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Generic: rizatriptan benzoate is used for the treatment of Angina Pectoris, Variant Cerebellar Ataxia Ischemic Attack, Transient Coronary Vasospasm Hypertension Ischemia Migraine Disorders Peripheral Vascular Diseases Migraine with Aura Stroke


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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/1D receptor 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 (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)

2 Dosage And Administration


  • •Adults: 5 or 10 mg single dose; separate repeat doses by at least 2 hours; maximum dose in a 24-hour period: 30 mg (2.1)
  • •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)
  • •Adjust dose if co-administered with propranolol (2.4)

2.1Dosing 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)].


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.

2.2Dosing 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.

2.4Dosage Adjustment for Patients on Propranolol



In adult patients taking propranolol, only the 5-mg dose of rizatriptan benzoate 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)].


For 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 Interactions (7.1) and Clinical Pharmacology (12.3)].

3 Dosage Forms And Strengths


Rizatriptan Benzoate Tablets: Rizatriptan Benzoate Tablets, USP are available 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 light pink, oval, unscored tablets debossed with RN5 on one side of the tablet and plain on the other side.
  • •The 10 mg tablets are light pink, oval, unscored tablets debossed with RN10 on one side of the tablet and plain on the other side.

  • •Rizatriptan Benzoate Tablets: 5 and 10 mg (3)

4 Contraindications


Rizatriptan benzoate tablets are contraindicated in patients with:

  • •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-HT1 agonist (e.g., another triptan), or of an ergotamine-containing medication (4)
  • •Hemiplegic or basilar migraine (4)
  • •MAO-A inhibitor used in the past 2 weeks (4)
  • •Hypersensitivity to rizatriptan or any of the excipients (4)

5 Warnings And Precautions


  • •Myocardial ischemia, myocardial infarction, and Prinzmetal’s 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)

5.1Myocardial Ischemia, Myocardial Infarction, and Prinzmetals 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-HT1 agonists, 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 tablet dose in a medically-supervised setting and performing an electrocardiogram (ECG) immediately following rizatriptan benzoate tablet administration. Periodic cardiovascular evaluation should be considered in intermittent long-term users of rizatriptan benzoate tablets who have cardiovascular risk factors.

5.2Arrhythmias


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 tablets if these disturbances occur.

5.3Chest, 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 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-HT1 agonists.

5.4Cerebrovascular 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 tablets 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)].

5.5Other Vasospasm Reactions


5-HT1 agonists, 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-HT1 agonist, the suspected vasospasm reaction should be ruled out before receiving additional rizatriptan benzoate tablet 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.

5.6Medication 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.

5.7Serotonin Syndrome


Serotonin 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 tablet treatment should be discontinued if serotonin syndrome is suspected [see Drug Interactions (7.4) and Patient Counseling Information (17)].

5.8Increase 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 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 are contraindicated in patients with uncontrolled hypertension [see Contraindications (4)].

6 Adverse Reactions


The following adverse reactions are discussed in more detail in other sections of the labeling:


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 Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1Clinical 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.


6.2Postmarketing 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 uled 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.

7 Drug Interactions


7.1Propranolol


The dose of rizatriptan benzoate tablets 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)].

7.2Ergot-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)].

7.3Other 5-HT Agonists


Because their vasospastic effects may be additive, co-administration of rizatriptan benzoate tablets and other 5-HT1 agonists within 24 hours of each other is contraindicated [see Contraindications (4)].

7.4SSRIs/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)].

7.5Monoamine Oxidase Inhibitors


Rizatriptan benzoate tablets are 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 Use In Specific Populations


  • •Pregnancy: Based on animal data, may cause fetal harm (8.1)

8.1 Pregnancy


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.


8.2 Lactation


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 tablets and any potential adverse effects on the breastfed infant from rizatriptan benzoate tablets or from the underlying maternal condition.


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 orally disintegrating tablets 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 orally disintegrating tablets 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 tablets 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 tablets [see Warnings and Precautions (5.1)].

10 Overdosage


No overdoses of rizatriptan benzoate tablets were reported during clinical trials in adults.

Some adult patients who received 40 mg of rizatriptan benzoate tablets 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 tablets, at total cumulative doses of 80 mg (given within 4 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 tablets, 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 tablets. 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.

11 Description


Rizatriptan benzoate tablets, USP contain rizatriptan benzoate, a selective 5-hydroxytryptamine1B/1D (5-HT1B/1D) receptor agonist.

