WARNINGS
MAXALT should only be used where a clear diagnosis of migraine has been established.
Risk of Myocardial Ischemia and/or Infarction and Other Adverse Cardiac Events:
Because of the potential of this class of compounds (5-HT1B/1D agonists) to cause coronary vasospasm, MAXALT should not be given to patients with documented ischemic or vasospastic coronary artery disease (see
CONTRAINDICATIONS
). It is strongly recommended that rizatriptan not be given to patients in whom unrecognized coronary artery disease (CAD) is predicted by the presence of risk factors (e.g., hypertension, hypercholesterolemia, smoker, obesity, diabetes, strong family history of CAD, female with surgical or physiological menopause, or male over 40 years of age) unless a cardiovascular evaluation provides satisfactory clinical evidence that the patient is reasonably free of coronary artery and ischemic myocardial disease or other significant underlying cardiovascular disease. The sensitivity of cardiac diagnostic procedures to detect cardiovascular disease or predisposition to coronary artery vasospasm is modest, at best. If, during the cardiovascular evaluation, the patient’s medical history, electrocardiographic or other investigations reveal findings indicative of, or consistent with, coronary artery vasospasm or myocardial ischemia, rizatriptan should not be administered (see
CONTRAINDICATIONS
).
For patients with risk factors predictive of CAD, who are determined to have a satisfactory cardiovascular evaluation, it is strongly recommended that administration of the first dose of rizatriptan take place in the setting of a physician’s office or similar medically staffed and equipped facility unless the patient has previously received rizatriptan. Because cardiac ischemia can occur in the absence of clinical symptoms, consideration should be given to obtaining on the first occasion of use an electrocardiogram (ECG) during the interval immediately following MAXALT, in these patients with risk factors.
It is recommended that patients who are intermittent long-term users of MAXALT and who have or acquire risk factors predictive of CAD, as described above, undergo periodic interval cardiovascular evaluation as they continue to use MAXALT.
The systematic approach described above is intended to reduce the likelihood that patients with unrecognized cardiovascular disease will be inadvertently exposed to rizatriptan.
Cardiac Events and Fatalities Associated with 5-HT1 Agonists: Serious adverse cardiac events, including acute myocardial infarction, have been reported within a few hours following the administration of rizatriptan. Life-threatening disturbances of cardiac rhythm and death have been reported within a few hours following the administration of other 5-HT1 agonists. Considering the extent of use of 5-HT1 agonists in patients with migraine, the incidence of these events is extremely low. MAXALT can cause coronary vasospasm. Because of the close proximity of the events to MAXALT use, a causal relationship cannot be excluded. In the cases where there has been known underlying coronary artery disease, the relationship is uncertain.
Premarketing experience with rizatriptan: Among the 3700 patients with migraine who participated in premarketing clinical trials of MAXALT, one patient was reported to have chest pain with possible ischemic ECG changes following a single dose of 10 mg.
Postmarketing experience with rizatriptan: Serious cardiovascular events have been reported in association with the use of MAXALT. The uncontrolled nature of postmarketing surveillance, however, makes it impossible to determine definitively the proportion of the reported cases that were actually caused by rizatriptan or to reliably assess causation in individual cases.
Cerebrovascular Events and Fatalities Associated with 5-HT1 Agonists: Cerebral hemorrhage, subarachnoid hemorrhage, stroke, and other cerebrovascular events have been reported 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 agonist having been administered in the incorrect belief that the symptoms experienced were a consequence of migraine, when they were not. It should be noted that patients with migraine may be at increased risk of certain cerebrovascular events (e.g., stroke, hemorrhage, transient ischemic attack).
Other Vasospasm-Related Events: 5-HT1 agonists may cause vasospastic reactions other than coronary artery vasospasm. Both peripheral vascular ischemia and colonic ischemia with abdominal pain and bloody diarrhea have been reported with 5-HT1 agonists.
Increase in Blood Pressure: Significant elevation in blood pressure, including hypertensive crisis, has been reported on rare occasions in patients receiving 5-HT1 agonists with and without a history of hypertension. In healthy young male and female subjects who received maximal doses of MAXALT (10 mg every 2 hours for 3 doses), slight increases in blood pressure (approximately 2-3 mmHg) were observed. Rizatriptan is contraindicated in patients with uncontrolled hypertension (see CONTRAINDICATIONS).
An 18% increase in mean pulmonary artery pressure was seen following dosing with another 5-HT1 agonist in a study evaluating subjects undergoing cardiac catheterization.
Serotonin Syndrome: The development of a potentially life-threatening serotonin syndrome may occur with triptans, including MAXALT treatment, particularly during combined use with selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs). If concomitant treatment with rizatriptan and an SSRI (e.g., fluoxetine, paroxetine, sertraline, fluvoxamine, citalopram, escitalopram) or SNRI (e.g., venlafaxine, duloxetine) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases. 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) (see PRECAUTIONS, Drug Interactions).
