Included as part of the PRECAUTIONS section.
Myocardial Ischemia, Myocardial Infarction, And Prinzmetal
ZOMIG is contraindicated in patients with ischemic or vasospastic
coronary artery disease (CAD). There have been rare reports of serious cardiac
adverse reactions, including acute myocardial infarction, occurring within a
few hours following administration of ZOMIG. Some of these reactions occurred
in patients without known CAD. 5-HT1 agonists including ZOMIG may cause
coronary artery vasospasm (Prinzmetal Angina), even in patients without a
history of CAD.
Perform a cardiovascular evaluation in triptan-naÃ¯ve
patients who have multiple cardiovascular risk factors (e.g., increased age,
diabetes, hypertension, smoking, obesity, strong family history of CAD) prior
to receiving ZOMIG. Do not administer ZOMIG if there is evidence of CAD or
coronary artery vasospasm [see CONTRAINDICATIONS]. For patients with
multiple cardiovascular risk factors who have a negative cardiovascular
evaluation, consider administrating the first ZOMIG dose in a
medically-supervised setting and performing an electrocardiogram (ECG)
immediately following ZOMIG administration. For such patients, consider periodic
cardiovascular evaluation in intermittent long-term users of ZOMIG.
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 ZOMIG if these disturbances occur. ZOMIG is contraindicated in patients
with Wolff-Parkinson-White Syndrome or arrhythmias associated with other
cardiac accessory conduction pathway disorders [see CONTRAINDICATIONS].
Chest, Throat, Neck and Jaw Pain/Tightness/Pressure
As with other 5-HT1 agonists, sensations of tightness,
pain, and pressure in the chest, throat, neck, and jaw commonly occur after
treatment with ZOMIG and is usually non-cardiac in origin. However, perform a
cardiac evaluation if these patients are at high cardiac risk. 5-HT1 agonists
including ZOMIG are contraindicated in patients with CAD or Prinzmetal's variant
angina [see CONTRAINDICATIONS].
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.
As with other acute migraine therapies, before treating headaches
in patients not previously diagnosed as migraineurs, and in migraineurs who
present with symptoms atypical for migraine, exclude other potentially serious neurological
conditions. ZOMIG is contraindicated in patients with a history of stroke or
transient ischemic attack [see CONTRAINDICATIONS].
Other Vasospasm Reactions
5-HT1 agonists, including ZOMIG, 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 a vasospastic reaction following the use of any 5-HT1
agonist, rule out a vasospastic reaction before receiving additional ZOMIG
doses [see CONTRAINDICATIONS].
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
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.
Serotonin syndrome may occur with triptans, including ZOMIG,
particularly during co-administration with selective serotonin reuptake
inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs),
tricyclic antidepressants (TCAs), and MAO inhibitors [see DRUG INTERACTIONS].
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 usually rapidly occurs within minutes to hours of receiving a new
or a greater dose of a serotonergic medication. Discontinue ZOMIG if serotonin
syndrome is suspected [see DRUG INTERACTIONS].
Increase In Blood Pressure
Significant elevations in systemic blood pressure have
been reported in patients treated with 5-HT1 agonists including patients
without a history of hypertension; very rarely, these increases in blood
pressure have been associated with serious adverse reactions. In healthy
subjects treated with 5 mg of ZOMIG, an increase of 1 and 5 mm Hg in the
systolic and diastolic blood pressure, respectively, was seen. In a study of patients
with moderate to severe liver impairment, 7 of 27 patients experienced 20 to 80
mm Hg elevations in systolic and/or diastolic blood pressure after a dose of 10
mg of ZOMIG.
As with all triptans, blood pressure should be monitored
in ZOMIG-treated patients. ZOMIG is contraindicated in patients with
uncontrolled hypertension [see CONTRAINDICATIONS].
Risks In Patients With Phenylketonuria
Phenylalanine can be harmful to patients with
phenylketonuria (PKU). ZOMIG-ZMT orally disintegrating tablets contain phenylalanine
(a component of aspartame). Each 2.5 mg and 5 mg orally disintegrating tablet
contains 2.81 and 5.62 mg of phenylalanine, respectively. ZOMIG tablets do not
Patient Counseling Information
See FDA Approved Patient Labeling (PATIENT INFORMATION).
Myocardial Ischemia and/or Infarction, Prinzmetal's angina,
Other Vasospastic Reactions, and Cerebrovascular Events
Inform patients that ZOMIG may cause serious
cardiovascular adverse reactions such as myocardial infarction or stroke, which
may result in hospitalization and even death. Although serious cardiovascular
reactions can occur without warning symptoms, instruct patients to be alert for
the signs and symptoms of chest pain, shortness of breath, weakness, slurring
of speech, and instruct them to ask for medical advice when observing any
indicative sign or symptoms. Instruct patients to seek medical advice if they
have symptoms of other vasospastic reactions [see WARNINGS AND PRECAUTIONS].
Medication Overuse Headache
Inform patients that use of drugs to treat acute
migraines 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].
Inform patients about the risk of serotonin syndrome with
the use of ZOMIG or other triptans, particularly during combined use with
selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine
reuptake inhibitors (SNRIs) [see WARNINGS AND PRECAUTIONS].
Inform patients that ZOMIG should not be used during pregnancy
unless the potential benefit justifies the potential risk to the fetus [see Use
in Specific Populations].
Advise patients to notify their healthcare provider if
they are breastfeeding or plan to breastfeed [see Use in Specific Populations].