Rizatriptan benzoate is described chemically as: 3-[2-(Dimethylamino)ethyl]-5-(1H-1,2,4-triazol-1-ylmethyl)indole monobenzoate and its structural formula is:

Its molecular formula is C15H19N5•C7H6O2, representing a molecular weight of the free base of 269.4. Rizatriptan benzoate, USP is a cream to white powder that is soluble in water at about 42 mg per mL (expressed as free base) at 25°C.

Rizatriptan benzoate tablets are available for oral administration in strengths of 5 and 10 mg (corresponding to 7.265 mg or 14.53 mg of the benzoate salt, respectively). Each compressed tablet contains the following inactive ingredients: lactose monohydrate, magnesium stearate, microcrystalline cellulose, pregelatinized starch (corn) and red iron oxide.

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



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 were 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.


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.


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, a metabolite with activity similar to that of parent compound at the 5-HT1B/1D receptor, 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/1D receptor.


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 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.


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.



[See also Drug Interactions (7).]

13 Nonclinical Toxicology


13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility


Oral 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.


Rizatriptan was neither mutagenic nor clastogenic in a 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.


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 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.

14 Clinical Studies


14.1Adults


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 tablets 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.
Table 2: Response Rates 2 Hours Following Treatment of Initial Headache in Studies 1, 2, 3, and 4

Study

Placebo

Rizatriptan Benzoate Tablets

5 mg

Rizatriptan Benzoate Tablets

10 mg

1

35%

(n = 304)

62%p-value < 0.05 in comparison with placebo.

(n = 458)

71% p-value < 0.05 in comparison with 5 mg.

(n = 456)

2Results for initial headache only.

37%

(n = 82)



77%

(n = 320)

3

23%

(n = 80)

63%

(n = 352)



4

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 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 tablets 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 tablets 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.

14.2Pediatric 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.

Endpoint

Placebo

Rizatriptan Benzoate

Orally Disintegrating Tablets

p-Value

No headache pain at 2 hours post-dose

24%

(n/m = 94/388)

33%

(n/m = 126/382)

0.01

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.

16 How Supplied/storage And Handling


Rizatriptan Benzoate Tablets, USP are available 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 light pink, oval, unscored tablets debossed with RN5 on one side of the tablet and plain on the other side. They are available as follows:

NDC 0378-1403-96bottles of 12 tablets

The 10 mg tablets are light pink, oval, unscored tablets debossed with RN10 on one side of the tablet and plain on the other side. They are available as follows:

NDC 0378-1404-96bottles of 12 tablets

Storage: Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]

Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.

17 Patient Counseling Information


Advise the patient to read the FDA-approved patient labeling (Patient Information).

Risk of Myocardial Ischemia and/or Infarction, Prinzmetal’s Angina, Other Vasospasm-Related Events, and Cerebrovascular Events: Inform patients that rizatriptan benzoate tablets 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 tablets 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 tablets should not be used during pregnancy unless the potential benefit justifies the potential risk to the fetus [see Use in Specific Populations (8.1)].

Lactation: Advise 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 tablets may cause somnolence and dizziness, instruct patients to evaluate their ability to perform complex tasks during migraine attacks and after administration of rizatriptan benzoate tablets.

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 a headache diary) [see Warnings and Precautions (5.6)].

Patient Information


Rizatriptan Benzoate Tablets, USP(rye″ za trip′ tan ben′ zoe ate)

Read this Patient Information before you start taking rizatriptan benzoate tablets and each time you get a refill. There may be new information. This information does not take the place of talking to your doctor about your medical condition or your treatment.

Unless otherwise stated, the information in this Patient Information leaflet applies to both rizatriptan benzoate tablets and to rizatriptan benzoate orally disintegrating tablets.

What is rizatriptan benzoate?

Rizatriptan benzoate is a prescription medicine that belongs to a class of medicines called Triptans. Rizatriptan benzoate is available as a traditional tablet and as an orally disintegrating tablet.

Rizatriptan benzoate tablets and rizatriptan benzoate orally disintegrating tablets are used to treat migraine attacks with or without aura in adults and in children 6 to 17 years of age.

Rizatriptan benzoate is not to be used to prevent migraine attacks.

Rizatriptan benzoate is not for the treatment of hemiplegic or basilar migraines.

It is not known if rizatriptan benzoate is safe and effective for the treatment of cluster headaches.

It is not known if taking more than 1 dose of rizatriptan benzoate in 24 hours is safe and effective in children 6 to 17 years of age.

