Download Zomig Rapimelt - EPGonline.org

‘Zomig Rapimelt’
Rapid, reliable and convenient
migraine treatment
Clinical Product Summary
‘Zomig’ and ‘Zomig Rapimelt’ are trade marks of the AstraZeneca
group of companies.
Contents
Foreword
2
Introduction
4
The ‘Zomig’ Range of Products
5
Pharmacokinetics
7
Clinical Efficacy
9
Fast onset of action
High and sustained efficacy
Relief of migraine-associated symptoms
Resumption of daily activities
Tolerability
15
Patient Preferences
16
Preference compared with conventional tablets
Preference compared with other orally disintegrating tablets
Post-marketing Experience
20
‘Zomig Rapimelt’ Product Summary
22
1
Foreword
Dr Andrew Dowson, The King’s Headache Services, King’s
College Hospital, London, UK
Primary goals in the acute treatment of migraine are to provide
rapid, reliable and sustained relief from headache pain and migraineassociated symptoms, by administration of well-tolerated and
patient-friendly medications.The emergence of the migraine-specific
treatments known as 5-Hydroxytryptamine 1B and 1D (5-HT1B/1D)
receptor agonists or ‘triptans’ in the early 1990s represented a
major step towards realisation of these goals.Today, several triptans
are available. Zolmitriptan (‘Zomig’†), a 2nd generation triptan, is
available in 3 different formulations, so that it is now possible to
make prescribing decisions on a case-by-case basis, in order to
provide treatments based on patient expectations, preferences,
migraine characteristics and lifestyles.
Conventional tablets are the most frequently used formulation and
are often preferred for the treatment of migraine. However, many
patients suffer from nausea during a migraine attack and have
difficulties swallowing conventional oral tablets. Fluid intake may
exacerbate nausea and provoke vomiting. Migraine attacks occur
unpredictably and can easily strike in situations where fluids to
take with the medication are not readily available. Patients ideally
require a treatment that enables any migraine to be promptly
treated in any given situation.
Zolmitriptan has been available as a conventional oral tablet
since 1997 and is established as a fast, effective and well-tolerated
therapy for the acute treatment of migraine. An orally disintegrating
tablet (ODT) formulation of zolmitriptan that dissolves on the
tongue, with no need for additional fluid intake, has also been
developed.This formulation offers a convenient alternative for
patients who cannot or prefer not to take conventional tablets.
The fact that the orally disintegrating tablet can be taken without
2
liquids allows patients to take the medication early in the course of
a migraine attack, which has been proven to improve response to
treatment.
Data presented in this clinical product summary show that the
orally disintegrating formulation of zolmitriptan is bioequivalent
to the conventional tablet. Placebo-controlled trials and postmarketing surveillance data confirm that orally disintegrating
zolmitriptan provides fast-acting, highly effective and well-tolerated
relief of migraine and its associated symptoms.Treatment
satisfaction data show that patients generally consider orally
disintegrating zolmitriptan to be a more convenient option than
conventional tablets and that it facilitates the treatment of migraine
whenever and wherever it strikes. Post-marketing studies also
suggest that zolmitriptan orally disintegrating tablet is preferred
to other available triptans.
†
Zomig Rapimelt  is the registered trade mark in Australia, Austria, Denmark, Finland,
Iceland, Ireland, Mexico, Norway, Portugal, Sweden and the UK. Elsewhere the
product is identified as Zomig Rapimelt  (Canada, Italy), ZomigOro  (France),
Ascotop  Schmeltztabletten (Germany), Zomig-ZMT (USA), Zomig Flas  (Spain),
Zomig Oro  (Switzerland), ZomigZip  (Holland), Zomig Instant  (Belgium), Zomig
Instant  (Luxembourg), Zomig OD  (Brazil) and Zomigon Rapimelt  (Greece).
3
Introduction
Migraine is a common medical condition characterised by
neurological, gastrointestinal and autonomic symptoms,[1] and is
estimated to affect 10% to 15% of the worldwide population.[2]
The chronic and debilitating nature of migraine, attacks of which
occur unpredictably and unexpectedly, can impede patients’ ability
to carry on with normal activities of daily living, thereby reducing
quality of life[3,4] and having a negative socioeconomic influence.[5–7]
Although the precise aetiology of migraine is not completely clear,
the trigeminovascular system is thought to play a vital role in its
pathogenesis.[8] Upon inappropriate activation of the trigeminal
nerve pathway, vasoactive neuropeptides are released, ultimately
resulting in neurogenic inflammation, pain, nausea, phonophobia
and photophobia. It is widely accepted that 5-HT1B and 5-HT1D
receptors play an integral role in the generation of migraine attacks.
Despite progress in the understanding of the underlying
pathophysiology of migraine and the development of drugs, such
as the triptans, that specifically target the disease process, migraine
is still an under-diagnosed and under-treated condition.[9,10]
‘Zomig’ attacks
migraine through
both central and
peripheral activity
Zolmitriptan (‘Zomig’), first introduced in 1997, is a highly effective
and selective 5-HT1B/1D receptor agonist that is able to inhibit
activation of the trigeminovascular system both peripherally and
centrally.[11–13] The N-desmethyl metabolite of zolmitriptan, 183C91,
also has high affinity for 5-HT1B/1D receptors.The structural formula
of zolmitriptan is shown in figure 1.
O
O
NH
H
N
N(CH3)2
Figure 1. Structural formula of zolmitriptan.
