ADIS NEW DRUG PROFILE CNS Drugs 2001; 15 (12): 969-976

1172-7047/01/0012-0969/$22.00/0

© Adis International Limited. All rights reserved.

Frovatriptan
Stephanie E. Easthope and Karen L. Goa
Adis International Limited, Auckland, New Zealand

Contents
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 969
1. Pharmacodynamic Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 970
2. Pharmacokinetic Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 971
3. Clinical Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 972
4. Tolerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 974
5. Frovatriptan: Current Status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 974

Abstract
h Frovatriptan, a new serotonin receptor agonist de- Features and properties of frovatriptan
veloped for the acute treatment of migraine, has (VML 251, SB 209509)
high affinity for serotonin 5-HT1B and 5-HT1D re-
Indication
ceptor subtypes and is a potent stimulator of con-
Acute treatment of migraine with or without aura
traction in human basilar arteries.
h A long terminal elimination half-life (≈26 hours) is Mechanism of action
Antimigraine agent Serotonin 5-HT1B/1D
a distinctive pharmacokinetic feature of frova- receptor agonist
triptan which appears to be independent of dose,
Dosage and administration
age, gender and renal function.
h A single oral dose of frovatriptan 2.5mg was effec-
Usual dosage in clinical trials
Route of administration
2.5mg
Oral
tive in the acute treatment of migraine providing Frequency of administration Once during migraine;
meaningful relief within 2 hours to approximately a second dose may be
twice as many recipients as placebo in clinical tri- taken for headache
recurrence
als.
h Consistent relief of migraine symptoms was Pharmacokinetic profile (2.5mg orally)

achieved in patients who treated a number of con- Peak whole blood 4.2 (males)
concentration (μg/L) 7.0 (females)
secutive attacks with frovatriptan and the incidence Time to peak whole blood 2.3 (males)
of 24-hour migraine recurrence was reduced. concentration (h) 3.0 (females)
h Frovatriptan was well tolerated in clinical trials, Area under the whole blood 42.9 (males)
with the overall incidence of adverse events occur- concentration-time curve (μg/L
h) 94.0 (females)
Absolute bioavailability (%) 22.1 (males)
ring with frovatriptan 2.5mg only slightly higher 29.6 (females)
than that reported with placebo. Mild to moderate Elimination half-life (h) ≈26
fatigue, nausea and paraesthesia were the most
Adverse events
commonly reported drug-related adverse events.
Most frequent Fatigue, nausea,
paraesthesia
970
O 5-HT1B and 5-HT1D was demonstrated by frova-
H2N
NH
Frovatriptan (VML 251, SB 209509)
Migraine is a common neurological disorder
which affects approximately 6% of men and 15 to
18% of women and is characterised by intermittent
and repeated attacks of headache with or without
aura.[1,2] Migraine without aura can last from 4 to
72 hours, is pulsating and of moderate to severe
intensity and may be accompanied by nausea, vom-
iting, photophobia and phonophobia. With aura,
the headache is often preceded by neurological
symptoms and deficits.[2]
The neurotransmitter serotonin has been im-
plicated as playing an indirect role in the devel-
opment of migraine. By interacting with serotonin
receptor subtypes such as 5-HT1B (a vascular recep-
tor) and 5-HT1D (a presynaptic autoreceptor), sero-
tonin mediates vasoconstriction and trigeminal
neuronal activation.[3,4] Agents selective for these re-
ceptor subtypes are therefore commonly used in the
acute treatment of migraine attacks.
Frovatriptan, a new 5-HT1B/1D receptor agonist
with a distinctive pharmacokinetic profile, has
been studied in patients with acute migraine.
1. Pharmacodynamic Profile
Receptor Binding
• Frovatriptan has high affinity for human recom-
binant 5-HT1B and 5-HT1D receptors [–log10 of the
apparent disassociation constant (pKi) = 8.6 and
8.4, respectively], and moderate affinity for 5-
HT1A, 5-HT1F and 5-HT7 receptors (pKi = 7.3, 7.0
and 6.7, respectively) in vitro. The drug has low
affinity for other serotonin receptor subtypes and
negligible affinity for histamine H1, α1-adrenergic
and dopamine D1, D2 and D3 receptors (pKi <5).[5]
© Adis International Limited. All rights reserved.
Easthope & Goa
• A potent effect on recombinant human receptors
NHCH3
triptan in vitro [–log10 of the concentration causing
50% maximal stimulation (pEC50) = 7.8 and 8.3,
respectively] and unlike sumatriptan and naratrip-
tan, frovatriptan was also a moderately potent full
agonist at 5-HT7 receptors (pEC50 = 6.2).[6] 5-HT7
receptors have a dilatory action and are expressed
in the human coronary artery; however, the exact
role of 5-HT7 receptors has not been established.[7]
Cardiovascular Effects
• Frovatriptan produced concentration-dependent
contractions in isolated basilar arteries from rabbits
and was ≈10-fold more potent than sumatriptan
(pEC50 = 7.2 vs 6.0).[5] In contrast to other 5-HT1B/1D
receptor agonists, frovatriptan produces a bell-shaped
concentration curve, with relaxation of coronary ar-
teries occurring at high concentrations.[5,8]
• There is a marked difference in the threshold
concentration of frovatriptan required to elicit con-
tractile activity in isolated human basilar (>2 nmol/L)
and coronary arteries (>20 nmol/L), indicating a
functional selectivity for cerebral vasculature.[8]
• Intravenous frovatriptan 0.2 to 790 nmol/kg
produced marked increases in carotid vascular re-
sistance in anaesthetised dogs but had little effect
on the systemic coronary circulation.[9] Doses >790
nmol/kg reduced coronary vasculature resistance.
• No significant effects on the cardiovascular sys-
tem of 34 healthy male volunteers were seen after
administration of a single oral dose of frovatriptan
1 to 60mg. Small, but significant transient increases
in systolic and diastolic blood pressure were seen
in volunteers receiving doses 32- to 40-fold higher
(80 to 100mg) than the lowest effective dose of fro-
vatriptan (2.5mg) [p ≤ 0.003].[10]
• A pilot study in 75 patients aged 33 to 75 years
with coronary artery disease or Framingham coro-
nary risk prediction scores >14 demonstrated no
increase in cardiovascular abnormalities (as mea-
sured by ECG, heart rate, blood pressure and tro-
ponin T levels) in patients receiving frovatriptan
2.5mg compared with placebo.[11]
CNS Drugs 2001; 15 (12)
Frovatriptan: New Drug Profile
2. Pharmacokinetic Profile
Absorption and Distribution
• The mean absolute bioavailability of a single oral
dose of frovatriptan 2.5mg was 22.1% in healthy
men (n = 6) and 29.6% in healthy women (n = 6)
[p < 0.01]. After an oral 2.5mg dose, mean maxi-
mum whole blood concentrations (Cmax) were 4.2
μg/L in men and 7.0 μg/L in women and the time
to Cmax (tmax) was 2.3 and 3 hours, respectively (p
< 0.05). The area under the whole blood concen-
tration-time curve (AUC) in women (94.0 μg/L
h)
was approximately twice as high as that in men
(42.9 μg/L
h) [corresponding values were 31.8
and 16.5 μg/L
h when normalised for body-
weight, p < 0.01].[12]
• Frovatriptan at steady state after an intraven-
ous infusion of 0.8mg had a volume of distribu-
tion of 4.2 and 3.0 L/kg in men and women, respec-
tively.[12] The blood-plasma concentration ratio
increased to an equilibrium of ≈2 : 1 about 2 hours
after oral administration of frovatriptan 2.5mg.[13,14]
• Compared with values obtained in migraine-
free periods, the Cmax, AUC, tmax and terminal
elimination half-life (t1⁄2) of a single oral dose of
frovatriptan 2.5mg were similar when the drug was
taken by 12 patients during a migraine attack.[15]
• Whole blood concentrations and the mean AUC
were higher in elderly male volunteers than in
young men given frovatriptan 2.5mg; however,
only the AUC values were significant different
(73.0 vs 42.9 mg/L
h, p < 0.01).[16]
Metabolism and Elimination
• Frovatriptan is primarily metabolised by (but
does not inhibit) cytochrome P450 (CYP) 1A2.[17,18]
• Frovatriptan blood and plasma concentrations
decline multiexponentially with the terminal elim-
ination phase apparent at ≈12 to ≈24 hours after
oral administration.[14] The t1⁄2 of frovatriptan was
≈26 hours and appears to be independent of dose,
route of administration, gender, age and renal func-
tion.[13,14]
© Adis International Limited. All rights reserved.
971
• Renal clearance of intravenous frovatriptan 0.8mg
was lower in women than men (0.14 and 0.19 L/h/kg,
respectively).[13] Urinary frovatriptan excretion
and renal clearance decreased with increasing se-
verity of renal impairment [fraction of unchanged
drug excreted = 0% in patients with cre- atinine clear-
ance of 0.6 to 1.8 L/h (10 to 30 ml/min) vs 0 to 14.3%
in healthy volunteers]; however, no significant dif-
ferences were seen in Cmax, tmax and AUC values
between healthy volunteers and patients with vari-
ous degrees of renal impairment.[19,20]
Potential Drug Interactions
• Coadministration of ergotamine 2mg and frova-
triptan 5mg had little effect on the rate of absorp-
tion or elimination of frovatriptan; however, the Cmax
and AUC of frovatriptan were reduced by ≈25%.[21]
This was not considered to be clinically significant.
• The CYP1A2 inhibitor fluvoxamine adminis-
tered at a dosage of 100 mg/day increased the Cmax
and AUC of frovatriptan 2.5mg by 27 to 39% in 16
healthy volunteers when coadministered in a cross-
over trial.[22] In a further eight healthy women also
receiving the combined oral contraceptive pill the
Cmax was increased by 49% and the AUC by 41%.
However, the increase in exposure to frovatriptan
was not considered to be clinically significant.
• The AUC of frovatriptan after administration of
a single oral 2.5mg dose was increased by ≈25% in
men and women when frovatriptan was coadmin-
istered with propranolol 80mg twice daily for 8
days in 12 healthy volunteers, and the Cmax by 23%
in men and 16% in women. The tmax and t1⁄2 of
frovatriptan were unaffected by coadministration
with propranolol; however, the fraction of the orig-
inal dose which was excreted unchanged in the
urine increased from 5.46 to 10.86% in male vol-
unteers and from 11.94 to 17.41% in women. The
increased bioavailability of frovatriptan when
coadministered with propranolol was not consid-
ered clinically significant nor necessitating dosage
adjustments.[23,24]
• No significant differences in the pharmacoki-
netic parameters of a single oral dose of frovatrip-
CNS Drugs 2001; 15 (12)
972 Easthope & Goa

tan 2.5mg were found when coadministered with mately twice as many recipients of frovatriptan
the monoamine oxidase-A inhibitor moclobemide 2.5mg had meaningful relief of migraine 2 and 4
150mg twice daily in 12 healthy volunteers who hours after drug administration when compared
had been pretreated with the same dosage of moclo- with patients receiving placebo (figure 1).[34,35]
bemide for 7 days.[25,26] • The incidence of headache recurrence in frova-
• The absorption, bioavailability and elimination triptan recipients 24 hours after treatment was
of frovatriptan were unaffected by moderate alco- lower than that of placebo recipients in both trials.
hol consumption in healthy volunteers. Only a Nine to 14% of recipients of frovatriptan 0.5 to 40mg
small nonsignificant trend towards lower AUC, had developed a recurrence of migraine symptoms
Cmax and renal clearance values was seen in smok- compared with 17 and 18% of placebo recipients in
ers, in whom CYP1A2 is induced when compared each of the trials.[27,28]
with nonsmokers.[18] Healthy women taking oral
• Times to meaningful relief in these two trials
contraceptives, which inhibit CYP1A2 had frova-
were 8.3 (median)[34] and 8.5 (mean)[35] hours for
triptan Cmax and AUC values 25 and 30% higher,
respectively, than women not taking oral contra-
Frovatriptan 2.5mg
ceptives. Placebo
2 hours post-treatment
80
3. Clinical Trials
70
The efficacy of frovatriptan for the acute treat- 60
50
ment of migraine attacks has been evaluated in sev- *
40 *
eral double-blind, randomised, placebo-controlled 30
trials[27-29] and one noncomparative follow-up 20
study.[30] The drug was given as single[27,28] or up
Response rate (%)