It is not known if rizatriptan benzoate is safe and effective in children under 6 years of age.

Who should not take rizatriptan benzoate tablets?

Do not take rizatriptan benzoate tablets if you:
  • •have or have had heart problems
  • •have or have had a stroke or a transient ischemic attack (TIA)
  • •have or have had blood vessel problems including ischemic bowel disease
  • •have uncontrolled high blood pressure
  • •have taken other Triptan medicines in the last 24 hours
  • •have taken ergot-containing medicines in the last 24 hours
  • •have hemiplegic or basilar migraines
  • •take monoamine oxidase (MAO) inhibitor or have taken a MAO inhibitor within the last 2 weeks
  • •are allergic to rizatriptan benzoate or any of the ingredients in rizatriptan benzoate tablets. See the end of this leaflet for a complete ul of ingredients in rizatriptan benzoate tablets.

Talk to your doctor before taking this medicine if you have any of the conditions uled above or if you are not sure if you take any of these medicines.

What should I tell my doctor before taking rizatriptan benzoate tablets?

Before you take rizatriptan benzoate tablets, tell your doctor if you:
  • •have or have had heart problems, high blood pressure, chest pain, or shortness of breath
  • •have any risk factors for heart problems or blood vessel problems such as:
    • ohigh blood pressure
    • ohigh cholesterol
    • osmoking
    • oobesity
    • odiabetes
    • ofamily history of heart problems
    • oyou are post menopausal
    • oyou are a male over 40
  • •have kidney or liver problems
  • •have any other medical condition
  • •are pregnant or plan to become pregnant. It is not known if rizatriptan benzoate tablets will harm your unborn baby. If you become pregnant while taking rizatriptan benzoate tablets, talk to your healthcare provider.
  • •are breastfeeding or plan to breastfeed. It is not known if rizatriptan passes into your breast milk. Talk to your doctor about the best way to feed your baby if you take rizatriptan benzoate tablets.

Tell your doctor about all the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal supplements.

Rizatriptan benzoate tablets and other medicines may affect each other causing side effects. Rizatriptan benzoate tablets may affect the way other medicines work, and other medicines may affect how rizatriptan benzoate tablets work.

Especially tell your doctor if you take:
  • •propranolol containing medicines such as Inderal®, Inderal® LA, or Innopran® XL
  • •medicines used to treat mood disorders, including selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs).

Ask your doctor or pharmacist for a ul of these medicines, if you are not sure.

Know the medicines you take. Keep a ul of them to show your doctor and pharmacist when you get a new medicine.

How should I take rizatriptan benzoate tablets?
  • •Take rizatriptan benzoate tablets exactly as your doctor tells you to take them.
  • •Your doctor will tell you how many rizatriptan benzoate tablets to take and when to take them.
  • •If your headache comes back after your first rizatriptan benzoate tablets dose:
    • oFor adults: A second dose may be taken 2 hours after the first dose. Do not take more than 30 mg of rizatriptan benzoate tablets in a 24-hour period (for example, do not take more than 3 10-mg tablets in a 24-hour period).
    • oFor children 6 to 17 years of age: It is not known if taking more than 1 dose of rizatriptan benzoate tablets in 24 hours is safe and effective. Talk to your doctor about what to do if your headache does not go away or comes back.
  • •If you take too many rizatriptan benzoate tablets, call your doctor or go to the nearest hospital emergency room right away.

What should I avoid while taking rizatriptan benzoate tablets?

Rizatriptan benzoate tablets may cause dizziness, weakness, or fainting. If you have these symptoms, do not drive a car, use machinery, or do anything that needs you to be alert.

What are the possible side effects of rizatriptan benzoate tablets?

