Included as part of the PRECAUTIONS section.
Myocardial Ischemia, Myocardial Infarction, And Prinzmetal's
FROVA is contraindicated in patients with ischemic or
vasospastic CAD. There have been rare reports of serious cardiac adverse
reactions, including acute myocardial infarction, occurring within a few hours
following administration of FROVA. Some of these reactions occurred in patients
without known CAD. FROVA may cause coronary artery vasospasm (Prinzmetal's
angina), even in patients without a history of CAD.
Perform a cardiovascular evaluation in triptan-naïve
patients who have multiple cardiovascular risk factors (e.g., increased age,
diabetes, hypertension, smoking, obesity, strong family history of CAD) prior
to receiving FROVA. Do not administer FROVA 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 FROVA dose in a
medically-supervised setting and performing an electrocardiogram (ECG)
immediately following FROVA administration. For such patients, consider
periodic cardiovascular evaluation in intermittent long-term users of FROVA.
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 FROVA if these disturbances occur. FROVA 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
Sensations of pain, tightness, pressure, and heaviness
have been reported in the chest, throat, neck, and jaw after treatment with
FROVA and are usually non-cardiac in origin. However, perform a cardiac
evaluation if these patients are at high cardiac risk. The use of FROVA is
contraindicated in patients with CAD and those with Prinzmetal's angina [see
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.
Before treating headaches in patients not previously
diagnosed as migraineurs, and in migraineurs who present with symptoms atypical
of migraine, other potentially serious neurological conditions need to be
excluded. FROVA is contraindicated in patients with a history of stroke or TIA [see
Other Vasospasm Reactions
FROVA, 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 5HT1 agonist,
rule out a vasospastic reaction before using FROVA [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 combination of these 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 FROVA, particularly
during co-administration with selective serotonin reuptake inhibitors (SSRIs),
serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants
(TCAs), and monoamine oxidase (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 occurs within minutes to hours of
receiving a new or a greater dose of a serotonergic medication. Discontinue
FROVA if serotonin syndrome is suspected.
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 treated with 5-HT1 agonists, including patients
without a history of hypertension.
Monitor blood pressure in patients treated with FROVA.
FROVA is contraindicated in patients with uncontrolled hypertension [see
There have been reports of anaphylaxis, anaphylactoid,
and hypersensitivity reactions including angioedema in patients receiving
FROVA. Such reactions can be life threatening or fatal. In general,
anaphylactic reactions to drugs are more likely to occur in individuals with a history
of sensitivity to multiple allergens. FROVA is contraindicated in patients with
a history of hypersensitivity reaction to FROVA [see CONTRAINDICATIONS].
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 FROVA 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
Inform patients that
anaphylactic/anaphylactoid reactions have occurred in patients receiving FROVA.
Such reactions can be life threatening or fatal. In general, anaphylactic
reactions to drugs are more likely to occur in individuals with a history of
sensitivity to multiple allergens [see CONTRAINDICATIONS].
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 FROVA or other triptans, particularly during combined use with
SSRIs, SNRIs, TCAs, and MAO inhibitors [see WARNINGS AND PRECAUTIONS and
Inform patients that FROVA should not be used during
pregnancy unless the potential benefit justifies the potential risk to the
fetus [see Use in Specific Populations].
Inform patients to notify their healthcare provider if
they are breastfeeding or plan to breastfeed [see Use in Specific
Carcinogenesis, Mutagenesis, Impairment Of Fertility
The carcinogenic potential of orally administered
frovatriptan was evaluated in an 84-week study in mice (4, 13, and 40
mg/kg/day), a 104-week study in rats (8.5, 27 and 85 mg/kg/day), and a 26-week
study in p53(+/-) transgenic mice (20, 62.5, 200, and 400 mg/kg/day). Although
a maximum tolerated dose was not achieved in the 84-week mouse study and in
female rats, plasma exposures at the highest doses studied were higher than
that achieved in humans at the maximum recommended human dose (MRHD) of 7.5
mg/day. There were no increases in tumor incidence in the 84-week mouse study
at doses producing plasma exposures (AUC) 140 times that in humans at the MRHD.
In the rat study, there was a statistically significant increase in the
incidence of pituitary adenomas in males only at 85 mg/kg/day, a dose
associated with a plasma AUC 250 times that in humans at the MRHD. In the
26-week p53(+/-) transgenic mouse study, the incidence of subcutaneous sarcomas
was increased in females at doses of 200 and 400 mg/kg/day.
These sarcomas were associated with subcutaneously
implanted animal identification transponders, and are not considered to be
relevant to humans. There were no other increases in tumor incidence of any
type in any dose group.
Frovatriptan was clastogenic in human lymphocyte
cultures, in the absence of metabolic activation. In the bacterial reverse
mutation assay (Ames test), frovatriptan produced an equivocal response in the
absence of metabolic activation. Frovatriptan was negative in an in vitro mouse
lymphoma tk assay and an in vivo mouse bone marrow micronucleus test.
Impairment Of Fertility
Male and female rats were dosed orally with frovatriptan
prior to and during mating and in females up to implantation, at doses of 100,
500, and 1000 mg/kg/day (equivalent to approximately 130, 650, and 1300 times
the MRHD on a mg/m 2 basis). At all dose levels, there was an
increase in the number of females that mated on the first day of pairing
compared to control animals. This occurred in conjunction with a prolongation
of the estrous cycle. In addition, females had a decreased mean number of
corpora lutea, and consequently a lower number of live fetuses per litter,
which suggested a partial impairment of ovulation. There were no other
Use In Specific Populations
Pregnancy Category C
There are no adequate and
well-controlled trials in pregnant women; therefore, frovatriptan should be
used during pregnancy only if the potential benefit justifies the potential
risk to the fetus.
When pregnant rats were administered frovatriptan during
the period of organogenesis at oral doses of 100, 500 and 1000 mg/kg/day
(equivalent to 130, 650 and 1300 times the maximum recommended human dose
[MRHD] of 7.5 mg/day on a mg/m² basis) there were dose related increases in
incidences of fetuses with dilated ureters, unilateral and bilateral pelvic
cavitation, hydronephrosis, and hydroureters. A no-effect dose for renal
effects was not established. This signifies a syndrome of related effects on a
specific organ in the developing embryo in all treated groups, which is
consistent with a slight delay in fetal maturation. This delay was also
indicated by a treatment related increased incidence of incomplete ossification
of the sternebrae, skull and nasal bones in all treated groups. Reduced fetal
weights and an increased incidence of embryolethality were observed in treated
rats; an increase in embryolethality occurred in both the embryo-fetal
developmental study and in the prenatal-postnatal developmental study. No
increase in embryolethality was observed at the lowest dose level studied (100
mg/kg/day, equivalent to 130 times the MRHD on a mg/m² basis). When pregnant
rabbits were dosed throughout organogenesis at oral doses up to 80 mg/kg/day
(equivalent to 210 times the MRHD on a mg/m² basis), no effects on fetal
development were observed.
It is not known whether frovatriptan 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 FROVA, 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 frovatriptan resulted in levels
of frovatriptan and/or its metabolites in milk up to four times higher than in
The safety and effectiveness in pediatric patients have
not been established. Therefore, FROVA is not recommended for use in patients
under 18 years of age. There are no additional adverse reactions identified in
pediatric patients based on postmarketing experience that were not previously
identified in adults.
Mean blood concentrations of frovatriptan in elderly
patients were 1.5-to 2-times higher than those seen in younger adults [see
CLINICAL PHARMACOLOGY]. No dosage adjustment is necessary.
Patients With Hepatic Impairment
No dosage adjustment is necessary when FROVA is given to
patients with mild to moderate hepatic impairment.
There is no clinical or pharmacokinetic experience with
FROVA in patients with severe hepatic impairment. Because a greater than
two-fold increase in AUC is predicted in patients with severe hepatic
impairment, there is a greater potential for adverse events in these patients,
and FROVA should therefore be used with caution in that population.