Rizatriptan Benzoate
Rizatriptan Benzoate Prescribing Information
Rizatriptan benzoate tablets are indicated for the acute treatment of migraine with or without aura in adults and in pediatric patients 6 to 17 years old.
- Rizatriptan benzoate tablets should only be used where a clear diagnosis of migraine has been established. If a patient has no response for the first migraine attack treated with rizatriptan benzoate tablets, the diagnosis of migraine should be reconsidered before rizatriptan benzoate tablets are administered to treat any subsequent attacks.
- Rizatriptan benzoate tablets are not indicated for use in the management of hemiplegic or basilar migraine [see.]
4 CONTRAINDICATIONSRizatriptan benzoate tablets are contraindicated in patients with:
- Ischemic coronary artery disease (angina pectoris, history of myocardial infarction, or documented silent ischemia), or other significant underlying cardiovascular disease[see Warnings and Precautions (5.1)].
- Coronary artery vasospasm including Prinzmetal's angina[see Warnings and Precautions(5.1)].
- History of stroke or transient ischemic attack (TIA)[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 (7.2and 7.3)].
- Hemiplegic or basilar migraine[see Indications and Usage ].
- Concurrent administration or recent discontinuation (i.e., within 2 weeks) of a MAO-A inhibitor[see Drug Interactions (7.5)and Clinical Pharmacology (12.3)].
- Hypersensitivity to rizatriptan or any of the excipients (angioedema and anaphylaxis seen)[see Adverse Reactions (6.2)].
- History of ischemic heart disease or coronary artery vasospasm
- History of stroke or transient ischemic attack
- Peripheral vascular disease
- Ischemic bowel disease
- Uncontrolled hypertension
- Recent (within 24 hours) use of another 5-HT1agonist (e.g., another triptan), or of an ergotamine-containing medication
- Hemiplegic or basilar migraine
- MAO-A inhibitor used in the past 2 weeks
- Hypersensitivity to rizatriptan or any of the excipients
- Ischemic coronary artery disease (angina pectoris, history of myocardial infarction, or documented silent ischemia), or other significant underlying cardiovascular disease
- 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.
- Adults: 5 or 10 mg single dose; separate repeat doses by at least two hours; maximum dose in a 24-hour period: 30 mg ()
2.1 Dosing Information in AdultsThe recommended starting dose of rizatriptan benzoate tablets are 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. - Pediatric patients 6 to 17 years: 5 mg single dose in patients less than 40 kg (88 lb); 10 mg single dose in patients 40 kg (88 lb) or more ()
2.2 Dosing Information in Pediatric Patients (Age 6 to 17 Years)Dosing in pediatric patients is based on the patient's body weight. The recommended dose of rizatriptan benzoate tablets is 5 mg in patients weighing less than 40 kg (88 lb), and 10 mg in patients weighing 40 kg (88 lb) or more.
The efficacy and safety of treatment with more than one dose of rizatriptan benzoate tablet within 24 hours in pediatric patients 6 to 17 years of age have not been established.
- Adjust dose if co-administered with propranolol ()
2.4 Dosage Adjustment for Patients on PropranololAdult Patients
In adult patients taking propranolol, only the 5-mg dose of rizatriptan benzoate tablets are 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 PatientsFor pediatric patients weighing 40 kg (88 lb) or more, taking propranolol, only a single 5-mg dose of rizatriptan benzoate tablets is recommended (maximum dose of 5 mg in a 24-hour period). Rizatriptan benzoate tablets should not be prescribed to propranolol-treated pediatric patients who weigh less than 40 kg (88 lb)
[see Drug Interactionsand Clinical Pharmacology ].
- 5 mg tablets are white to off-white, capsule-shaped, compressed tablets debossed “RZT” on one side and “5” on other side.
- 10 mg tablets are white to off-white, capsule-shaped, compressed tablets debossed “RZT” on one side and “10” on other side.
- Pregnancy: Based on animal data, may cause fetal harm ()
8.1 PregnancyRisk Summary
Available human data on the use of rizatriptan benzoate tablets 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 Risk
In women with migraine, there is an increased risk of adverse perinatal outcomes in the mother, including pre-eclampsia and gestational hypertension.DataHuman Data
The Pregnancy Registry for rizatriptan benzoate tablets 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 tablets. Additionally, there was significant loss to follow-up in the prospective pregnancy reports, further complicating this assessment of an association between rizatriptan benzoate tablets 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 from birth and throughout lactation at all but the lowest dose tested (2 mg/kg/day). Plasma exposure (AUC) at the no-effect dose (2 mg/kg/day) for adverse effects on postnatal development was similar to that in humans at the MRHD.
Oral administration of rizatriptan (0, 5, 100, or 250 mg/kg/day) throughout organogenesis and lactation resulted in neonatal mortality, reduced body weight (which persisted into adulthood), and impaired neurobehavioral function in offspring at all but the lowest dose tested. Plasma exposure (AUC) at the no-effect dose for adverse effects on postnatal development (5 mg/kg/day) was approximately 8 times that in humans at the MRHD.
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.]
5.1 Myocardial Ischemia, Myocardial Infarction, and Prinzmetal's AnginaRizatriptan benzoate tablets should not be given to patients with ischemic or vasospastic coronary artery disease. There have been rare reports of serious cardiac adverse reactions, including acute myocardial infarction, occurring within a few hours following administration of rizatriptan benzoate tablets. Some of these reactions occurred in patients without known coronary artery disease (CAD). 5-HT1agonists, including rizatriptan benzoate tablets may cause coronary artery vasospasm (Prinzmetal's Angina), even in patients without a history of CAD.
Triptan-naïve patients who have multiple cardiovascular risk factors (e.g., increased age, diabetes, hypertension, smoking, obesity, strong family history of CAD) should have a cardiovascular evaluation prior to receiving rizatriptan benzoate tablets. If there is evidence of CAD or coronary artery vasospasm, rizatriptan benzoate tablets should not be administered[see Contraindications (4)]. For patients who have a negative cardiovascular evaluation, consideration should be given to administration of the first rizatriptan benzoate tablets dose in a medically supervised setting and performing an electrocardiogram (ECG) immediately following rizatriptan benzoate tablets administration. Periodic cardiovascular evaluation should be considered in intermittent long-term users of rizatriptan benzoate tablets who have cardiovascular risk factors. - Coronary artery vasospasm including Prinzmetal's angina [see.]
5.1 Myocardial Ischemia, Myocardial Infarction, and Prinzmetal's AnginaRizatriptan benzoate tablets should not be given to patients with ischemic or vasospastic coronary artery disease. There have been rare reports of serious cardiac adverse reactions, including acute myocardial infarction, occurring within a few hours following administration of rizatriptan benzoate tablets. Some of these reactions occurred in patients without known coronary artery disease (CAD). 5-HT1agonists, including rizatriptan benzoate tablets may cause coronary artery vasospasm (Prinzmetal's Angina), even in patients without a history of CAD.
Triptan-naïve patients who have multiple cardiovascular risk factors (e.g., increased age, diabetes, hypertension, smoking, obesity, strong family history of CAD) should have a cardiovascular evaluation prior to receiving rizatriptan benzoate tablets. If there is evidence of CAD or coronary artery vasospasm, rizatriptan benzoate tablets should not be administered[see Contraindications (4)]. For patients who have a negative cardiovascular evaluation, consideration should be given to administration of the first rizatriptan benzoate tablets dose in a medically supervised setting and performing an electrocardiogram (ECG) immediately following rizatriptan benzoate tablets administration. Periodic cardiovascular evaluation should be considered in intermittent long-term users of rizatriptan benzoate tablets who have cardiovascular risk factors. - History of stroke or transient ischemic attack (TIA) [see.]
5.4 Cerebrovascular EventsCerebral hemorrhage, subarachnoid hemorrhage, and stroke have occurred in patients treated with 5-HT1agonists, and some have resulted in fatalities. In a number of cases, it appears possible that the cerebrovascular events were primary, the 5-HT1agonist having been administered in the incorrect belief that the symptoms experienced were a consequence of migraine, when they were not. Also, patients with migraine may be at increased risk of certain cerebrovascular events (e.g., stroke, hemorrhage, transient ischemic attack). Discontinue rizatriptan benzoate tablets, USP if a cerebrovascular event occurs.
