Rizatriptan Benzoate (Page 2 of 7)

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 to 3 mmHg) were observed. Rizatriptan benzoate is 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:

6.1 Clinical Trials Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

Adults
Incidence in Controlled Clinical Trials

Adverse reactions to rizatriptan benzoate were assessed in controlled clinical trials that included over 3700 adult patients who received single or multiple doses of rizatriptan benzoate tablets. The most common adverse reactions during treatment with rizatriptan benzoate (≥5% in either treatment group and greater than placebo) were asthenia/fatigue, somnolence, pain/pressure sensation and dizziness. These adverse reactions appeared to be dose related. Table 1 lists the adverse reactions (incidence ≥2% and greater than placebo) after a single dose of rizatriptan benzoate in adults.

Table 1: Incidence (≥ 2% and Greater than Placebo) of Adverse Reactions After a Single Dose of Rizatriptan Benzoate Tablets or Placebo in Adults
Adverse Reactions % of Patients
Rizatriptan Benzoate Tablets 5 mg (N=977) Rizatriptan Benzoate Tablets 10 mg (N=1167) Placebo (N=627)
Atypical Sensations 4 5 4
Paresthesia 3 4 <2
Pain and other Pressure Sensations 6 9 3
Chest Pain:
tightness/pressure and/or heaviness <2 3 1
Neck/throat/jaw:
pain/tightness/pressure <2 2 1
Regional Pain:
tightness/pressure and/or heaviness <1 2 0
Pain, location unspecified 3 3 <2
Digestive 9 13 8
Dry Mouth 3 3 1
Nausea 4 6 4
Neurological 14 20 11
Dizziness 4 9 5
Headache <2 2 <1
Somnolence 4 8 4
Other
Asthenia/fatigue 4 7 2

The frequencies of adverse reactions in clinical trials did not increase when up to three doses were taken within 24 hours. Adverse reaction frequencies were also unchanged by concomitant use of drugs commonly taken for migraine prophylaxis (including propranolol), oral contraceptives, or analgesics. The incidences of adverse reactions were not affected by age or gender. There were insufficient data to assess the impact of race on the incidence of adverse reactions.

Other Events Observed in Association with the Administration of Rizatriptan Benzoate in Adults

In the following section, the frequencies of less commonly reported adverse events are presented that were not reported in other sections of the labeling. Because the reports include events observed in open studies, the role of rizatriptan benzoate in their causation cannot be reliably determined. Furthermore, variability associated with adverse event reporting, the terminology used to describe adverse events, limit the value of the quantitative frequency estimates provided. Event frequencies are calculated as the number of patients who used rizatriptan benzoate and reported an event divided by the total number of patients exposed to rizatriptan benzoate (N=3716). All reported events occurred at an incidence ≥1%, or are believed to be reasonably associated with the use of the drug. Events are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse events are those defined as those occurring in at least (>)1/100 patients; infrequent adverse experiences are those occurring in 1/100 to 1/1000 patients; and rare adverse experiences are those occurring in fewer than 1/1000 patients.

General: Infrequent was facial edema. Rare were syncope and edema/swelling.

Atypical Sensations: Frequent were warm sensations.

Cardiovascular:Frequent was palpitation. Infrequent were tachycardia, cold extremities, and bradycardia.

Digestive: Frequent were diarrhea and vomiting. Infrequent were dyspepsia, tongue edema and abdominal distention.

Musculoskeletal: Infrequent were muscle weakness, stiffness, myalgia and muscle cramp/spasm.

Neurological/Psychiatric: Frequent were hypoesthesia, euphoria and tremor. Infrequent were vertigo, insomnia, confusion/disorientation, gait abnormality, memory impairment, and agitation.

Respiratory:Frequent was dyspnea. Infrequent was pharyngeal edema.

Special Senses: Infrequent were blurred vision and tinnitus. Rare was eye swelling.

Skin and Skin Appendage: Frequent was flushing. Infrequent were sweating, pruritus, rash, and urticaria. Rare was erythema, hot flashes.
The adverse reaction profile seen with rizatriptan benzoate orally disintegrating tablets was similar to that seen with rizatriptan benzoate tablets.

Pediatric Patients 6 to 17 Years of Age

Incidence in Controlled Clinical Trials in Pediatric Patients

Adverse reactions to rizatriptan benzoate orally disintegrating tablets were assessed in a controlled clinical trial in the acute treatment of migraines (Study 7) that included a total of 1382 pediatric patients 6 to17 years of age, of which 977 (72%) administered at least one dose of study treatment (rizatriptan benzoate orally disintegrating tablets and/or placebo) [see Clinical Studies (14.2)]. The incidence of adverse reactions reported for pediatric patients in the acute clinical trial was similar in patients who received rizatriptan benzoate tablets to those who received placebo. The adverse reaction pattern in pediatric patients is expected to be similar to that in adults.

Other Events Observed in Association with the Administration of rizatriptan benzoate orally disintegrating tablets in Pediatric Patients
In the following section, the frequencies of less commonly reported adverse events are presented. Because the reports include events observed in open studies, the role of rizatriptan benzoate orally disintegrating tablets in their causation cannot be reliably determined. Furthermore, variability associated with adverse event reporting, the terminology used to describe adverse events, limit the value of the quantitative frequency estimates provided.
Event frequencies are calculated as the number of pediatric patients 6 to 17 years of age who used rizatriptan benzoate orally disintegrating tablets and reported an event divided by the total number of patients exposed to rizatriptan benzoate orally disintegrating tablets (N=1068). All reported events occurred at an incidence ≥1%, or are believed to be reasonably associated with the use of the drug. Events are further classified within system organ class and enumerated in order of decreasing frequency using the following definitions: frequent adverse events are those occurring in (>)1/100 pediatric patients; infrequent adverse experiences are those occurring in 1/100 to 1/1000 pediatric patients; and rare adverse experiences are those occurring in fewer than 1/1000 patients.

General: Frequent was fatigue.
Ear and labyrinth disorders: Infrequent was hypoacusis.
Gastrointestinal disorders: Frequent was abdominal discomfort.
Nervous system disorders: Infrequent were coordination abnormal, disturbance in attention, and presyncope.Psychiatric disorders: Infrequent was hallucination.

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