Frova Information
Frova (Frovatriptan) Description
Frova (Frovatriptan) (Frova (Frovatriptan) triptan succinate) tablets contain Frova (Frovatriptan) triptan
succinate, a selective 5-hydroxy-tryptamine
(5-HT) receptor subtype agonist, as the active
ingredient. Frova (Frovatriptan) triptan succinate is chemically designated as R-(+)
3-methylamino-6-carboxamido-1,2,3,4-tetrahydrocarbazole monosuccinate
monohydrate and it has the following structure:
The empirical formula is
CHNO.CHO.HO,
representing a molecular weight of 379.4. Frova (Frovatriptan) triptan succinate is a
white to off-white powder that is soluble in water. Each Frova (Frovatriptan) tablet
for oral administration contains 3.91 mg Frova (Frovatriptan) triptan succinate,
equivalent to 2.5 mg of Frova (Frovatriptan) triptan base. Each tablet also contains the
inactive ingredients lactose NF, microcrystalline cellulose NF,
colloidal silicon dioxide NF, sodium starch glycolate NF, magnesium
stearate NF, hydroxypropylmethylcellulose USP, polyethylene glycol 3000
USP, triacetin USP, and titanium dioxide USP.
Frova (Frovatriptan) Clinical Pharmacology
Frova (Frovatriptan) triptan is a 5-HT receptor agonist that binds with
high affinity for 5-HT and 5-HT
receptors. Frova (Frovatriptan) triptan has no significant effects on
GABA mediated channel activity and has no
significant affinity for benzodiazepine binding sites.
Frova (Frovatriptan) triptan is believed to act on extracerebral,
intracranial arteries and to inhibit excessive dilation of these
vessels in migraine. In anesthetized dogs and cats, intravenous
administration of Frova (Frovatriptan) triptan produced selective constriction
of the carotid vascular bed and had no effect on blood pressure
(both species) or coronary resistance (in dogs).
Mean maximum blood concentrations (C) in
patients are achieved approximately 2 - 4 hours after
administration of a single oral dose of Frova (Frovatriptan) triptan 2.5 mg. The
absolute bioavailability of an oral dose of Frova (Frovatriptan) triptan 2.5 mg
in healthy subjects is about 20% in males and 30% in females.
Food has no significant effect on the bioavailability of
Frova (Frovatriptan) triptan, but delays t by one hour.
Binding of Frova (Frovatriptan) triptan to serum proteins is low
(approximately 15%). Reversible binding to blood cells at
equilibrium is approximately 60%, resulting in a blood:plasma
ratio of about 2:1 in both males and females. The mean steady
state volume of distribution of Frova (Frovatriptan) triptan following
intravenous administration of 0.8 mg is 4.2 L/kg in males and
3.0 L/kg in females.
In vitro,
1B/1D
After an intravenous dose, mean clearance of Frova (Frovatriptan) triptan
was 220 and 130 mL/min in males and females, respectively. Renal
clearance accounted for about 40% (82 mL/min) and 45% (60
mL/min) of total clearance in males and females, respectively.
The mean terminal elimination half-life of Frova (Frovatriptan) triptan in both
males and females is approximately 26 hours.
The pharmacokinetics of Frova (Frovatriptan) triptan are similar in
migraine patients and healthy subjects.
The efficacy of Frova (Frovatriptan) in the acute treatment of migraine
headaches was demonstrated in five randomized, double-blind,
placebo-controlled, outpatient trials. Two of these were
dose-finding studies in which patients were randomized to
receive doses of Frova (Frovatriptan) triptan ranging from 0.5 - 40 mg. The
three studies evaluating only one dose studied 2.5 mg. In these
controlled short-term studies combined, patients were
predominately female (88%) and Caucasian (94%) with a mean age
of 42 years (range 18 - 69). Patients were instructed to treat a
moderate to severe headache. Headache response, defined as a
reduction in headache severity from moderate or severe pain to
mild or no pain, was assessed for up to 24 hours after dosing.
The associated symptoms nausea, vomiting, photophobia and
phonophobia were also assessed. Maintenance of response was
assessed for up to 24 hours post dose. In two of the trials a
second dose of Frova (Frovatriptan) was provided after the initial treatment,
to treat recurrence of the headache within 24 hours. Other
medication, excluding other 5-HT agonists and
ergotamine containing compounds, was permitted from 2 hours
after the first dose of Frova (Frovatriptan) . The frequency and time to use of
additional medications were also recorded.
In all five placebo-controlled trials, the percentage of
patients achieving a headache response 2 hours after treatment
was significantly greater for those taking Frova (Frovatriptan) compared to
those taking placebo (Table 1).
Lower doses of Frova (Frovatriptan) triptan (1 mg or 0.5 mg) were not
effective at 2 hours. Higher doses (5 mg to 40 mg) of
Frova (Frovatriptan) triptan showed no added benefit over 2.5 mg but did cause a
greater incidence of adverse events.
Comparisons of drug performance based
upon results obtained in different clinical trials are never
reliable. Because trials are conducted at different times,
with different samples of patients, by different
investigators, employing different criteria and/or different
interpretations of the same criteria, under different
conditions (dose, dosing regimen, etc.), quantitative
estimates of treatment response and the timing of response
may be expected to vary considerably from study to
study.
The estimated probability of achieving an initial
headache response by 2 hours following treatment is depicted in
Figure 1.
Figure 1
Estimated Probability of Achieving Initial Headache
Response Within 2 Hours
Figure 1 shows a Kaplan-Meier plot
of the probability over time of obtaining headache response
(no or mild pain) following treatment with Frova (Frovatriptan) triptan 2.5
mg or placebo. The probabilities displayed are based on
pooled data from four placebo-controlled trials described in
(Trials 1, 3, 4 and 5). Patients who
did not achieve a response were censored at 24
hours.
In patients with migraine-associated nausea, photophobia
and phonophobia at baseline there was a decreased incidence of
these symptoms in Frova (Frovatriptan) treated patients compared to placebo.
The estimated probability of patients taking a second dose or
other medication for their migraine over the 24 hours following
the initial dose of study treatment is summarized in Figure 2.
Figure 2
Estimated Probability of Patients Taking a Second Dose or
Other Medication for Migraine Over the 24 Hours Following the
Initial Dose of Study Treatment
Figure 2 is a Kaplan-Meier plot
showing the probability of patients taking a second dose or
other medication for migraine over the 24 hours following
the initial dose of study medication based on the data from
four placebo-controlled trials described in (Trials 1, 3, 4 and 5). The plot includes those
patients who had a response to the initial dose and those
who did not. The protocols did not permit remedication
within 2 hours of the initial dose.
Efficacy was unaffected by a history of aura; gender;
age, or concomitant medications commonly used by migraine
patients Frova (Frovatriptan) .
Frova (Frovatriptan) Indications And Usage
Frova (Frovatriptan) is indicated for the acute treatment of migraine attacks
with or without aura in adults.
Frova (Frovatriptan) is not intended for the prophylactic therapy of migraine or
for use in the management of hemiplegic or basilar migraine (see
). The safety and effectiveness of
Frova (Frovatriptan) have not been established for cluster headache, which is present
in an older, predominately male, population.
Frova (Frovatriptan) Contraindications
Frova (Frovatriptan) should not be given to patients with ischemic heart disease
(e.g. angina pectoris, history of myocardial infarction, or documented
silent ischemia), or to patients who have symptoms or findings
consistent with ischemic heart disease, coronary artery vasospasm,
including Prinzmetal’s variant angina or other significant
underlying cardiovascular disease (see ).
Frova (Frovatriptan) should not be given to patients with cerebrovascular
syndromes including (but not limited to) strokes of any type as well as
transient ischemic attacks.
