2.1 Dosing Information in Adults

The recommended starting dose of rizatriptan benzoate tablets is either 5 mg or 10 mg for the acute treatment of migraines in adults. The 10 mg dose may provide a greater effect than the 5 mg dose, but may have a greater risk of adverse reactions [see Clinical Studies (14.1)].

2.2 Dosing Information in Pediatric Patients (Age 6 to 17 Years)

Dosing in pediatric patients is based on the patient's body weight. The recommended dose of rizatriptan benzoate tablets is 5 mg in patients weighing less than 40 kg (88 lb), and 10 mg in patients weighing 40 kg (88 lb) or more.  



The efficacy and safety of treatment with more than one dose of rizatriptan benzoate tablets within 24 hours in pediatric patients 6 to 17 years of age have not been established.

2.4 Dosage Adjustment for Patients on Propranolol

Rizatriptan Benzoate Tablets

• Rizatriptan benzoate tablets 5 mg, are pale pink to pink colored, biconvex, capsule-shaped, uncoated tablets, debossed with ‘414’ on one side and ‘C’ on the other side. 
• Rizatriptan benzoate tablets 10 mg, are pale pink to pink colored, biconvex, capsule-shaped, uncoated tablets, debossed with ‘415’ on one side and ‘C’ on the other side.

5.1 Myocardial Ischemia, Myocardial Infarction, and Prinzmetal's Angina

Rizatriptan benzoate  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. Some of these reactions occurred in patients without known coronary artery disease (CAD). 5-HT1 agonists, including rizatriptan benzoate 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. If there is evidence of CAD or coronary artery vasospasm, rizatriptan benzoate 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  dose in a medically-supervised setting and performing an electrocardiogram (ECG) immediately following rizatriptan benzoate administration. Periodic cardiovascular evaluation should be considered in intermittent long-term users of rizatriptan benzoate who have cardiovascular risk factors.

5.2 Arrhythmias

Life-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-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 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-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 a 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 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  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 should not be administered to patients with a 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 Raynaud's 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 a migraine attack, a 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 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.

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 a new or a greater dose of a 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 a 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 2 hours for 3 doses), slight increases in blood pressure (approximately 2-3 mmHg) were observed. Rizatriptan benzoate is contraindicated in patients with uncontrolled hypertension [see Contraindications (4)].

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.

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.

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

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 6 times those in maternal plasma.  



The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for rizatriptan benzoate and any potential adverse effects on the breastfed infant from rizatriptan benzoate or from the underlying maternal condition.  



Data



Following oral administration of rizatriptan to lactating rats at a 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 6 years of age have not been established.

The efficacy and safety of rizatriptan benzoate in the acute treatment of migraine in patients aged 6 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 a cardiovascular evaluation prior to receiving rizatriptan benzoate  [see Warnings and Precautions (5.1)].

12.1 Mechanism of Action

Rizatriptan binds with high affinity to human cloned 5-HT1B/1D receptors. Rizatriptan benzoate 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

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14.1 Adults

The efficacy of rizatriptan benzoate tablets was established in four multicenter, randomized, placebo-controlled trials. Patients enrolled in these studies were primarily female (84%) and Caucasian (88%), with a mean age of 40 years (range of 18 to 71). Patients were instructed to treat a moderate to severe headache. Headache response, defined as a reduction of moderate or severe headache pain to no or mild headache pain, was assessed for up to 2 hours (Study 1) or up to 4 hours after dosing (Studies 2, 3 and 4). Associated symptoms of nausea, photophobia, and phonophobia and maintenance of response up to 24 hours post-dose were evaluated. A second dose of rizatriptan benzoate tablets was allowed 2 to 24 hours after dosing for treatment of recurrent headache in Studies 1 and 2. Additional analgesics and/or antiemetics were allowed 2 hours after initial treatment for rescue in all four studies.

In all studies, the percentage of patients achieving headache response 2 hours after treatment was significantly greater in patients who received either rizatriptan benzoate 5 or 10 mg compared to those who received placebo. In a 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.

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 2 hours following treatment in pooled Studies 1, 2, 3, and 4 is depicted in Figure 1.

Figure 1: Estimated Probability of Achieving an Initial Headache Response by 2 Hours in Pooled Studies 1, 2, 3, and 4††

†† Figure 1 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 4 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 2 hours were censored at 2 hours.

For patients with migraine-associated photophobia, phonophobia, and nausea at baseline, there was a 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 a second dose of study treatment or other medication. The estimated probability of patients taking a 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 a 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 4 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 2 hours and those who had no response to the initial dose. Remedication was not allowed within 2 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.

14.2 Pediatric Patients 6 to 17 Years of Age

The efficacy of rizatriptan benzoate orally disintegrating tablets in pediatric patients 6 to 17 years was evaluated in a multicenter, randomized, double-blind, placebo-controlled, parallel group clinical trial (Study 7). Patients had to have at least a 6-month history of migraine attacks (with or without aura) usually lasting 3 hours or more (when untreated). The patient population was historically non-responsive to NSAIDs and acetaminophen therapy.  



Patients were instructed to treat a single migraine attack with headache pain of moderate to severe intensity. The treatment phase of the study had two stages. Stage 1 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 a weight-based dosing strategy, patients 20 kg to <40 kg (44 lb to <88 lb) received rizatriptan benzoate orally disintegrating tablets 5 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 2 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 7 results are summarized in Table 4.



Table 4: Response Rates 2 Hours Following Treatment of Initial Headache in Pediatric Patients 6 to 17 Years of Age in Study 7

n = Number of evaluable patients with no headache pain at 2 hours post-dose.

m = Number of evaluable patients in population  



The observed percentage of pediatric patients achieving no headache pain within 2 hours following initial treatment with rizatriptan benzoate orally disintegrating tablets is shown in Figure 5.  



Figure 5: Observed Percentage of Patients Reporting No Headache Pain by 2 Hours Post-Dose in Study 7

The prevalence of the exploratory endpoints of absence of migraine-associated symptoms (nausea, photophobia, and phonophobia) at 2 hours after taking the dose was not statistically significantly different between patients who received rizatriptan benzoate orally disintegrating tablets and those who received placebo.

Storage

Store rizatriptan benzoate tablets at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature].