Rizatriptan Benzoate ODT

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

2.1 Dosing Information in Adults The recommended starting dose of rizatriptan benzoate orally disintegrating 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 orally disintegrating 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 orally disintegrating tablets within 24 hours in pediatric patients 6 to 17 years of age have not been established. 2.3 Administration of Rizatriptan Benzoate Orally Disintegrating Tablets For rizatriptan benzoate orally disintegrating tablets, administration with liquid is not necessary. Orally disintegrating tablets are packaged in a blister within a carton and patients should not remove the blister from the carton until just prior to dosing. The blister pack should then be peeled open with dry hands and the orally disintegrating tablet placed on the tongue, where it will dissolve and be swallowed with the saliva. 2.4 Dosage Adjustment for Patients on Propranolol Adult Patients In adult patients taking propranolol, only the 5-mg dose of rizatriptan benzoate orally disintegrating 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 orally disintegrating tablets is recommended (maximum dose of 5 mg in a 24-hour period). Rizatriptan benzoate orally disintegrating 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)].v

Rizatriptan Benzoate Orally Disintegrating Tablets USP 5 mg orally disintegrating tablets are white to off-white colored, circular, biconvex, uncoated tablets debossed with ‘F24’ on one side and plain on other side with a peppermint flavor. 10 mg orally disintegrating tablets are white to off-white colored, circular, biconvex, uncoated tablets debossed with ‘F25’ on one side and plain on other side with a peppermint

Rizatriptan benzoate orally disintegrating 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) [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-HT1 agonist, ergotamine-containing medication, or ergot-type medication (such as dihydroergotamine or methysergide) [see Drug Interactions (7.2 and 7.3)]. • Hemiplegic or basilar migraine [see Indications and Usage (1)]. • Concurrent administration or recent discontinuation (i.e., within 2 weeks) of a MAO-A inhibitor [see Drug Interactions (7.5) and Clinical Pharmacology (12.3)]. •Hypersensitivity to rizatriptan or any of the excipients (angioedema and anaphylaxis seen) [see Adverse Reactions (6.2)].

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 Adverse Reactions % of Patients Rizatriptan Benzoate Tablets 5 mg (N=977) Rizatriptan Benzoate Tablets 10 mg (N=1167) Placebo (N=627) Atypical Sensations Paresthesia Pain and other Pressure Sensations Chest Pain: tightness/pressure and/or heaviness Neck/throat/jaw: pain/tightness/pressure Regional Pain: tightness/pressure and/or heaviness Pain, location unspecified Digestive Dry Mouth Nausea Neurological Dizziness Headache Somnolence Other Asthenia/fatigue 4 3 6 )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 Incidence in Controlled Clinical Trials in Pediatric Patients Adverse reactions to rizatriptan benzoate orally disintegrating tablets were assessed in a controlled clinical trial in the acute treatment of migraines (Study 7) that included a total of 1382 pediatric patients 6 to17 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 p …

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. A specific MAO-A inhibitor increased the systemic exposure of rizatriptan and its metabolite [see Contraindications (4) and Clinical Pharmacology (12.3)].

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 and continuing throughout gestation and lactation resulted in reduced body weight in offspring …

Rizatriptan benzoate orally disintegrating tablets, USP contain rizatriptan benzoate, a 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: [structure] Its molecular formula is C15H19N5•C7H6O2, representing a molecular weight of the free base of 269.4. Rizatriptan benzoate, USP is a white to off-white, crystalline solid that is soluble in water at about 42 mg per mL (expressed as free base) at 25°C. Rizatriptan benzoate orally disintegrating 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 orally disintegrating tablet contains following inactive ingredients: microcrystalline cellulose, colloidal silicon dioxide, carboxymethyl cellulose calcium, magnesium stearate, mannitol, aspartame, and peppermint flavor. USP Dissolution Test 2.

No overdoses of rizatriptan benzoate were reported during clinical trials in adults. Some adult patients who received 40 mg of rizatriptan benzoate 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, at total cumulative doses of 80 mg (given within four hours), two of the subjects experienced syncope, dizziness, bradycardia including third degree AV block, vomiting, and/or incontinence. In the long-term, open label study, involving 606 treated pediatric migraineurs 12 to 17 years of age (of which 432 were treated for at least 12 months), 151 patients (25%) took two 10 mg doses of rizatriptan benzoate orally disintegrating tablets within a 24-hour period. Adverse reactions for 3 of these patients included abdominal discomfort, fatigue, and dyspnea. In addition, based on the pharmacology of rizatriptan benzoate, hypertension or myocardial ischemia could occur after overdosage. Gastrointestinal decontamination, (i.e., gastric lavage followed by activated charcoal) should be considered in patients suspected of an overdose with 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.

Rizatriptan Benzoate Orally Disintegrating Tablets, USP are available in strengths of 5 mg and 10 mg containing 7.265 mg or 14.53 mg of rizatriptan benzoate, USP equivalent to 5 mg or 10 mg of rizatriptan, respectively. The 5 mg tablets are white to off-white, round shaped uncoated tablets debossed with 'L58' on one side and plain on other side. They are available as follows: NDC 33342-093-48 PVC/PE/PVDC blister card of 10 tablets per triple laminated pouch, 4 Triple laminated pouches per carton (40 tablets total). NDC 33342-093-04 Container pack of 12 tablets NDC 33342-093-23 Container pack of 18 tablets NDC33342-093-07 Container pack 30 tablets NDC33342-093-46 Container pack of 200 tablets NDC33342-093-12 Unit Dose Blister Package of 100 (10 x 10) tablets NDC33342-093-52 Unit Dose Blister Package of 3 (1 x 3) tablets NDC33342-093-73 Unit Dose Blister Package of 9 (3 x 3) tablets NDC33342-093-72 Unit Dose Blister Package of 18 (6 x 3) tablets NDC33342-093-41 Unit Dose Blister Package of 18 (3 x 6) tablets NDC33342-093-45 Unit Dose Blister Package of 12 (2 x 6) tablets The 10 mg tablets are white to off-white, round shaped uncoated tablets debossed with 'L59' on one side and plain on other side. They are available as follows: NDC 33342-094-47 PVC/PE/PVDC blister card of 5 tablets per triple laminated pouch, 4 Triple laminated pouches per carton (20 tablets total). NDC33342-094-04 Container pack of 12 tablets NDC72189-609-18 Container pack of 18 tablets NDC33342-094-07 Container pack 30 tablets NDC33342-094-46 Container pack of 200 tablets NDC33342-094-12 Unit Dose Blister Package of 100 (10 x 10) tablets NDC33342-094-52 Unit Dose Blister Package of 3 (1 x 3) tablets NDC33342-094-73 Unit Dose Blister Package of 9 (3 x 3) tablets NDC33342-094-72 Unit Dose Blister Package of 18 (6 x 3) tablets NDC33342-094-41 Unit Dose Blister Package of 18 (3 x 6) tablets NDC33342-094-45 Unit Dose Blister Package of 12 (2 x 6) tablets