PRECAUTIONS
General
As with other 5-HT1B/1D agonists, sensations of tightness, pain, pressure, and heaviness have been reported after treatment with MAXALT in the precordium, throat, neck and jaw. These events have not been associated with arrhythmias or definite ischemic ECG changes in clinical trials (one patient experienced chest pain with possible ischemic ECG changes). Because drugs in this class may cause coronary artery vasospasm, patients who experience signs or symptoms suggestive of angina following dosing should be evaluated for the presence of CAD or a predisposition to Prinzmetal’s variant angina before receiving additional doses of medication, and should be monitored electrocardiographically if dosing is resumed and similar symptoms recur. Similarly, patients who experience other symptoms or signs suggestive of decreased arterial flow, such as ischemic bowel syndrome or Raynaud’s syndrome following the use of any 5-HT1 agonist are candidates for further evaluation (see WARNINGS).
Rizatriptan should also be administered with caution to patients with diseases that may alter the absorption, metabolism, or excretion of drugs (see CLINICAL PHARMACOLOGY, Special Populations).
Renally Impaired Patients: Rizatriptan should be used with caution in dialysis patients due to a decrease in the clearance of rizatriptan (see CLINICAL PHARMACOLOGY, Special Populations).
Hepatically Impaired Patients: Rizatriptan should be used with caution in patients with moderate hepatic insufficiency due to an increase in plasma concentrations of approximately 30% (see CLINICAL PHARMACOLOGY, Special Populations).
For a given attack, if a patient has no response to the first dose of rizatriptan, the diagnosis of migraine should be reconsidered before administration of a second dose.
Binding to Melanin-Containing Tissues
The propensity for rizatriptan to bind melanin has not been investigated. Based on its chemical properties, rizatriptan may bind to melanin and accumulate in melanin rich tissue (e.g., eye) over time. This raises the possibility that rizatriptan could cause toxicity in these tissues after extended use. There were, however, no adverse ophthalmologic changes related to treatment with rizatriptan in the one year dog toxicity study. Although no systematic monitoring of ophthalmologic function was undertaken in clinical trials, and no specific recommendations for ophthalmologic monitoring are offered, prescribers should be aware of the possibility of long-term ophthalmologic effects.
Phenylketonurics
Phenylketonuric patients should be informed that MAXALT-MLT Orally Disintegrating Tablets contain phenylalanine (a component of aspartame). Each 5-mg orally disintegrating tablet contains 1.05 mg phenylalanine, and each 10-mg orally disintegrating tablet contains 2.10 mg phenylalanine.
Information for Patients
Migraine or treatment with MAXALT may cause somnolence in some patients. Dizziness has also been reported in some patients receiving MAXALT. Patients should, therefore, evaluate their ability to perform complex tasks during migraine attacks and after administration of MAXALT.
Physicians should instruct their patients to read the patient package insert before taking MAXALT. See the accompanying PATIENT INFORMATION leaflet.
Patients should be cautioned about the risk of serotonin syndrome with the use of rizatriptan or other triptans, especially during combined use with selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs) (see WARNINGS).
MAXALT-MLT Orally Disintegrating Tablets
Patients should be instructed not to remove the blister from the outer pouch until just prior to dosing. The blister pack should then be peeled open with dry hands and the orally disintegrating tablet placed on the tongue, where it will dissolve and be swallowed with the saliva.
Laboratory Tests
No specific laboratory tests are recommended for monitoring patients prior to and/or after treatment with MAXALT.
Drug Interactions
(See also CLINICAL PHARMACOLOGY, Drug Interactions.)
Propranolol: Rizatriptan 5 mg should be used in patients taking propranolol, as propranolol has been shown to increase the plasma concentrations of rizatriptan by 70% (see CLINICAL PHARMACOLOGY, Drug Interactions; DOSAGE AND ADMINISTRATION).
Ergot-containing drugs: Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because there is a theoretical basis that these effects may be additive, use of ergotamine-containing or ergot-type medications (like dihydroergotamine or methysergide) and rizatriptan within 24 hours is contraindicated (see CONTRAINDICATIONS).
Other 5-HT1 agonists: The administration of rizatriptan with other 5-HT1 agonists has not been evaluated in migraine patients. Because their vasospastic effects may be additive, coadministration of rizatriptan and other 5-HT1 agonists within 24 hours of each other is not recommended (see CONTRAINDICATIONS).
Selective Serotonin Reuptake Inhibitors/Serotonin Norepinephrine Reuptake Inhibitors and Serotonin Syndrome: Cases of life-threatening serotonin syndrome have been reported during combined use of selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs) and triptans (see WARNINGS).
Monoamine oxidase inhibitors: Rizatriptan should not be administered to patients taking MAO-A inhibitors and non-selective MAO inhibitors; it has been shown that moclobemide (a specific MAO-A inhibitor) increased the systemic exposure of rizatriptan and its metabolite (see CLINICAL PHARMACOLOGY, Drug Interactions; CONTRAINDICATIONS).
Drug/Laboratory Test Interactions
MAXALT is not known to interfere with commonly employed clinical laboratory tests.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis: The lifetime carcinogenic potential of rizatriptan was evaluated in a 100-week study in mice and a 106-week study in rats at oral gavage doses of up to 125 mg/kg/day. Exposure data were not obtained in those studies, but plasma AUC’s of parent drug measured in other studies after 5 and 21 weeks of oral dosing in mice and rats, respectively, indicate that the exposures to parent drug at the highest dose level in the carcinogenicity studies would have been approximately 150 times (mice) and 240 times (rats) average AUC’s measured in humans after three 10 mg doses, the maximum recommended total daily dose. There was no evidence of an increase in tumor incidence related to rizatriptan in either species.
Mutagenesis: Rizatriptan, with and without metabolic activation, was neither mutagenic, nor clastogenic in a battery of in vitro and in vivo genetic toxicity studies, including: the microbial mutagenesis (Ames) assay, the in vitro mammalian cell mutagenesis assay in V-79 Chinese hamster lung cells, the in vitro alkaline elution assay in rat hepatocytes, the in vitro chromosomal aberration assay in Chinese hamster ovary cells and the in vivo chromosomal aberration assay in mouse bone marrow.
Impairment of Fertility: In a fertility study in rats, altered estrus cyclicity and delays in time to mating were observed in females treated orally with 100 mg/kg/day rizatriptan. Plasma drug exposure (AUC) at this dose was approximately 225 times the exposure in humans receiving the maximum recommended daily dose (MRDD) of 30 mg. The no-effect dose was 10 mg/kg/day (approximately 15 times the human exposure at the MRDD). There were no other fertility-related effects in the female rats. There was no impairment of fertility or reproductive performance in male rats treated with up to 250 mg/kg/day (approximately 550 times the human exposure at the MRDD).
Pregnancy:
Pregnancy Category C
In a general reproductive study in rats, birth weights and pre- and post-weaning weight gain were reduced in the offspring of females treated prior to and during mating and throughout gestation and lactation with doses of 10 and 100 mg/kg/day. Maternal drug exposures (AUC) at these doses were approximately 15 and 225 times, respectively, the exposure in humans receiving the maximum recommended daily dose (MRDD) of 30 mg. In a pre- and post-natal developmental toxicity study in rats, an increase in mortality of the offspring at birth and for the first three days after birth, a decrease in pre- and post-weaning weight gain, and decreased performance in a passive avoidance test (which indicates a decrease in learning capacity of the offspring) were observed at doses of 100 and 250 mg/kg/day. The no-effect dose for all of these effects was 5 mg/kg/day, approximately 7.5 times the exposure in humans receiving the MRDD. With doses of 100 and 250 mg/kg/day, the decreases in average weight of both the male and female offspring persisted into adulthood. All of these effects on the offspring in both reproductive toxicity studies occurred in the absence of any apparent maternal toxicity.
In embryofetal development studies, no teratogenic effects were observed when pregnant rats and rabbits were administered doses of 100 and 50 mg/kg/day, respectively, during organogenesis. Fetal weights were decreased in conjunction with decreased maternal weight gain at the highest doses (maternal exposures approximately 225 and 115 times the human exposure at the MRDD in rats and rabbits, respectively). The developmental no-effect dose in these studies was 10 mg/kg/day in both rats and rabbits (maternal exposures approximately 15 times human exposure at the MRDD). Toxicokinetic studies demonstrated placental transfer of drug in both species.
There are no adequate and well-controlled studies in pregnant women; therefore, rizatriptan should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., maintains a registry to monitor the pregnancy outcomes of women exposed to MAXALT while pregnant. Healthcare providers are encouraged to report any prenatal exposure to MAXALT by calling the Pregnancy Registry at (800) 986-8999.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when MAXALT is administered to women who are breast-feeding. Rizatriptan is extensively excreted in rat milk, at a level of 5-fold or greater than maternal plasma levels.
Pediatric Use
Safety and effectiveness of rizatriptan in pediatric patients have not been established; therefore, MAXALT is not recommended for use in patients under 18 years of age.
The efficacy of MAXALT Tablets (5 mg) in patients aged 12 to 17 years was not established in a randomized placebo-controlled trial of 291 adolescent migraineurs (see Clinical Studies). Adverse events observed were similar in nature to those reported in clinical trials in adults. Postmarketing experience with other triptans includes a limited number of reports that describe pediatric patients who have experienced clinically serious adverse events that are similar in nature to those reported rarely in adults. The long-term safety of rizatriptan in pediatric patients has not been studied.
Geriatric Use
The pharmacokinetics of rizatriptan were similar in elderly (aged ≥ 65 years) and in younger adults. Because migraine occurs infrequently in the elderly, clinical experience with MAXALT is limited in such patients. In clinical trials, there were no apparent differences in efficacy or in overall adverse experience rates between patients under 65 years of age and those 65 and above (n=17).
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