10
to two[29] or three[30] oral doses. The primary effi- 0
cacy endpoint was the proportion of patients whose
headache severity decreased from severe or mod- 4 hours post-treatment
80
erate (grades 3 or 2) to mild or none (grades 1 or 70 **
0) 2 hours after treatment using the International **
60
Headache Society (IHS) classification of migraine 50
severity.[31,32] The 4-hour response rates, 24-hour 40
headache recurrence rates, time to meaningful re- 30
20
lief and need for rescue medication were also as-
10
sessed in some studies.[27,28,33-35] Clinical efficacy 0
data were presented at meetings.[27-30,33-35] 90 91 126 118
• Frovatriptan at doses of 2.5, 5, 10, 20 and 40mg No. of patients
was found to be significantly more effective than
placebo in two randomised double-blind dose- Ryan & Keywood[27] Goldstein et al.[28]

finding trials involving 1442 patients experiencing

acute migraine (p < 0.05).[27,28] No relationship be-
tween dose and efficacy was found in patients re-
ceiving frovatriptan ≥2.5mg (all being signifi-
cantly more effective than placebo);[27,28] however,
doses <2.5mg were not significantly more effective
than placebo.[28] Based on these findings, 2.5mg is
considered the lowest effective dose. Approxi-
Fig. 1. Efficacy of frovatriptan 2.5mg in the acute treatment of
migraine at 2 and 4 hours after drug administration. Patients with
meaningful relief of symptoms [a reduction in pain from severe or
moderate (grade 3 or 2) to mild or none (grade 1 or 0) according
to the International Headache Society guidelines] in two rando-
[27,28]
mised, double-blind trials. Some data have been extra-
[34,35]
polated from graphs presented in posters of these studies.
* p < 0.05, ** p < 0.005 vs placebo.

© Adis International Limited. All rights reserved. CNS Drugs 2001; 15 (12)
Frovatriptan: New Drug Profile 973

9 Study 1 • Meaningful relief within 24 hours of the first

Study 2
8
Study 3
dose was achieved in 84% of 13 878 acute migraine
7 attacks treated by 496 patients with up to three
6 doses of frovatriptan 2.5mg in a 12-month non-
comparative study.[37] Frovatriptan was consis-
Time (h)

5
4 tently effective in subsequent attacks, with mean-
3 ingful relief obtained in 80% of recipients treating
2 a second attack and 75% of patients treating the last
1 attack. Treatment was rated as ‘fair’ to ‘excellent’
0 by 82% of the 496 trial participants at the end of
123 424 264 251 850 531
No. of patients
Placebo Frovatriptan 2.5mg
Fig. 2. Median time to meaningful relief in patients treating an
acute migraine attack. Patients treated up to three migraine at-
tacks with one to two oral doses of frovatriptan 2.5mg or placebo
and recorded the time taken for migraine severity to reduce from
severe or moderate (grade 3 or 2) to mild or none (grade 1 or 0)
according to the International Headache Society guidelines. Data
are from 3 phase III trials summarised in an abstract and a
poster.[29,36]
placebo, and 3.7 (median)[34] and 4 (mean)[35] hours
for frovatriptan 2.5mg (p ≤ 0.0005). The percentage
of patients requiring rescue medication ranged from
48 to 50% for placebo and 23 to 36% for frova-
triptan ≤40mg (p-values not reported).[34,35]
• Preliminary data from three phase III clinical tri-
als in 2443 patients assessing the efficacy of frova-
triptan 2.5mg compared with placebo were presented
at meetings.[29,36] Each study demonstrated signif-
icantly superior 2-hour response rates for frova-
triptan 2.5mg when compared with placebo (36 to
46% vs 21 to 27%, p ≤ 0.001). The response rate at 4
hours was also superior to placebo (56 to 65% vs 31
to 38%, p < 0.001). The median time to meaningful
relief in frovatriptan-treated patients was shorter
than in placebo recipients (figure 2) and was sig-
nificant in two of three attacks in study 1 and in all
three attacks of study 2. In study 3, only the first
attack was placebo-controlled and significance was
achieved (p < 0.05).[36]
the study.
• A retrospective pooled analysis of five rando-
mised double-blind trials with 3128 participants
and including one comparison with sumatriptan
100mg, examined the rate of 24-hour migraine re-
currence following successful treatment with
frovatriptan 2.5mg within 4 hours.[33] 20 to 31% of
placebo recipients and 32% of sumatriptan-treated
patients who had meaningful relief at 4 hours went
on to develop a headache after 24 hours. By com-
parison, successfully treated frovatriptan recipi-
ents had a 7 to 25% headache recurrence rate (no
p-values were given for this pooled analysis). The
number of patients with successful treatment at 2
and 4 hours was not reported.
• The median time to headache recurrence in the
five studies ranged from 11.0 to 21.4 hours in pa-
tients treated with frovatriptan 2.5mg, 14.0 hours
in patients receiving sumatriptan 100mg and 6.2 to
13.4 hours in recipients of placebo (p-values not
reported).[33]
• A second retrospective pooled analysis of pla-
cebo controlled trials reported the mean headache
recurrence rate in patients receiving treatment with
frovatriptan to be 17%.[38] This was lower than the
mean headache recurrence rates of all comparative
treatments (23 to 40%) and was significantly cor-
related with the t1⁄2 (r = –0.98, p = 0.0024).
• Frovatriptan relieved symptoms of menstrually
associated migraine1 (MAM) as reported in an ana-
1 Menstrually associated migraine (MAM) is defined as a
migraine attack occurring between the 3 days prior to and 4
days after the first day of menstruation.

© Adis International Limited. All rights reserved. CNS Drugs 2001; 15 (12)
974 Easthope & Goa

Frovatriptan 2.5mg verity. The incidence of adverse events appears to

Placebo
be dose related; however, a single dose of frova-
9 Ryan & Keywood[34] triptan 2.5mg produced a rate only slightly higher
8 than placebo (45% vs 34%).[27,34]
7 • The most commonly reported adverse events
6 after a dose of 2.5mg were dizziness (6.1 and 8.0%),
5 nausea (4.0 and 6.1%), fatigue (3.1 and 5.0%), para-
4 esthesia (3.1 and 4%), headache (1.5 and 2.0%) and
3 somnolence (1 and 3.8%).[34,35] Of these, only fa-
Patients reporting adverse event (%)

2
tigue, nausea and paraesthesia appeared to be more
frequent in frovatriptan 2.5mg recipients than pla-
1
cebo recipients (figure 3).
0
Dizziness Fatigue Nausea Paraesthesia • The tolerability of frovatriptan appears to be dose-
related, with >5% of patients experiencing dizziness,
9 Goldstein & Keywood[35] nausea, paraesthesia, headache, somnolence and
8 chest pain when given 10mg of frovatriptan (four
7 times greater than the lowest effective dose). After
6
taking 40mg of frovatriptan (16 times greater than
the lowest effective dose) >10% of patients reported
5
dizziness, fatigue, nausea and chest pain.[34,35]
4
• Frovatriptan 2.5mg was well tolerated in a 12-
3
month noncomparative trial in which 496 patients
2 could self-administer up to three doses for the treat-
1 ment of acute migraine.[40] The adverse events pro-
0 file was similar to that in short-term studies, with
Dizziness Fatigue Nausea Paraesthesia dizziness (8%), nausea (6%) and fatigue (5%) re-
ported most commonly; headache, paraesthesia and
Fig. 3. Adverse events reported by >3% of trial participants in two
[34,35]
somnolence each occurred in 4% of patients. The
randomised trials. Patients with at least a 12-month history incidence was greatest during the first 13 weeks of
of migraine were given a single oral dose of frovatriptan 2.5mg or
the study, and the number of doses taken did not
placebo for the treatment of acute migraine attack.
affect the adverse events profile.
• Analysis of a comparative trial in 962 patients
lysis of 578 attacks reported by 98 women over 6 with migraine randomised to treatment with frova-
months in a noncomparative trial.[39] 84% of MAM triptan 2.5mg or sumatriptan 100mg found that the
attacks were relieved within 24 hours of frova- overall incidence of adverse effects was signifi-
triptan administration; however, data for 2- and 4- cantly less in the patients receiving frovatriptan
hour response rates were not presented. (36 vs 43%, p = 0.03).[41] Furthermore, the incidence
of adverse events in the gastrointestinal system and
body as a whole was significantly less in patients
4. Tolerability treated with frovatriptan (p < 0.05).
• Frovatriptan was well tolerated at all doses ad-
5. Frovatriptan: Current Status
ministered (0.5 to 40mg) during two dose-finding
clinical trials. The majority of adverse events de- Frovatriptan is a 5-HT1B/1D receptor agonist that
scribed were transient and of mild to moderate se- has been approved in the US and France for the

© Adis International Limited. All rights reserved. CNS Drugs 2001; 15 (12)
Frovatriptan: New Drug Profile
acute treatment of migraine with or without aura in
adults.[42,43] Approval in other European countries
is pending the outcome of assessment under the
Mutual Recognition Procedure. Clinical data indi-
cate that frovatriptan is effective in the treatment
of acute migraine attacks and is well tolerated.
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Correspondence: Stephanie Easthope, Adis International
Limited, 41 Centorian Drive, Private Bag 65901, Mairangi
Bay, Auckland 10, New Zealand.
E-mail: demail@adis.co.nz
CNS Drugs 2001; 15 (12)