Handling of ZOMIG-ZMT Orally Disintegrating Tablets
Inform patients not to break ZOMIG-ZMT oral
disintegrating tablets. Inform patients that the orally disintegrating tablet
is packaged in a blister. Instruct patients not to remove the oral disintegrating
tablet from the blister until just prior to dosing. Instruct patients that
prior to dosing, peel open the blister pack and place the orally disintegrating
tablet on the tongue, where it will dissolve and be swallowed with the saliva [see
DOSAGE AND ADMINISTRATION].
Patients with Phenylketonuria
Inform patients with phenylketonuria (PKU) that ZOMIGZMT contains
phenylalanine (a component of aspartame) [see WARNINGS AND PRECAUTIONS].
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Zolmitriptan was administered to mice and rats at doses
up to 400 mg/kg/day. Mice were dosed for 85 weeks (males) and 92 weeks
(females); rats were dosed for 101 weeks (males) and 86 weeks (females). There
was no evidence of druginduced tumors in mice at plasma exposures (AUC) up to approximately
700 times that in humans at the maximum recommended human dose (MRHD) of 10
mg/day. In rats, there was an increase in the incidence of thyroid follicular
cell hyperplasia and thyroid follicular cell adenomas in male rats receiving
400 mg/kg/day. No increase in tumors was observed in rats at 100 mg/kg/day, a
dose associated with a plasma AUC approximately 700 times that in humans at the
Zolmitriptan was positive in an in vitro bacterial
reverse mutation (Ames) assay and in an in vitro chromosomal aberration assay
in human lymphocytes. Zolmitriptan was negative in an in vitro mammalian gene
cell mutation (CHO/HGPRT) assay and in oral in vivo mouse micronucleus assays
in mouse and rat.
Impairment of Fertility
Studies of male and female rats administered zolmitriptan
prior to and during mating and up to implantation showed no impairment of
fertility at oral doses up to 400 mg/kg/day. The plasma exposure (AUC) at this
dose was approximately 3000 times that in humans at the MRHD.
Use In Specific Populations
Pregnancy Category C: There are no adequate and
wellcontrolled studies in pregnant women; therefore, ZOMIG should be used
during pregnancy only if the potential benefit justifies the potential risk to
the fetus. In reproductive toxicity studies in rats and rabbits, oral
administration of zolmitriptan to pregnant animals resulted in embryolethality
and fetal abnormalities (malformations and variations) at clinically relevant
When zolmitriptan was administered to pregnant rats
during the period of organogenesis at oral doses of 100, 400, and 1200
mg/kg/day (plasma exposures (AUCs) ≈280, 1100, and 5000 times the human
AUC at the maximum recommended human dose (MRHD) of 10 mg/day), there was a
dose-related increase in embryolethality. A no-effect dose for embryolethality
was not established. When zolmitriptan was administered to pregnant rabbits
during the period of organogenesis at oral doses of 3, 10, and 30 mg/kg/day (plasma
AUCs ≈1, 11, and 42 times the human AUC at the MRHD), there were
increases in embryolethality and in fetal malformations and variations. The
no-effect dose for adverse effects on embryo-fetal development was associated
with aplasma AUC similar to that in humans at the MRHD. When female rats were
given zolmitriptan during gestation, parturition, and lactation at oral doses of
25, 100, and 400 mg/kg/day (plasma AUCs ≈70, 280, and 1100 times that in human
at the MRHD), an increased incidence of hydronephrosis was found in the
offspring. The no-effect dose was associated with a plasma AUC ≈280 times
that in humans at the MRHD.
It is not known whether zolmitriptan is excreted in human
milk. Because many drugs are excreted in human milk, and because of the
potential for serious adverse reactions in nursing infants from ZOMIG, a
decision should be made whether to discontinue nursing or to discontinue the
drug, taking into account the importance of the drug to the mother.
In rats, oral dosing with zolmitriptan resulted in levels
in milk up to 4 times higher than in plasma.
The safety and effectiveness in pediatric patients have
not been established. Therefore, ZOMIG is not recommended for use in patients
under 18 years of age.
One randomized, placebo-controlled clinical trial of
ZOMIG tablets (2.5, 5 and 10 mg) evaluated 696 pediatric patients (aged 12-17
years) with migraines. This study did not demonstrate the efficacy of ZOMIG
compared to placebo in the treatment of migraine in adolescents. Adverse
reactions in the adolescent patients treated with ZOMIG were similar in nature
and frequency to those reported in clinical trials in adults treated with
ZOMIG. ZOMIG has not been studied in pediatric patients less than 12 years old.
In the postmarketing experience with triptans, including ZOMIG,
there were no additional adverse reactions seen in pediatric patients that were
not seen in adults.
Clinical studies of ZOMIG 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.
In general, dose selection for an elderly patient should be cautious, usually starting
at the low end of the dosing range, reflecting the greater frequency of
decreased hepatic, renal, or cardiac function, and of concomitant disease or
other drug therapy.
A cardiovascular evaluation is recommended for geriatric patients
who have other cardiovascular risk factors (e.g., diabetes, hypertension,
smoking, obesity, strong family history of coronary artery disease) prior to
receiving ZOMIG [see WARNINGS AND PRECAUTIONS].
The pharmacokinetics of zolmitriptan were similar in
geriatric patients (aged > 65 years) compared to younger patients [see CLINICAL
Patients With Hepatic Impairment
After oral ZOMIG administration, zolmitriptan blood
levels were increased in patients with moderate to severe hepatic impairment,
and significant elevation in blood pressure was observed in some of these
patients [see WARNINGS AND PRECAUTIONS]. Therefore, adjust the ZOMIG
dose and administer with caution in patients with moderate or severe hepatic
impairment [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY].