating tablets to other people, even if they have the same symptoms that you have. It may harm them. This Patient Information leaflet summarizes the most important information about rizatriptan benzoate orally disintegrating tablets. If you would like more information, talk to your doctor. You can ask your pharmacist or doctor for information about rizatriptan benzoate orally disintegrating tablets that is written for health professionals. For more information, call Unichem Pharmaceuticals (USA), Inc. at 1-866-562-4616What are the ingredients in rizatriptan benzoate orally disintegrating tabletsActive ingredient in rizatriptan benzoate orally disintegrating tablets: rizatriptan benzoate. Inactive ingredients in rizatriptan benzoate orally disintegrating tablets: colloidal silicon dioxide, crospovidone, magnesium stearate, mannitol, microcrystalline cellulose, orange flavor, sucralose. The brand names mentioned are registered trademarks of their respective manufacturers.This Patient Information has been approved by the U.S. Food and Drug Administration.Additional patient information leaflets can be obtained by calling Unichem at 1-866-562-4616.Manufactured by: UNICHEM LABORATORIES LTD. Pilerne Ind. Estate, Pilerne, Bardez, Goa 403 511, India Manufactured for:. 5.2 Arrhythmias. Life-threatening disturbances of cardiac rhythm, including ventricular tachycardia and ventricular fibrillation leading to death, have been reported within few hours following the administration of 5-HT1 agonists. Discontinue rizatriptan benzoate if these disturbances occur.. 5.3 Chest, Throat, Neck and/or Jaw Pain/Tightness/Pressure. As with other 5-HT1 agonists, sensations of tightness, pain, pressure, and heaviness in the precordium, throat, neck and jaw commonly occur after treatment with rizatriptan benzoate and are usually non-cardiac in origin. However, if cardiac origin is suspected, patients should be evaluated. Patients shown to have CAD and those with Prinzmetals variant angina should not receive 5-HT1 agonists.. 5.4 Cerebrovascular Events. Cerebral hemorrhage, subarachnoid hemorrhage, and stroke have occurred in patients treated with 5-HT1 agonists, and some have resulted in fatalities. In number of cases, it appears possible that the cerebrovascular events were primary, the 5-HT1 agonist having been administered in the incorrect belief that the symptoms experienced were 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 rizatriptan benzoate if 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. Rizatriptan benzoate should not be administered to patients with history of stroke or transient ischemic attack [see Contraindications (4)].. 5.5 Other Vasospasm Reactions. 5-HT1 agonists, including rizatriptan benzoate, may cause non-coronary vasospastic reactions, such as peripheral vascular ischemia, gastrointestinal vascular ischemia and infarction (presenting with abdominal pain and bloody diarrhea), splenic infarction, and Raynauds syndrome. In patients who experience symptoms or signs suggestive of non-coronary vasospasm reaction following the use of any 5-HT1 agonist, the suspected vasospasm reaction should be ruled out before receiving additional rizatriptan benzoate doses. Reports of transient and permanent blindness and significant partial vision loss have been reported with the use of 5-HT1 agonists. Since visual disorders may be part of migraine attack, causal relationship between these events and the use of 5-HT1 agonists have not been clearly established. 5.6 Medication Overuse Headache. Overuse of acute migraine drugs (e.g., ergotamine, triptans, opioids, or combination of drugs for 10 or more days per month) may lead to exacerbation of headache (medication overuse headache). Medication overuse headache may present as migraine-like daily headaches, or as marked increase in frequency of migraine attacks. Detoxification of patients, including withdrawal of the overused drugs, and treatment of withdrawal symptoms (which often includes transient worsening of headache) may be necessary.. 5.7 Serotonin Syndrome. Serotonin syndrome may occur with triptans, including rizatriptan benzoate particularly during co-administration with selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and MAO inhibitors [see Drug Interactions (7.5)]. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The onset of symptoms can occur within minutes to hours of receiving new or greater dose of serotonergic medication. Rizatriptan benzoate treatment should be discontinued if serotonin syndrome is suspected [see Drug Interactions (7.4) and Patient Counseling Information (17)].. 5.8 Increase in Blood Pressure. Significant elevation in blood pressure, including hypertensive crisis with acute impairment of organ systems, has been reported on rare occasions in patients with and without history of hypertension receiving 5-HT1 agonists, including rizatriptan benzoate. In healthy young adult male and female patients who received maximal doses of rizatriptan benzoate (10 mg every hours for doses), slight increases in blood pressure (approximately 2-3 mmHg) were observed. Rizatriptan benzoate is contraindicated in patients with uncontrolled hypertension [see Contraindications (4)].