Rizatriptan Benzoate

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 Angina

  
  
  

  Rizatriptan 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 Angina

  
  
  

  Rizatriptan 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 Events

  
  
  

  Cerebral 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 Reactions

  
  
  

  5-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 Reactions

  
  
  

  5-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 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 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

  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 tablets within 24 hours is contraindicated

  [see Contraindications (4)]

  .

  and

  7.3 Other 5-HT₁Agonists

  
  
  

  Because 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 USAGE

  
  
  

  Rizatriptan benzoate tablets are indicated for the acute treatment of migraine with or without aura in adults and in pediatric patients 6 to 17 years old.
  
  
  
  

  Limitations of Use

  • Rizatriptan benzoate tablets should only be used where a clear diagnosis of migraine has been established. If a patient has no response for the first migraine attack treated with rizatriptan benzoate tablets, the diagnosis of migraine should be reconsidered before rizatriptan benzoate tablets are administered to treat any subsequent attacks.
  • Rizatriptan benzoate tablets are not  indicated  for  use  in  the  management  of  hemiplegic  or  basilar  migraine
    [see Contraindications (4)]
    .
  • Rizatriptan benzoate tablets are not indicated for the prevention of migraine attacks.
  • Safety and effectiveness of rizatriptan benzoate tablets have not been established for cluster headache.

  
  
  

  Rizatriptan benzoate  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

  7.5 Monoamine Oxidase Inhibitors

  
  
  

  Rizatriptan 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)]

  .

  and

  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 (C_max) are reached in approximately 1-1.5 hours (T_max). 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 C_maxof 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 T_maxdelayed 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-HT_1B/1Dreceptor. N-monodesmethyl-rizatriptan, a metabolite with activity similar to that of parent compound at the 5-HT_1B/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-HT_1B/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 (K_i=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 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 AUC_0-∞and C_maxof rizatriptan (10 mg orally) were about 30% and 11% higher in females as compared to males, respectively, while T_maxoccurred 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 AUC_0-∞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 C_maxof 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 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 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.

  ]
  .