Rizatriptan benzoate tablets may cause serious side effects. Call your doctor or go to the nearest hospital emergency room right away if you think you are having any of the serious side effects of rizatriptan benzoate tablets including:
  • heart attack. Symptoms of a heart attack may include:
    • ochest discomfort in the center of your chest that lasts for more than a few minutes or that goes away and comes back
    • ochest discomfort that feels like uncomfortable pressure, squeezing, fullness or pain
    • opain or discomfort in your arms, back, neck, jaw or stomach
    • oshortness of breath with or without chest discomfort
    • obreaking out in a cold sweat
    • onausea or vomiting
    • ofeeling lightheaded
  • stroke. Symptoms of a stroke may include the following sudden symptoms:
    • onumbness or weakness in your face, arm or leg, especially on one side of your body
    • oconfusion, problems speaking or understanding
    • oproblems seeing in 1 or both of your eyes
    • oproblems walking, dizziness, loss of balance or coordination
    • osevere headache with no known cause
  • blood vessel problems. Symptoms of blood vessel problems may include:
    • ostomach pain
    • obloody diarrhea
    • ovision problems
    • ocoldness and numbness of hands and feet
  • serotonin syndrome. A condition called serotonin syndrome can happen when Triptan medicines such as rizatriptan benzoate tablets are taken with certain other medicines. Symptoms of serotonin syndrome may include:
    • oagitation
    • ohallucinations
    • ocoma
    • ofast heartbeat
    • ofast changes in your blood pressure
    • oincreased body temperature
    • omuscle spasm
    • oloss of coordination
    • onausea, vomiting or diarrhea
  • increased blood pressure.

The most common side effects of rizatriptan benzoate tablets in adults include:
  • •feeling sleepy or tired
  • •pain or pressure in your chest or throat
  • •dizziness

Tell your doctor if you have any side effect that bothers you or that does not go away.

If you take rizatriptan benzoate tablets too often, this may result in you getting chronic headaches. In such cases, you should contact your doctor, as you may have to stop taking rizatriptan benzoate tablets.

These are not all the possible side effects of rizatriptan benzoate tablets. For more information, ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store rizatriptan benzoate tablets?
  • •Store rizatriptan benzoate tablets at room temperature between 20° to 25°C (68° to 77°F).
  • •Safely throw away medicine that is out of date or no longer needed.

Keep rizatriptan benzoate tablets and all medicines out of the reach of children.

General information about the safe and effective use of rizatriptan benzoate tablets.

Medicines are sometimes prescribed for purposes other than those uled in a Patient Information leaflet. Do not use rizatriptan benzoate tablets for a condition for which they were not prescribed. Do not give rizatriptan benzoate tablets to other people, even if they have the same symptoms that you have. They may harm them.

This Patient Information leaflet summarizes the most important information about rizatriptan benzoate tablets. If you would like more information, talk to your doctor. You can ask your pharmacist or doctor for information about rizatriptan benzoate tablets that is written for health professionals.

For more information, call Mylan at 1-877-446-3679 (1-877-4-INFO-RX).

What are the ingredients in rizatriptan benzoate tablets?

Active ingredient in rizatriptan benzoate tablets: rizatriptan benzoate.

Inactive ingredients in rizatriptan benzoate tablets: lactose monohydrate, magnesium stearate, microcrystalline cellulose, pregelatinized starch (corn) and red iron oxide.

This Patient Information has been approved by the U.S. Food and Drug Administration.

The brands uled are trademarks of their respective owners.

Manufactured for: Mylan Pharmaceuticals Inc. Morgantown, WV 26505 U.S.A.

Manufactured by: Mylan Laboratories Limited Hyderabad — 500 096, India

75070485

Revised: 11/2019MX:RZTP:R3

Principal Display Panel - 5 Mg


NDC 0378-1403-96

Rizatriptan Benzoate Tablets, USP 5 mg

Rx only     12 Tablets

Each tablet contains7.265 mg of rizatriptan benzoate, USPequivalent to 5 mg of rizatriptan.

Usual Dosage: See accompanyingprescribing information.

Keep this and all medication out of the reach of children.

Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]

Manufactured for: Mylan Pharmaceuticals Inc. Morgantown, WV 26505 U.S.A.

Made in India

Mylan.com

RMX1403ES1

Dispense in a tight, light-resistantcontainer as defined in the USPusing a child-resistant closure.

Keep container tightly closed.

Code No.: MH/DRUGS/25/NKD/89

Principal Display Panel - 10 Mg


NDC 0378-1404-96

Rizatriptan Benzoate Tablets, USP 10 mg

Rx only     12 Tablets

Each tablet contains14.53 mg of rizatriptan benzoate, USPequivalent to 10 mg of rizatriptan.

Usual Dosage: See accompanyingprescribing information.

Keep this and all medication out of the reach of children.

Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]

Manufactured for: Mylan Pharmaceuticals Inc. Morgantown, WV 26505 U.S.A.

Made in India

Mylan.com

RMX1404ES1

Dispense in a tight, light-resistantcontainer as defined in the USPusing a child-resistant closure.

Keep container tightly closed.

Code No.: MH/DRUGS/25/NKD/89

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