Frova (Frovatriptan) should not be given to patients with peripheral vascular
disease including (but is not limited to) ischemic bowel disease (see
)
Frova (Frovatriptan) should not be given to patients with uncontrolled
hypertension (see ).
Frova (Frovatriptan) should not be administered to patients with hemiplegic or
basilar migraine.
Frova (Frovatriptan) should not be used within 24 hours of treatment with
another 5-HT agonist, an ergotamine containing or ergot-type
medication such as dihydroergotamine (DHE) or methysergide.
Frova (Frovatriptan) is contraindicated in patients who are hypersensitive to
Frova (Frovatriptan) triptan or any of the inactive ingredients in the
tablets.
Frova (Frovatriptan) Warnings
Frova (Frovatriptan) should only be used where a clear diagnosis of migraine has
been established.
Because of the potential of this class of compound
(5-HT agonists) to cause coronary vasospasm,
Frova (Frovatriptan) triptan should not be given to patients with documented
ischemic or vasospastic coronary artery disease (CAD) (see
). It is strongly recommended
that Frova (Frovatriptan) triptan not be given to patients in whom unrecognized
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, Frova (Frovatriptan) triptan should not be
administered (see ).
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
Frova (Frovatriptan) triptan take place in the setting of a
physician’s office or similar medically staffed and
equipped facility unless the patient has previously received
Frova (Frovatriptan) triptan. 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 administration of Frova (Frovatriptan) in
these patients with risk factors.
It is recommended that patients who are intermittent
long-term users of 5-HT agonists, including Frova (Frovatriptan)
and who have or acquire risk factors predictive of CAD, as
described above, undergo periodic cardiovascular evaluation as
they continue to use Frova (Frovatriptan) .
The systematic approach described above is intended to
reduce the likelihood that patients with unrecognized
cardiovascular disease would be inadvertently exposed to
Frova (Frovatriptan) triptan.
In young healthy subjects, there were statistically
significant increases in systolic and diastolic blood pressure
after single doses of 80 mg Frova (Frovatriptan) triptan (32 times the clinical
dose) and above. These increases were transient, resolved
spontaneously and were not clinically significant. At the
recommended dose of 2.5 mg, transient changes in systolic blood
pressure were recorded in some elderly subjects (65 - 77 years).
Any increases were generally small, resolved spontaneously, and
blood pressure remained within the normal range. Frova (Frovatriptan) triptan is
contraindicated in patients with uncontrolled hypertension (see
).
An 18% increase in mean pulmonary artery pressure was
seen following dosing with another 5-HT agonist in a
study evaluating subjects undergoing cardiac
catheterization.
Frova (Frovatriptan) Precautions
Physicians should instruct their patients to read the
patient package insert before taking Frova (Frovatriptan) . See at the end of this labeling for the
text of the separate leaflet provided for patients.
Patients should be cautioned about the risk of serotonin
syndrome with the use of Frova (Frovatriptan) or other triptans, especially
during combined use with selective serotonin reuptake inhibitors
(SSRIs) or serotonin norepinephrine reuptake inhibitors
(SNRIs).
Ergot-containing drugs have been reported to cause
prolonged vasospastic reactions. Due to a theoretical risk of a
pharmacodynamic interaction, use of ergotamine-containing or
ergot-type medications (like dihydroergotamine or methysergide)
and Frova (Frovatriptan) within 24 hours of each other should be avoided (see
).
Concomitant use of other 5HT agonists
within 24 hours of Frova (Frovatriptan) treatment is not recommended (see
).
Selective Serotonin Reuptake
Inhibitors / Serotonin Norepinephrine Reuptake Inhibitors
and Serotonin Syndrome
WARNINGS
Carcinogenesis:
Impairment of Fertility:
2
When pregnant rats were administered Frova (Frovatriptan) triptan 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] on a mg/m basis) there
were dose related increases in incidences of both litters and
total numbers 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. Slightly lower fetal weights and an
increased incidence of early embryonic deaths in treated rats
were observed; although not statistically significant compared
to control, the latter effect occurred in both the embryo-fetal
developmental study and in the prenatal-postnatal developmental
study. There was no evidence of this latter effect at the lowest
dose level studied, 100 mg/kg/day (equivalent to 130 times the
MRHD on a mg/m basis). When pregnant rabbits were
dosed throughout organogenesis at doses up to 80 mg/kg/day
(equivalent to 210 times the MRHD on a mg/m basis)
no effects on fetal development were observed.
There are no adequate and well-controlled studies in
pregnant women; therefore, Frova (Frovatriptan) triptan should be used during
pregnancy only if the potential benefit justifies the potential
risk to the fetus.
Frova (Frovatriptan) Adverse Reactions
Serious cardiac events, including some that
have been fatal, have occurred following use of 5-HT
agonists. These events are extremely rare and most have been
reported in patients with risk factors predictive of CAD. Events
reported have included coronary artery vasospasm, transient
myocardial ischemia, myocardial infarction, ventricular tachycardia
and ventricular fibrillation (see , and ).
Among 1554 patients treated with Frova (Frovatriptan) in four
placebo-controlled trials (Trials 1, 3, 4 and 5 in ), only 1% (16) patients withdrew because of
treatment-emergent adverse events. In a long term, open-label
study where patients were allowed to treat multiple migraine
attacks with Frova (Frovatriptan) for up to 1 year, 5% (26/496) patients
discontinued due to treatment-emergent adverse events.
The treatment-emergent adverse events that occurred most
frequently following administration of Frova (Frovatriptan) triptan 2.5 mg
(in at least 2%
of patients), and at an incidence ≥1% greater than
with placebo, in the four placebo-controlled trials were
dizziness, paresthesia, headache, dry mouth, fatigue, flushing,
hot or cold sensation and chest pain.
Table 2 lists treatment-emergent adverse events reported
within 48 hours of drug administration that occurred with
Frova (Frovatriptan) triptan 2.5 mg at an incidence of ≥ 2%
and more often than on placebo, in the first attack in four
placebo-controlled trials (Trials 1, 3, 4 and 5 in ). These studies involved 2392 patients (1554
Frova (Frovatriptan) triptan 2.5 mg and 838 placebo). The events cited reflect
experience gained under closely monitored conditions of clinical
trials in a highly selected patient population. In actual
clinical practice or in other clinical trials, these incidence
estimates may not apply, as the conditions of use, reporting
behavior, and the kinds of patients treated may differ.
Other events that occurred at ≥2% on
Frova (Frovatriptan) triptan that were equally or more common in the placebo
group were somnolence and nausea.
Frova (Frovatriptan) is generally well tolerated. The incidence of
adverse events in clinical trials did not increase when up to 3
doses were used within 24 hours. The majority of adverse events
were mild or moderate and transient. The incidence of adverse
events in four placebo-controlled clinical trials was not
affected by gender, age or concomitant medications commonly used
by migraine patients. There were insufficient data to assess the
impact of race on the incidence of adverse events.
In the paragraphs that follow, the incidence of less
commonly reported adverse events in four placebo-controlled
trials are presented. Variability associated with adverse event
reporting, the terminology used to describe adverse events etc,
limit the value of the incidence estimates provided. The
incidence of each adverse event is calculated as the number of
patients reporting the event at least once divided by the number
of patients who used Frova (Frovatriptan) . All adverse events reported within
48 hours of drug administration in the first attack in four
placebo controlled trials involving 2392 patients (1554
Frova (Frovatriptan) triptan 2.5 mg and 838 placebo) are included, except those
already listed in , those too general to be informative, those not
reasonably associated with the use of the drug and those which
occurred at the same or a greater incidence in the placebo
group. Events are further classified within body system
categories and enumerated in order of decreasing frequency using
the following definitions: frequent adverse events are those
occurring in at least 1/100 patients, infrequent adverse events
are those occurring in between 1/100 and 1/1000 patients, and
rare adverse events are those occurring in fewer than 1/1000
patients.
Central and peripheral
nervous system:
Gastrointestinal:
Body as a whole:
Psychiatric:
Musculoskeletal:
Respiratory:
Vision disorders:
Skin and
appendages:
Hearing and vestibular
disorders:
Heart rate and
rhythm:
Metabolic and nutritional
disorders:
Special senses, other
disorders:
Urinary system
disorders:
Cardiovascular disorders,
general:
Platelet, bleeding and
clotting disorders:
Autonomic nervous
system:
Because these events are reported voluntarily from a
population of uncertain size, it is not always possible to
reliably estimate their frequency. Information is often
incomplete so that a definite causal relationship to drug
exposure can often not be established.
Central and peripheral
nervous system:
Frova (Frovatriptan) Drug Abuse And Dependence
Although the abuse potential of Frova (Frovatriptan) has not been specifically
assessed in clinical trials, no abuse of, tolerance to, withdrawal from,
or drug-seeking behavior was observed in patients who received Frova (Frovatriptan) .
The 5-HT agonists, as a class, have not been associated with
drug abuse.
Frova (Frovatriptan) Overdosage
There is no direct experience of any patient taking an overdose
of Frova (Frovatriptan) . The maximum single dose of Frova (Frovatriptan) triptan given to male and
female patients with migraine was 40 mg (16 times the clinical dose) and
the maximum single dose given to healthy male subjects was 100 mg (40
times the clinical dose) without significant adverse events.
As with other 5-HT receptor agonists, there is no
specific antidote for Frova (Frovatriptan) triptan. The elimination half-life of
Frova (Frovatriptan) triptan is 26 hours, therefore if overdose occurs, the patient
should be monitored closely for at least 48 hours and be given any
necessary symptomatic treatment.
The effects of hemo- or peritoneal dialysis on blood
concentrations of Frova (Frovatriptan) triptan are unknown.
Frova (Frovatriptan) Dosage And Administration
The recommended dose is a single tablet of Frova (Frovatriptan) (Frova (Frovatriptan) triptan
2.5 mg) taken orally with fluids.
If the headache recurs after initial relief, a second tablet may
be taken, providing there is an interval of at least 2 hours between
doses. The total daily dose of Frova (Frovatriptan) triptan should not exceed 3 tablets
(3 x 2.5 mg per day).
There is no evidence that a second dose of Frova (Frovatriptan) triptan is
effective in patients who do not respond to a first dose of the drug for
the same headache.
The safety of treating an average of more than 4 migraine attacks
in a 30-day period has not been established.
Frova (Frovatriptan) How Supplied
Frova (Frovatriptan) tablets, containing 2.5 mg of Frova (Frovatriptan) triptan (base) as the
succinate, are available as round, white, film-coated tablets debossed
with 2.5 on one side and “E” on the other side. The
tablets are available in:
Blister card of 9 tablets, 1 blister card per carton (NDC
63481-025-09)
Store at controlled room temperature, 25°C
(77°F) excursions permitted to 15 - 30°C
(59°F - 86°F) [see USP Controlled Room Temperature].
Protect from moisture.
U.S. Patent Nos 5,962,501, 5,827,871, 5,637,611 and 5,464,864 and
5,616,603.
Manufactured for:
Chadds Ford, PA 19317
Manufactured by:Almac Pharma Services LimitedCraigavon,
BT63 5UA, UK
Frova (Frovatriptan) is a registered trademark of Vernalis Development
Limited.
© 2007 Endo Pharmaceuticals
Inc.
PX544-3 / April, 2007
Frova (Frovatriptan)
Frova (Frovatriptan) Package Label - Principal Display Panel – Tablet Blister Pack
Frova (Frovatriptan) Package Label - Principal Display Panel – Tablet Blister Pack Professional Sample