As with other acute migraine therapies, before treating headaches in patients not previously diagnosed as migraineurs, and in migraineurs who present with atypical symptoms, care should be taken to exclude other potentially serious neurological conditions. Rizatriptan benzoate tablets should not be administered to patients with a history of stroke or transient ischemic attack[see Contraindications (4)]. - Peripheral vascular disease (PVD) [see.]
5.5 Other Vasospasm Reactions5-HT1agonists, including rizatriptan benzoate tablets, 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 Raynaud’s syndrome. In patients who experience symptoms or signs suggestive of non-coronary vasospasm reaction following the use of any 5-HT1agonist, the suspected vasospasm reaction should be ruled out before receiving additional rizatriptan benzoate tablets doses.
Reports of transient and permanent blindness and significant partial vision loss have been reported with the use of 5-HT1agonists. Since visual disorders may be part of a migraine attack, a causal relationship between these events and the use of 5-HT1agonists have not been clearly established. - Ischemic bowel disease [see.]
5.5 Other Vasospasm Reactions5-HT1agonists, including rizatriptan benzoate tablets, 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 Raynaud’s syndrome. In patients who experience symptoms or signs suggestive of non-coronary vasospasm reaction following the use of any 5-HT1agonist, the suspected vasospasm reaction should be ruled out before receiving additional rizatriptan benzoate tablets doses.
Reports of transient and permanent blindness and significant partial vision loss have been reported with the use of 5-HT1agonists. Since visual disorders may be part of a migraine attack, a causal relationship between these events and the use of 5-HT1agonists have not been clearly established. - Uncontrolled hypertension [see.]
5.8 Increase in Blood PressureSignificant elevation in blood pressure, including hypertensive crisis with acute impairment of organ systems, has been reported on rare occasions in patients with and without a history of hypertension receiving 5-HT1agonists, including rizatriptan benzoate tablets. In healthy young adult male and female patients who received maximal doses of rizatriptan benzoate tablets (10 mg every 2 hours for 3 doses), slight increases in blood pressure (approximately 2-3 mmHg) were observed. Rizatriptan benzoate tablets is contraindicated in patients with uncontrolled hypertension
[see Contraindications (4)]. - 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.and
7.2 Ergot-Containing DrugsErgot-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 tablets within 24 hours is contraindicated
[see Contraindications (4)].]7.3 Other 5-HT1AgonistsBecause their vasospastic effects may be additive, co-administration of rizatriptan benzoate tablets and other 5-HT1agonists within 24 hours of each other is contraindicated
[see Contraindications (4)]. - Hemiplegic or basilar migraine [see Indications and Usage ()].
1 INDICATIONS AND USAGERizatriptan benzoate tablets are indicated for the acute treatment of migraine with or without aura in adults and in pediatric patients 6 to 17 years old.
Limitations of Use- Rizatriptan benzoate tablets should only be used where a clear diagnosis of migraine has been established. If a patient has no response for the first migraine attack treated with rizatriptan benzoate tablets, the diagnosis of migraine should be reconsidered before rizatriptan benzoate tablets are administered to treat any subsequent attacks.
- Rizatriptan benzoate tablets are not indicated for use in the management of hemiplegic or basilar migraine[see Contraindications (4)].
- Rizatriptan benzoate tablets are not indicated for the prevention of migraine attacks.
- Safety and effectiveness of rizatriptan benzoate tablets have not been established for cluster headache.