4
The ‘Zomig’ Range of Products
Although triptans have been traditionally formulated as conventional
oral tablets, this may not be the most suitable formulation for all
patients or for every situation.The results of clinical trials and
patient surveys have shown that highly effective pain relief with a
rapid onset of action is a top priority for patients and physicians
alike.[10,14] Although oral therapy has generally been considered the
preferred route of administration, some patients dislike taking
conventional tablets, others have difficulty swallowing tablets during
an attack, and some find that swallowing tablets can induce and/or
exacerbate nausea and vomiting. Furthermore, it is not always
possible to access liquids quickly in the event of a migraine attack.
A survey of patients with migraine in France, Germany, Italy, the UK
and the USA found that only a minority of patients (36%) were
very satisfied with the migraine therapy currently used and that
many supplemented prescribed medication with alternative
therapies.[10] Data also show that 34% of migraine patients do not
feel in control of life,[5] 78% report limitations of daily routines and
45% worry about an attack while driving.[15] When patients were
asked which form of migraine medication was preferred, 73% chose
tablets that dissolve in the mouth and can be taken without
liquid.[5]
Conventional ‘Zomig’ tablets, first launched in 1997, are now
available worldwide for the acute treatment of migraine attacks
with or without aura, and are the cornerstone of oral therapy for
many patients. Clinical trials have established that the conventional
‘Zomig’ tablet is reliably effective and well tolerated in the acute
5
‘Zomig Rapimelt’
can be taken
whenever and
wherever a
migraine attack
strikes
treatment of migraine, with an onset of effect reported as early as
30 minutes after dosing.[16,17] ‘Zomig’ is also widely available as an
orally disintegrating tablet that dissolves rapidly on the tongue and
can be taken discreetly as soon as a migraine headache starts with
no need for additional fluid intake.
This convenient Rapimelt formulation provides excellent relief
for patients who, for whatever reason, prefer not to/cannot take
conventional tablets.The convenience of ‘Zomig Rapimelt’ may also
allow patients to take the medication earlier in the course of a
migraine attack, when water or other liquids may not be available.
Clinical research has shown that treating migraine early in the
course of an attack results in a more effective response to
therapy.[18] The ‘Zomig’ range of products is completed by the
nasal spray formulation. ‘Zomig’ Nasal Spray offers even faster relief
than the oral route of administration via an easy to use, one-dose,
discreet device for intra-nasal delivery.
In summary, ‘Zomig’ is available in a range of delivery options that
suits different lifestyles and situations.These formulations have been
carefully developed to satisfy the needs and preferences of a wide
range of patients. Physicians can therefore match treatments to
individual patients, and a thorough assessment of each patient’s
expectations, needs and preferences should be performed before
a prescribing decision is made.
The following sections describe the ability of ‘Zomig Rapimelt’
to provide fast and consistently effective relief of migraine with
excellent tolerability. Patient perceptions of the convenience and
practicality of ‘Zomig Rapimelt’ are also discussed.
6
Pharmacokinetics
The pharmacokinetic profile of ‘Zomig Rapimelt’ can by summarised by:
•
•
Bioequivalence to the conventional oral tablet
•
Elimination kinetics similar to those of the conventional
oral tablet
Rapid detection of the parent drug in the plasma, appearing
at similar rates to the conventional oral tablet
All of the above factors predict that, like the conventional oral tablet,
‘Zomig Rapimelt’ will be associated with rapid, long-lasting and reliable
efficacy, paralleled by excellent tolerability.
After being placed on the tongue,‘Zomig Rapimelt’ dissolves in seconds.
The drug is rapidly dispersed and absorbed via the gastrointestinal
route, with appearance of zolmitriptan in the plasma within 30 minutes
of dosing.[19] The resultant zolmitriptan plasma concentration-time
curve is similar to that observed after administration of a conventional
‘Zomig’ tablet (figure 2). Bioequivalence of ‘Zomig Rapimelt’ and the
conventional tablet has been confirmed for both parent compound
and the active N-desmethyl metabolite.[19] A slightly delayed time to
zolmitriptan maximum plasma concentration (tmax) has been noted with
‘Zomig Rapimelt’ (3 hours vs 1.5 hours; table I). However, as can be
seen from figure 2, there is a plateau of plasma concentrations between
the 2nd and 5th hours post-dose, suggesting that the precise time of tmax
within this time frame is of no clinical importance. Similar onset of
action can be expected for ‘Zomig Rapimelt’ and ‘Zomig’ conventional
tablet, since the plasma concentrations of zolmitriptan for each
formulation are similar during the first 45 minutes after dosing (figure 2).
7
'Zomig' oral tablet 5 mg (2 x 2.5 mg)
'Zomig Rapimelt' 5 mg (2 x 2.5 mg)
10
Plasma concentration
(ng/mL)
‘Zomig Rapimelt’
is bioequivalent to
and offers all the
benefits of the
‘Zomig’
conventional
tablet
1
0.1
3
0
6
9
12
15
Nominal time (h)
Figure 2. Geometric mean plasma concentrations of zolmitriptan following dosing
with ‘Zomig Rapimelt’ (2 x 2.5 mg) compared with the conventional oral tablet
(2 x 2.5 mg) in healthy volunteers.[19]
In order for two formulations of a drug to have similar clinical
characteristics they must be bioequivalent.Accordingly, the
bioequivalence of ‘Zomig Rapimelt’ to conventional ‘Zomig’ tablets
shows that ‘Zomig Rapimelt’ is well equipped to provide the rapid,
long-lasting, reliable and well-tolerated relief from migraine pain
that has become the hallmark of the conventional ‘Zomig’ tablet.
