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
). 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
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
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
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
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
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.
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).
CLINICAL PHARMACOLOGY, Drug
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
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).
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
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).
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
The pharmacokinetics of rizatriptan were similar in elderly (aged
greater than or equal to 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