Rizatriptan benzoate tablets are a serotonin (5-HT)1B/1Dreceptor agonist (triptan) indicated for the acute treatment of migraine with or without aura in adults and in pediatric patients 6 to 17 years of age
Limitations of Use:- Use only after clear diagnosis of migraine has been established
- Not indicated for the prophylactic therapy of migraine
- Not indicated for the treatment of cluster headache
- Concurrent administration or recent discontinuation (i.e., within 2 weeks) of a MAO-A inhibitor [see.and
7.5 Monoamine Oxidase InhibitorsRizatriptan benzoate tablets 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)].]12.3 PharmacokineticsAbsorption
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 a migraine headache did not appear to affect the absorption or pharmacokinetics of rizatriptan. Food has no significant effect on the bioavailability of rizatriptan but delays the time to reach peak concentration by an hour. In clinical trials, rizatriptan benzoate tablets was administered without regard to food.The bioavailability and Cmaxof 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 Tmaxdelayed 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/1Dreceptor. N-monodesmethyl-rizatriptan, a metabolite with activity similar to that of parent compound at the 5-HT1B/1Dreceptor, is formed to a minor degree. Plasma concentrations of N-monodesmethyl-rizatriptan are approximately 14% of those of parent compound, and it is eliminated at a similar rate. Other minor metabolites, the N-oxide, the 6-hydroxy compound, and the sulfate conjugate of the 6-hydroxy metabolite are not active at the 5-HT1B/1Dreceptor.Elimination
The total radioactivity of the administered dose recovered over 120 hours in urine and feces was 82% and 12%, respectively, following a single 10-mg oral administration of14C-rizatriptan. Following oral administration of14C-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 a competitive inhibitor (Ki=1400 nM) of cytochrome P450 2D6, but only at high, clinically irrelevant concentrations.Special PopulationsGeriatric: 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 6 to 17 years of age. Exposures following single dose administration of 5 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 Cmaxof rizatriptan (10 mg orally) were about 30% and 11% higher in females as compared to males, respectively, while Tmaxoccurred 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 a 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, ‘A’ subtype (MAO-A). Plasma concentrations of rizatriptan may be increased by drugs that are selective MAO-A inhibitors (e.g., moclobemide) or nonselective MAO inhibitors [type A and B] (e.g., isocarboxazid, phenelzine, tranylcypromine, and pargyline). In a drug interaction study, when rizatriptan benzoate tablets 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 Cmaxof 119% and 41% respectively; and the AUC of the active N-monodesmethyl metabolite of rizatriptan was increased more than 400%. The interaction would be expected to be greater with irreversible MAO inhibitors. No pharmacokinetic interaction is anticipated in patients receiving selective MAO-B inhibitors[see Contraindications (4)and Drug Interactions (7.5)].Propranolol: In a study of concurrent administration of propranolol 240 mg/day and a single dose of rizatriptan 10 mg in healthy adult subjects (n=11), mean plasma AUC for rizatriptan was increased by 70% during propranolol administration, and a four-fold increase was observed in one subject. The AUC of the active N-monodesmethyl metabolite of rizatriptan was not affected by propranolol[see Dosage and Administration (2.4)and Drug Interactions (7.1)].Nadolol/Metoprolol: In a drug interactions study, effects of multiple doses of nadolol 80 mg or metoprolol 100 mg every 12 hours on the pharmacokinetics of a single dose of 10 mg rizatriptan were evaluated in healthy subjects (n=12). No pharmacokinetic interactions were observed.Paroxetine: In a study of the interaction between the selective serotonin reuptake inhibitor (SSRI) paroxetine 20 mg/day for two weeks and a single dose of rizatriptan benzoate tablets 10 mg in healthy subjects (n=12), neither the plasma concentrations of rizatriptan nor its safety profile were affected by paroxetine[see Warnings and Precautions (5.7), Drug Interactions (7.4), and Patient Counseling Information (17)].Oral contraceptives: In a study of concurrent administration of an oral contraceptive during 6 days of administration of rizatriptan benzoate tablets (10 mg/day to 30 mg/day) in healthy female volunteers (n=18), rizatriptan did not affect plasma concentrations of ethinyl estradiol or norethindrone. - Hypersensitivity to rizatriptan or any of the excipients (angioedema and anaphylaxis seen) [see.]
6.2 Postmarketing ExperienceThe 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 tablets 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.
- Myocardial ischemia, myocardial infarction, and Prinzmetal's angina: Perform cardiac evaluation in patients with multiple cardiovascular risk factors ()
5.1 Myocardial Ischemia, Myocardial Infarction, and Prinzmetal's AnginaRizatriptan benzoate tablets should not be given to patients with ischemic or vasospastic coronary artery disease. There have been rare reports of serious cardiac adverse reactions, including acute myocardial infarction, occurring within a few hours following administration of rizatriptan benzoate tablets. Some of these reactions occurred in patients without known coronary artery disease (CAD). 5-HT1agonists, including rizatriptan benzoate tablets may cause coronary artery vasospasm (Prinzmetal's Angina), even in patients without a history of CAD.