Table I. Pharmacokinetic parameters of zolmitriptan and 183C91 after 3 single 5 mg (2 x 2.5 mg doses) doses of
‘Zomig Rapimelt’ or the conventional oral tablet in healthy volunteers[19]
AUC (ng•h/ml)
Cmax (ng/ml)
tmax (hours)
t1/2 (hours)
Geometric CV
mean
Geometric CV
mean
Median Range
Mean SD
‘Zomig Rapimelt’
Zolmitriptan (n=18)
51.1
51.9
8.8
43.6
3.0
0.6–5.0
2.9
0.4
183C91 (n=18)
36.5
18.1
5.8
20.2
3.0
1.0–6.0
3.0
0.5
Conventional tablet
Zolmitriptan (n=18)
51.4
45.9
9.7
32.7
1.5
0.5–3.0
3.1
0.5
183C91 (n=18)
35.3
14.7
5.6
20.9
3.0
0.7–5.0
3.3
0.7
Abbreviations: AUC = area under the plasma concentration–time curve; Cmax = maximum plasma concentration;
CV = coefficient of variation; n = number of volunteers assessed; SD = standard deviation; t1/2 = elimination half-life;
tmax = time to maximum plasma concentration.
8
Clinical Efficacy
Predictions regarding the efficacy of ‘Zomig Rapimelt’ for the acute
treatment of migraine on the basis of its pharmacokinetic profile
have been demonstrated in controlled clinical trials. Features of the
efficacy of ‘Zomig Rapimelt’ in the acute treatment of migraine
include:
•
•
•
a fast (30-minute) onset of action
early and high pain-free status
high, sustained pain relief.
Three randomised, multicentre, double-blind, placebo-controlled
trials involving patients with an established diagnosis of migraine
have recently been performed. Active treatment was ‘Zomig
Rapimelt’ 2.5 mg in studies A[20] and B[21] and ‘Zomig Rapimelt’
5 mg in study C.[22] Study B differed slightly to studies A and C, in
that patients were instructed to treat an attack as soon as possible,
regardless of headache pain intensity, whereas in the other
2 studies, only attacks with moderate or severe pain were treated.
Intention-to-treat populations consisted of 470 patients who treated
a single migraine headache in study A, and 565 and 670 patients
who treated up to 2 migraine attacks in studies B and C,
respectively. In study B, 32.4% of attacks were of mild intensity
at baseline.
9
‘Zomig Rapimelt’
starts to
work within
30 minutes
‘Zomig Rapimelt’
abolishes migraine
headache within
1 hour
10
Fast onset of action
Headache response, defined as a reduction in the intensity of pain
from severe or moderate at baseline to mild or none, has been
achieved as early as 30 minutes after dosing in higher proportions
of patients treated with ‘Zomig Rapimelt’ relative to patients
treated with placebo (figures 3 and 4). In study A, in which
headache response at 30 minutes was assessed as a secondary
end-point, there was a clear difference in headache response
between ‘Zomig Rapimelt’ and placebo at 30 minutes (16% vs
10%, p=0.054; figure 3).This study also demonstrated that
‘Zomig Rapimelt’ provided an improvement in headache (1-point
improvement in headache pain intensity) from 30 minutes
(22% vs 15% for placebo; p=0.039). In study C, in which headache
response at 30 minutes was the primary efficacy end-point,
16% of migraine attacks treated with ‘Zomig Rapimelt’ responded
at 30 minutes compared with 13% of attacks treated with placebo
(p<0.05; figure 4).When 30-minute response rates from studies A
and B were pooled, the overall response was 20.1% for ‘Zomig
Rapimelt’ and 12.7% for placebo (p<0.005).[17] This fast onset of
action is consistent with pharmacokinetic observations that ‘Zomig
Rapimelt’ is bioequivalent to the conventional tablet, which has also
been shown to induce a significantly better response than placebo
as soon as 30 minutes after dosing.[16,17]
‘Zomig Rapimelt’ was able to achieve significantly greater pain-free
rates than placebo as early as 1 hour after dosing in all 3 studies.
Figure 5 shows that, in study B, a pain-free outcome at 1 hour
was achieved in 13.3% of attacks treated with ‘Zomig Rapimelt’
compared with 8.1% of attacks treated with placebo (p<0.005).
A pooled analysis of studies A and B showed that 1-hour pain-free
rates were significantly higher for ‘Zomig Rapimelt’ than placebo
(7.8% vs 3.4%; p<0.05).[19]
75
'Zomig Rapimelt' 2.5 mg
**
Response rate
(patients [%])
Placebo
50
**
25
*
2
ho
ur
ur
1
ho
s
te
in
u
30
m
s
0
Time post-dose
Figure 3. Headache response rates at 30 minutes to 2 hours after dosing
with ‘Zomig Rapimelt’ 2.5 mg or placebo, in study A.[20] *p=0.054 vs placebo;
**p<0.0001 vs placebo.
75
'Zomig Rapimelt' 5 mg
Response rate
(attacks [%])
Placebo
**
50
**
25
*
ho
ur
s
2
ho
ur
1
30
m
in
ut
es
0
Time post-dose
Figure 4. Headache response rates from 30 minutes to 2 hours after dosing
with ‘Zomig Rapimelt’ 5 mg or placebo, in study C.[22] *p<0.05 vs placebo;
**p<0.0001 vs placebo.
11
‘Zomig Rapimelt’
provides high and
lasting relief
from migraine
headache
High and sustained efficacy
Headache response at 2 hours, which was the primary efficacy outcome
in study A and a secondary outcome in study C, occurred in significantly
greater proportions of patients treated with ‘Zomig Rapimelt’ than in
patients who received placebo (figures 3 and 4).There was a 63%
headache response at 2 hours in patients receiving ‘Zomig Rapimelt’
in study A compared with a 22% placebo response rate (p<0.0001).
In study C, these were 59% and 31%, respectively (p<0.0001).The high
2-hour headache responses seen in studies A and C were sustained
(defined as headache response at 2 hours with no recurrence of
headache pain for 24 hours) over a 24-hour period in 40% and 43%
of patients, respectively (vs 12% and 16%, respectively, for placebo).
Pain-free rate at 2 hours was the primary efficacy end-point of
study B; approximately twice the proportion of attacks treated with
‘Zomig Rapimelt’ than those treated with placebo were pain-free at
2 hours (40.1% vs 19.8%; p<0.001; figure 5).This pain-free outcome
was sustained (defined as patients with no pain at 24 hours postdosing and no need for re-medication, or free from headache
recurrence from 2 to 24 hours) in 31.1% of attacks treated with
‘Zomig Rapimelt’ and 14.6% of those treated with placebo (p<0.001).
75
'Zomig Rapimelt' 2.5 mg
Pain-free rate
(attacks [%])
Placebo
50
**
25
*
ho
ur
s
2
r
ho
u
1
30
m
in
ut
es
0
Time post-dose
Figure 5. Pain-free rates from 30 minutes to 2 hours after dosing with
‘Zomig Rapimelt’ 2.5 mg or placebo, in study B.[21] *p<0.005 vs placebo;
**p<0.001 vs placebo.
12
Relief of migraine-associated symptoms
Where present, migraine-associated nausea, photophobia and
phonophobia were improved by ‘Zomig Rapimelt’ in all 3 studies. For
example, in study B, nausea resolved 2 hours after dosing with ‘Zomig
Rapimelt’ in 66.3% of attacks where present at baseline (vs 38.9% for
placebo; p<0.001; figure 6). Photophobia and phonophobia resolved at
2 hours in 59% of attacks each (vs 37.7% and 41%, respectively, for
placebo; p<0.001 for both symptoms; figure 6). Similarly, in patients
who had symptoms at baseline in study C, nausea had resolved in
57% of attacks (vs 45% for placebo; p<0.05), photophobia in 47% of
attacks (vs 26% for placebo; p<0.0001) and phonophobia in 52% of
attacks (vs 31% for placebo; p<0.0001) at 2 hours after administration
of ‘Zomig Rapimelt’.
‘Zomig Rapimelt’
effectively
resolves all
symptoms
associated with
migraine
In study A, 52% of patients were free from nausea, 46% from
photophobia and 53% from phonophobia 2 hours after dosing with
‘Zomig Rapimelt’ (compared with 32%, 25% and 26%, respectively,
for placebo).
'Zomig Rapimelt' 2.5 mg
Placebo
Resolution of associated
symptoms (attacks [%])
75
*
*
*
50
25
a
N
au
se
ho
bi
on
op
Ph
Ph
ot
op
ho
b
ia
a
0
Figure 6. Resolution of migraine-associated symptoms 2 hours after dosing with
‘Zomig Rapimelt’ 2.5 mg or placebo in study B.[21] *p<0.001 vs placebo.
13
‘Zomig Rapimelt’
helps patients to
regain control
of life
Resumption of daily activities
As assessed in studies B and C, ‘Zomig Rapimelt’ aided resumption
of daily activities in patients in whom these activities were impaired
during migraine attacks. In study B, patients were able to resume
activities within 2 hours of taking ‘Zomig Rapimelt’ in 55.8% of
attacks (vs 34.0% for placebo; p<0.001; figure 7). Similarly, in
study C, patients were able to return to normal daily activities in
52% of attacks 2 hours after dosing with ‘Zomig Rapimelt’ (vs 26%
for placebo; p<0.0001). Resumption of daily activities was not
assessed in study A.
As mentioned on page 7, ‘Zomig Rapimelt’ is bioequivalent to
‘Zomig’ conventional tablet and will therefore demonstrate similar
clinical characteristics. Accordingly, ‘Zomig Rapimelt’ is expected to
provide rapid, long-lasting and reliable efficacy both within and
between patients, as shown by ‘Zomig’ conventional tablet.
Resumption of daily
activities (attacks [%])
75
'Zomig Rapimelt' 2.5 mg
Placebo
***
***
50
**
25
*
ho
ur
s
2
ho
ur
s
ur
ho
1
1.
5
30
m
in
ut
es
0
Time post-dose
Figure 7. Ability to resume normal activities of daily living 30 minutes to 2 hours
after dosing with ‘Zomig Rapimelt’ 2.5 mg or placebo in study B.[21] *p=0.06 vs
placebo; **p<0.005 vs placebo; ***p<0.001 vs placebo.
14
Tolerability
As predicted by pharmacokinetic observations regarding the
bioequivalence of ‘Zomig Rapimelt’ to the conventional oral tablet,
‘Zomig Rapimelt’ is well tolerated in the acute treatment of
migraine. Adverse events most commonly reported in patients
treated with ‘Zomig Rapimelt’ 2.5 mg and 5 mg in placebocontrolled studies A, B and C included the typical triptan class
effects of throat tightness, paraesthesia, dizziness, somnolence and
asthenia (table II).The majority of adverse events were transient, of
mild to moderate intensity, and did not lead to withdrawal. Indeed,
no patients were withdrawn from study A because of adverse
events after taking ‘Zomig Rapimelt’, and only 1.1% (3/282) and
2.1% (7/329) of patients were withdrawn from studies B and C,
respectively.