Triptan-naïve patients who have multiple cardiovascular risk factors (e.g., increased age, diabetes, hypertension, smoking, obesity, strong family history of CAD) should have a cardiovascular evaluation prior to receiving rizatriptan benzoate tablets. If there is evidence of CAD or coronary artery vasospasm, rizatriptan benzoate tablets should not be administered[see Contraindications (4)]. For patients who have a negative cardiovascular evaluation, consideration should be given to administration of the first rizatriptan benzoate tablets dose in a medically supervised setting and performing an electrocardiogram (ECG) immediately following rizatriptan benzoate tablets administration. Periodic cardiovascular evaluation should be considered in intermittent long-term users of rizatriptan benzoate tablets who have cardiovascular risk factors. - Arrhythmias: Discontinue dosing if occurs ()
5.2 ArrhythmiasLife-threatening disturbances of cardiac rhythm, including ventricular tachycardia and ventricular fibrillation leading to death, have been reported within a few hours following the administration of 5-HT1agonists. Discontinue rizatriptan benzoate tablets if these disturbances occur.
- Chest/throat/neck/jaw pain, tightness, pressure, or heaviness; Generally not associated with myocardial ischemia; Evaluate patients at high risk ()
5.3 Chest, Throat, Neck and/or Jaw Pain/Tightness/PressureAs with other 5-HT1agonists, sensations of tightness, pain, pressure, and heaviness in the precordium, throat, neck and jaw commonly occur after treatment with rizatriptan benzoate tablets and are usually non-cardiac in origin. However, if a cardiac origin is suspected, patients should be evaluated. Patients shown to have CAD and those with Prinzmetal's variant angina should not receive 5-HT1agonists.
- Cerebral hemorrhage, subarachnoid hemorrhage, and stroke: Discontinue dosing if occurs ()
5.4 Cerebrovascular EventsCerebral hemorrhage, subarachnoid hemorrhage, and stroke have occurred in patients treated with 5-HT1agonists, and some have resulted in fatalities. In a number of cases, it appears possible that the cerebrovascular events were primary, the 5-HT1agonist having been administered in the incorrect belief that the symptoms experienced were a consequence of migraine, when they were not. Also, patients with migraine may be at increased risk of certain cerebrovascular events (e.g., stroke, hemorrhage, transient ischemic attack). Discontinue rizatriptan benzoate tablets, USP if a cerebrovascular event occurs.
As with other acute migraine therapies, before treating headaches in patients not previously diagnosed as migraineurs, and in migraineurs who present with atypical symptoms, care should be taken to exclude other potentially serious neurological conditions. Rizatriptan benzoate tablets should not be administered to patients with a history of stroke or transient ischemic attack[see Contraindications (4)]. - Gastrointestinal ischemic events, peripheral vasospastic reactions: Discontinue dosing if occurs ()
5.5 Other Vasospasm Reactions5-HT1agonists, including rizatriptan benzoate tablets, 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 Raynaud’s syndrome. In patients who experience symptoms or signs suggestive of non-coronary vasospasm reaction following the use of any 5-HT1agonist, the suspected vasospasm reaction should be ruled out before receiving additional rizatriptan benzoate tablets doses.
Reports of transient and permanent blindness and significant partial vision loss have been reported with the use of 5-HT1agonists. Since visual disorders may be part of a migraine attack, a causal relationship between these events and the use of 5-HT1agonists have not been clearly established. - Medication overuse headache: Detoxification may be necessary ()
5.6 Medication Overuse HeadacheOveruse of acute migraine drugs (e.g., ergotamine, triptans, opioids, or a 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 a marked increase in frequency of migraine attacks. Detoxification of patients, including withdrawal of the overused drugs, and treatment of withdrawal symptoms (which often includes a transient worsening of headache) may be necessary.
- Serotonin syndrome: Discontinue dosing if occurs ()
5.7 Serotonin SyndromeSerotonin syndrome may occur with triptans, including rizatriptan benzoate tablets 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 a new or a greater dose of a serotonergic medication. Rizatriptan benzoate tablets treatment should be discontinued if serotonin syndrome is suspected[see Drug Interactions (7.4)and Patient Counseling Information (17)].