‘Zomig Rapimelt’
is well tolerated
Table II. Adverse events reported by >2% of patients in any treatment group in study A,[20] study B[21] or study C[22]
Adverse event
(% patients)
Total
Tightness
Paraesthesia
Dizziness
Somnolence
Asthenia
Nausea
Hyperesthesia
Myalgia
Vasodilation
Heaviness
Dry mouth
Aggravation reaction
Hypertonia
Pharyngitis
Study A
Study B
Study C
Placebo
(n=240)
‘Zomig Rapimelt’
2.5 mg (n=231)
Placebo
(n=284)
‘Zomig Rapimelt’
2.5 mg (n=282)
Placebo
(n=329)
‘Zomig Rapimelt’
5 mg (n=342)
12.1
0
0.8
0.8
1.7
1.3
1.3
0
27.3
2.6
2.2
2.6
3.0
3.5
2.2
2.2
11.6
0.4
1.1
2.5
2.1
0.7
2.1
0
26.6
5.0
4.6
5.3
4.6
2.1
2.1
1.1
11.4
0.3
0.3
2.0
2.0
0.9
0
29.5
6.4
5.2
4.9
4.6
3.6
3.3
1.4
0.7
1.8
0.7
1.4
2.5
1.4
1.8
0
1.4
0
1.8
0.6
0.9
0.3
0.3
0
3.3
3.3
2.4
2.4
2.1
2.1
2.1
Abbreviation: n = number of patients.
15
Patient Preferences
‘Zomig Rapimelt’
is a convenient
treatment for
patients
Patients need migraine treatments to be rapidly and highly
effective.[10,14] However, different triptans have been found to have
broadly similar efficacy profiles when used in clinical practice, so it is
difficult to differentiate between triptans on an efficacy basis alone.
With the increasing choice of migraine therapies and drug
formulations available, patient preference is an important factor to
consider when selecting the most appropriate migraine therapy.
A survey of migraineurs found that 73% of patients would prefer to
use tablets that dissolve in the mouth without the need for fluids.[10]
As migraine can affect sufferers at any time, patients also need a
treatment that can be taken anywhere, immediately after the onset of
an attack.‘Zomig Rapimelt’ dissolves rapidly on the tongue without
the need for fluid intake, facilitating early treatment in situations
where fluids are not readily available. Such early treatment of migraine
has been shown to improve treatment outcomes.[18]
Preference compared with conventional
tablets
Patients prefer
‘Zomig Rapimelt’
to conventional
tablets
16
In efficacy study A, 469 patients provided general treatment
preference and acceptability data for ‘Zomig Rapimelt’. Overall, 70%
of these patients preferred ‘Zomig Rapimelt’ to conventional tablets
(figure 8). Most patients considered ‘Zomig Rapimelt’ to be easier to
handle (92%) and a more convenient treatment option (78%) than
conventional tablets, while 70% stated that it could be taken earlier
in the course of a migraine attack than a conventional tablet. Patient
preference for ‘Zomig Rapimelt’ over conventional tablets was not
100
Patients (%)
75
50
25
th
Pr
ef
er
ov
er
co
nv
en
tio
na
an M
lt
ab
co or
le
nv e c
t
en on
t
v
i
th
on en
an
al ie
ta nt
co Can
bl
nv ta
et
en ke
tio s
o
na o
l t ne
ab r
Ea
le
sy
t
to
Li
ha
ke
nd
th
le
e
or
an
ge
ta
st
e
0
Figure 8. Preference for and acceptability of ‘Zomig Rapimelt’, as specified by
patients from study A.[20]
affected by the presence of nausea (70% and 69% for patients with
and without nausea at baseline, respectively), while 80% liked the
orange flavour.
In a recent multicentre, randomised, open-label, crossover study
patients with an established diagnosis of migraine received ‘Zomig
Rapimelt’ 2.5 mg or a conventional sumatriptan tablet 50 mg for the
acute treatment of 2 consecutive migraine attacks of any intensity
(intention-to-treat population of 186 patients).[23] Overall,‘Zomig
Rapimelt’ was preferred to the conventional sumatriptan tablet by
significantly more patients (60.1% vs 39.9%; p=0.013).
Patients prefer
‘Zomig Rapimelt’
to sumatriptan
In terms of efficacy, significantly more patients considered ‘Zomig
Rapimelt’ a more effective treatment than sumatriptan conventional
tablet (77% vs 63%; p=0.0063).‘Zomig Rapimelt’ was also considered
to be the least disruptive, easiest and most convenient therapy to
take by most patients, and therefore the best treatment for
maintenance of an active lifestyle (figure 9).Very high percentages of
patients agreed that ‘Zomig Rapimelt’ allows attacks to be treated
anywhere (91.4%) and any time (90.2%). Importantly, 95.5% of
patients who had a history of difficulty swallowing tablets considered
17
Patients find
‘Zomig Rapimelt’
more convenient
and easy to take
than sumatriptan
'Zomig Rapimelt' 2.5 mg
Sumatriptan oral tablet 50 mg
100
Patients (%)
75
*
**
**
**
**
50
25
Le
C
on
si
de
re
d
an
ef
f
tre ect
at ive
m
as
en
t
t
op dis
Ea
tio rup
si
n tiv
es
to e
to
ta
pt
ke
io
n
t
o
M
ta
os
ke
tc
o
En
op nv
ab
t e
le ion nie
s
to nt
m
of a
ta
ke
ac int
e
tiv n
e an
lif ce
es
ty
le
0
Figure 9. Patient preferences for and opinions of ‘Zomig Rapimelt’ 2.5 mg and
conventional oral sumatriptan 50 mg in a study by Dowson and Charlesworth.[23]
*p<0.01 vs conventional sumatriptan tablet; **p<0.0001 vs conventional
sumatriptan tablet.
‘Zomig Rapimelt’ to be easier to take than the conventional
sumatriptan tablet (vs 4.5% for sumatriptan tablet), as did 59.6%
of patients with nausea and/or vomiting at baseline (vs 40.4% for
sumatriptan tablet).
Preference compared with other orally
disintegrating tablets
In a recent patient preference study a total of 171 patients with
an established history of migraine assessed the taste and ease of
use of ‘Zomig Rapimelt’ 2.5 mg and rizatriptan ODT 10 mg during
a migraine-free period.[24] Results showed that 81% of patients
liked ‘Zomig Rapimelt’ overall, compared with 68% who liked
rizatriptan ODT (p<0.05). Similarly, 84% of patients would be likely
to use ‘Zomig Rapimelt’ again, compared with 71% who would use
rizatriptan ODT again (p<0.05). Overall, when all formulation
attributes were taken into consideration, 70% of patients preferred
‘Zomig Rapimelt’ to rizatriptan ODT (27%; p<0.001).‘Zomig
18
‘Zomig Rapimelt’
is preferred
to rizatriptan
orally
disintegrating
tablet
'Zomig Rapimelt' 2.5 mg
Rizatriptan ODT 10 mg
100
Patients (%)
75
50
25
un
d
ho ers
w ta
to nd
op
en
Ea
si
er
to
to
ta
of ke
pa ou
ck t
ag
e
Ea
M
or
e
si
er
co
nv
en
ie
to nt
us
e
0
Figure 10. Patient preferences for package attributes of zolmitriptan and
rizatriptan orally disintegrating tablets.[24]
Rapimelt’ was also the preferred product with respect to various
aspects of taste (table III) and, in an overall taste assessment,
significantly more patients preferred ‘Zomig Rapimelt’ than
rizatriptan ODT (73% vs 24%; p=0.01).The product packaging
of ‘Zomig Rapimelt’ was also preferred over rizatriptan ODT
(figure 10). Of the 37 adverse events reported in the study,
23 occurred in association with rizatriptan ODT and 14 in
association with ‘Zomig Rapimelt’.
Table III. Patient preference data for ‘Zomig Rapimelt’ and the rizatriptan ODT formulation[24]
Like the taste of the product
Strength of taste is ‘just about right’
Sweetness is ‘just about right’
Taste is not too bitter
Experienced an aftertaste
Aftertaste was ‘unpleasant’
Aftertaste was ‘just about right’
Agree that it does not leave a bad taste
Agree that it has no medicine taste
‘Zomig Rapimelt’ 2.5 mg
(patients [%])
Rizatriptan ODT 10 mg
(patients [%])
70
68
71
71
56
13
74
77
67
46
35
55
36
89
28
40
38
46
p<0.05 for all comparisons.
19
Post-marketing Experience
The results of a 3-month non-comparative, non-interventional
post-marketing surveillance study have confirmed ‘Zomig Rapimelt’
to be a highly effective, well-tolerated, convenient and preferred
migraine therapy in real life. Efficacy analysis was performed on the
data from 14 543 patients, and data were available for 13 913 patients
who remained in the study for ≥76 days. For the first migraine
attack of the study period, headache pain had improved within
2 hours of taking ‘Zomig Rapimelt’ in 94% of patients (figure 11).
Improvement of migraine
Improved ability to perform activities of
daily living/functional capacity
Patients (% )
100
75
50
25
ho
ur
s
>2
2
ho
ur
s
r
ho
u
1
30
m
in
ut
es
0
Time post-dose
Figure 11. Percentage of patients with improvement in migraine and percentage
of patients with improved ability to perform activities of daily living/functional
capacity from 30 minutes to >2 hours after dosing with ‘Zomig Rapimelt’ in a
post-marketing surveillance study.[19]
20
Ability to perform normal activities had improved within 2 hours of
taking ‘Zomig Rapimelt’ in 84% of patients where this was impaired
at baseline (figure 11). Nausea was the most common symptom to
accompany headache pain in an attack (92%); both nausea and
vomiting had decreased within 2 hours of taking ‘Zomig Rapimelt’
in 91% of patients.The disability associated with migraine, which
can be assessed by using the Migraine Disability Assessment Scale
(MIDAS) questionnaire, was reduced by over half at the end of the
study (28.5 at entry vs 11.4 at the end of study). In comparison to
the minority of patients (12%) who reported very good or good
efficacy with previous therapy, 94% of patients considered ‘Zomig
Rapimelt’ to have good or very good efficacy.The tolerability of
‘Zomig Rapimelt’ was considered to be good or very good
throughout the study period in 96% of patients. Furthermore, the
majority of patients (81%) considered that the advantage of taking
‘Zomig Rapimelt’ without fluid intake was important or very
important, and the study also demonstrated that 95% of patients
would be willing to continue using ‘Zomig Rapimelt’ in the future.
The excellent
efficacy,
tolerability and
convenience
benefits of ‘Zomig
Rapimelt’ have
been confirmed in
a real-life setting
21
‘Zomig Rapimelt’
Product Summary
22
•
Bioequivalence with ‘Zomig’ conventional tablet and,
therefore, similar efficacy, safety and tolerability benefits
•
•
•
•
Onset of efficacy as early as 30 minutes
•
•
•
•
•
Convenient and easy to take
•
Pleasant orange flavour
High, sustained efficacy
Excellent tolerability profile
Favourable patient preference profile compared with
other oral triptans
The preferred melt tablet for migraine
Allows early treatment of migraine
Acceptable to patients with nausea
Preferred by patients with difficulty in swallowing
conventional tablets
References
1.
International Headache Society. Classification
and diagnostic criteria for headache disorders,
cranial neuralgias and facial pain. Cephalalgia 1988;
8 (Suppl. 7): 1–96
2.
Lipton RB, Silberstein SD, Stewart WE.
An update on the epidemiology of migraine.
Headache 1994; 34: 319–28
3.
Osterhaus JT,Townsend RJ, Gandek B, et al.
Measuring the functional status and well-being of
patients with migraine headache. Headache 1994;
34: 337–43
4.
Von Korff M, Stewart WF, Simon DJ, et al.
Migraine and reduced work performance: a
population-based diary study. Neurology 1998; 50:
1741–5
5.
Clarke CE, Macmillan L, Sondhi S, et al.
Economic and social impact of migraine. QJ Med
1996; 89: 77–84
6.
Ferrari MD. The economic burden of migraine
to society. Pharmacoeconomics 1998; 13: 667–76
7.
Hu XH, Markson LE, Lipton RB, et al. Burden
of migraine in the United States: disability and
economic costs.Arch Intern Med 1999; 159: 813–8
8.
Lance JW. Current concepts of migraine
pathogenesis. Neurology 1993; 43 (6 Suppl. 3):
S11–15
9.
Lipton RB, Diamond S, Reed M, et al. Migraine
diagnosis and treatment: results from the American
Migraine Study II. Headache 2001; 41: 638–45
10. MacGregor EA, Brandes J, Eikermann A.
Migraine prevalence and treatment patterns:
the global Migraine and Zolmitriptan Evaluation
(MAZE) survey. Headache 2003; 43: 19–26
11. Goadsby PJ, Hoskin KL. Inhibition of trigeminal
neurons by intravenous administration of the
serotonin (5HT)1B/D receptor agonist zolmitriptan
(311C90): are brain stem sites a therapeutic target
in migraine? Pain 1996; 67: 355–9
12. Martin GR, Robertson AD, MacLennan SJ,
et al. Receptor specificity and trigemino-vascular
inhibitory actions of a novel 5-HT1B/1D receptor
partial agonist, 311C90 (zolmitriptan). Br J
Pharmacol 1997; 121: 156–64
13. Hughes AM, Dixon R, Dane A, et al. Effects
of zolmitriptan (Zomig) on central serotonergic
neurotransmission as assessed by active oddball
auditory event-related potentials in volunteers
without migraine. Cephalalgia 1999; 19: 100–6
14. Lipton RB, Hamelsky SW, Dayno JM.What do
patients with migraine want from acute migraine
treatment? Headache 2002; 42 (Suppl. 1): 3–9
15. Edmeads J, Findlay H,Tugwell P, et al. Impact
of migraine and tension-type headache on lifestyle, consulting behaviour, and medication use:
a Canadian population survey. Can J Neurol Sci
1993; 20: 131–7
16. Loder E, Silberstein S, Giammarco R, et al.
Oral zolmitriptan exhibits efficacy as early as
30 minutes in menstrually-associated migraine:
results of a large multicenter placebo-controlled
study. Neurology 2002; 58 (7 Suppl. 3): A414–15
17. Rapoport A, Dowson A, Charlesworth B, et al.
Zolmitriptan conventional and orally disintegrating
tablets achieve headache response as early as
30 minutes post-treatment: results of a pooled data
analysis. Neurology 2003; 60 (5 Suppl. 1): P03.150
18. Klapper J, Charlesworth B, Soisson T, et al.
Treatment of mild migraine with oral zolmitriptan
2.5 mg provides high pain-free response rates and
prevents progression to more severe migraine in
patients with significant migraine-related disability.
Headache 2002; 42: 395
19. AstraZeneca. Data on file
20. Dowson AJ, MacGregor EA, Purdy RA, et al.
Zolmitriptan orally disintegrating tablet is effective
in the acute treatment of migraine. Cephalalgia
2002; 22: 101–6
21. Tuchman MM, Spierings E, Abu-Shakra,
et al. Significant 1 hour pain free rates with
zolmitriptan 2.5 mg orally disintegrating tablet in
treatment of migraine: results of a large doubleblind, placebo-controlled trial. Eur J Neurol
2002; 9 (Suppl. 2): 154
22. Spierings E, Dodick D, Pearlman E, et al.
Zolmitriptan orally disintegrating tablet shows
significant efficacy as early as 30 min, and high
sustained response rates: results of a large
placebo controlled trial. Cephalalgia 2002; 22: 605
23. Dowson A, Charlesworth B. Patients with
migraine prefer zolmitriptan orally disintegrating
tablet to sumatriptan conventional tablet. Int J
Clin Pract 2003; 57(7): 573–6
24. Charlesworth B,Wasiewski W, Moran D.
Migraine patients prefer the zolmitriptan orally
disintegrating tablet formulation to the rizatriptan
wafer tablet formulation: an assessment of taste
and ease of use. Headache 2002; 42: 391–2
23
ABBREVIATED CORE DATA SHEET ‘ZOMIG’; ‘ZOMIG RAPIMELT’; ‘ZOMIG NASAL SPRAY’
1. USES
Acute treatment of migraine attacks with or without aura.
2. DOSAGE
The recommended dose of ‘Zomig’ tablets and ‘Zomig Rapimelt’
to treat a migraine attack is 2.5 mg.
‘Zomig’ tablets should be swallowed whole with water.The
‘Zomig Rapimelt’ orodispersible tablet rapidly dissolves when
placed on the tongue and is swallowed with the patient’s saliva.
A drink of water is not required.
The recommended dose of ‘Zomig nasal spray’ to treat a
migraine attack is 5 mg. It is administered as a single dose into
one nostril.
For all formulations of ‘Zomig’: If symptoms persist, or return
within 24 hours, a second dose has been shown to be effective.
If a second dose is required, it should not be taken within
2 hours of the initial dose.
If satisfactory relief is not achieved with a 2.5 mg dose,
subsequent attacks can be treated with 5 mg doses.
In the event of recurrent attacks, it is recommended that the
total intake of ‘Zomig’, in a 24-hour period, should not exceed
10 mg.
Safety and efficacy of ‘Zomig’ in paediatrics and adults over the
age of 65 has yet to be established.
Although metabolism is reduced in patients with mild or
moderate liver disease (see full prescribing information), no
dosage adjustment is required. However, for patients with severe
liver disease, a maximum dose of 5 mg in 24 hours is
recommended.
A maximum intake of 5 mg ‘Zomig’ in 24 hours is recommended
in patients taking a MAO-A inhibitor (e.g. moclobemide). A
maximum dose of 5 mg ‘Zomig’ in 24 hours is recommended in
patients taking cimetidine. Based on the overall interaction profile,
an interaction with the cytochrome P450 isoenzyme inhibitors
of CYP1A2 cannot be excluded.Therefore, the same dosage
reduction is recommended with compounds of this type, such as
fluvoxamine and the quinolone antibiotics (e.g. ciprofloxacin).
Following administration of rifampicin, no clinically relevant
differences in the pharmacokinetics of zolmitriptan or its active
metabolite were observed. Concomitant use of other 5HT1B/1D
agonists should be avoided within 12 hours of ‘Zomig’
treatment. Ergot-containing drugs have been reported to cause
prolonged vasospastic reactions. Because there is a theoretical
basis that these effects may be additive, 24 hours should elapse
between the use of ergotamine containing or ergot-type
medications (like dihydroergotamine or methysergide) and
zolmitriptan. Conversely it is advised to wait at least 6 hours
following use of ‘Zomig’ before administering an ergotamine
containing preparation.
There is no clinical experience of ‘Zomig’ in pregnancy. As with
other medicines administered in pregnancy, the benefits for the
mother should be weighed against the risks to the foetus.There
is no information regarding the passage into human milk. Use is
unlikely to result in an impairment of the ability to drive and
operate machinery; however, take into account that somnolence
may occur.
Patients with phenylketonuria should be informed that each
‘Zomig Rapimelt’ orodispersible tablet contains 2.81 mg of
phenylalanine (a component of aspartame).
5. SIDE EFFECTS
3. CONTRAINDICATIONS
Hypersensitivity to any of the ingredients, uncontrolled
hypertension, ischaemic heart disease or coronary
vasospasm/Prinzmetal’s angina.
4. PRECAUTIONS
A clear diagnosis of migraine must be established. Care must be
taken to exclude potentially serious neurological conditions. No
data in basilar or hemiplegic migraine. Migraineurs may be at risk
of certain cerebrovascular events. Cerebral haemorrhage,
subarachnoid haemorrhage, stroke, and other cerebrovascular
events have been reported in patients treated with 5-HT1B/1D
agonists.
‘Zomig’ should not be given to patients with Wolff-ParkinsonWhite syndrome or arrhythmias associated with other cardiac
accessory conduction pathways.
In very rare cases, as with other 5HT1B/1D agonists, coronary
vasospasm, angina pectoris and myocardial infarction have been
reported. In patients with risk factors for ischaemic heart disease,
cardiovascular evaluation prior to commencement of treatment is
recommended (see Contraindications).
As with other 5HT1B/1D agonists, atypical sensations over the
precordium have been reported after administration of ‘Zomig’.
Where such symptoms are thought to indicate ischaemic heart
disease, no further doses of zolmitriptan should be given and
appropriate evaluation carried out.
As with other 5HT1B/1D agonists, transient increases in systemic
blood pressure have been reported in patients with and without
a history of hypertension; very rarely these increases in blood
pressure have been associated with significant clinical events.
As with other 5HT1B/1D agonists, there have been rare reports of
anaphylaxis/anaphylactoid reactions in patients receiving ‘Zomig’.
24
The most commonly reported for all ‘Zomig’ formulations:
nausea, dizziness, somnolence, warm sensation, asthenia and dry
mouth. For ‘Zomig’ Nasal Spray, the most commonly reported:
taste disturbance, hyperaesthesia, and discomfort of nasal cavity.
Abnormalities or disturbances of sensation have been reported,
heaviness, tightness, pain or pressure may occur in the throat,
neck, limbs and chest, as may myalgia, muscle weakness,
paraesthesia, dysaesthesia. As with other 5HT1B/1D agonists,
transient increases in systemic blood pressure, very rarely
associated with significant clinical events, have been reported.
As with other 5HT1B/1D agonists, there have been rare reports of
and hypersensitivity reactions (including anaphylaxis/anaphylactoid
reactions, urticaria and angioedema), tachycardia and palpitations.
In very rare cases, as with other 5HT1B/1D agonists, angina
pectoris, myocardial infarction, headache, gastrointestinal
ischaemic events including ischaemic colitis, gastrointestinal
infarction or necrosis, which may present as bloody diarrhoea
or abdominal pain, have been reported.
6. PRESENTATION
Film-coated tablets containing 2.5 mg or 5 mg zolmitriptan.
Orodispersible tablets containing 2.5 mg zolmitriptan.
Single use nasal spray device containing 5 mg zolmitriptan.
Revised: July 2002
Consult full prescribing information before prescribing.
Further information available on request.
AstraZeneca
R&D Alderley Park, Macclesfield, Cheshire SK10 4TG England
ZOMIG, ZOMIG RAPIMELT, ZOMIG NASAL SPRAY
are Trade Marks of the AstraZeneca Group of Companies.
For full prescribing information, please refer to your local PI.
ASZAZO1584
Zmg/2003/017 (August 03)