A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Imitrex Pharmacology, Pharmacokinetics, Studies, Metabolism - Sumatriptan Succinate (intranasal)
Imitrex Pharmacology, Pharmacokinetics, Studies, Metabolism - Sumatriptan Succinate (intranasal)
CLINICAL PHARMACOLOGY
Mechanism of Action
Sumatriptan is an agonist
for a vascular 5-hydroxytryptamine1
receptor subtype (probably a member
of the 5-HT1D family) having only a weak
affinity for 5-HT1A, 5-HT5A, and 5-HT7
receptors and no significant
affinity (as measured using standard
radioligand binding assays) or pharmacological activity at 5-HT2,
5-HT3, or 5-HT4
receptor subtypes or
at alpha1-, alpha2-, or beta-adrenergic; dopamine1,;
dopamine2; muscarinic; or benzodiazepine
receptors.
The vascular 5-HT1
receptor subtype that
sumatriptan activates is present
on cranial arteries
in both dog and primate, on the human
basilar artery, and in the vasculature
of human dura
mater and mediates vasoconstriction.
This action in humans
correlates with the relief
of migraine headache.
In addition to causing
vasoconstriction, experimental data from animal studies wshow
that sumatriptan also activates 5-HT1 receptors on peripheral
terminals of the trigeminal
nerve innervating cranial
blood vessels. Such an action
may contribute to the antimigrainous effect
of sumatriptan in humans.
In the anesthetized dog, sumatriptan selectively reduces the carotid
arterial blood wflow
with little or no effect
on arterial blood
pressure or total peripheral
resistance. In the cat, sumatriptan
selectively constricts the carotid
arteriovenous
anastomoses, while having little effect
on blood flow or resistance
in cerebral or extracerebral tissues.
Pharmacokinetics
In a study of 20 female
volunteers, the mean maximum
concentration
following a 5- and 20-mg intranasal
dose was 5 and 16 ng/ml,
respectively. The mean Cmax following a 6-mg subcutaneous
injection is 71 ng/ml
(range: 49 to 110 ng/ml). The mean
Cmax is 18 ng/ml (range: 7 to 47 ng/ml) following oral
dosing with 25 mg and 51
mg/ml (range: 28 to 100 ng/ml) following oral
dosing with 100 mg of sumatriptan.
In a study of 24 male
volunteers, the bioavailability relative to subcutaneous
injection was low, approximately 17%, primarily due to presystemic
metabolism and partly
due to incomplete absorption.
Protein binding, determined by equilibrium
dialysis over the concentration
range of 10 to 1000 ng/ml, is low, approximately 14% to 21%. The
effect of sumatriptan on the protein
binding of other drugs has not been evaluated, but would be expected
to be minor, given the low rate
of protein binding.
The mean volume
of distribution
after a subcutaneous
dosing is 2.7 L/kg and the total plasma
clearance is approximately
1200 ml/min.
The elimination
half-life of sumatriptan
administered as a nasal
spray is approximately 2 hours, similar to the half-life
seen after subcutaneous injection. Only 3% of the dose
is excreted in the urine
as unchanged sumatriptan; 42% of the dose
is excreted as the major metabolite, the indole
acetic acid analogue of sumatriptan.
Clinical and pharmacokinetic data indicate that administration
of two 5-mg doses, 1 dose
in each nostril, is equivalent
to administration
of a single 10-mg dose
in one nostril.
Special Populations
Renal Impairment: The effect
of renal impairment
on the pharmacokinetics of sumatriptan has not been examined, but
little clinical effect would be expected as sumatriptan is largely
metabolized to an inactive substance.
Hepatic Impairment: The effect
of hepatic disease
on the pharmacokinetics of subcutaneously and orally administered
sumatriptan has been evaluated, but the intranasal
dosage form
has not been studied in hepatic
impairment. There were no statistically significant
differences in the pharmacokinetics
of subcutaneously administered sumatriptan in hepatically impaired
patients compared to healthy controls. However, the liver
plays an important role
in the presystemic clearance
of orally administered sumatriptan. In one small study involving
oral sumatriptan in hepatically
impaired patients (n=8) matched for sex, age, and weight
with healthy subjects, the hepatically impaired patients had an
approximately 70% increase in AUC
and Cmax and a tmax 40 minutes earlier compared
to the healthy subjects. The bioavailability of nasally absorbed
sumatriptan following intranasal administration, which would not
undergo first-pass metabolism, should not be altered in hepatically
impaired patients. The bioavailability of the swallowed portion
of the intranasal
sumatriptan dose has not
been determined, but would be increased in these patients. The swallowed
intranasal dose is
small, however, compared to the usual oral
dose, so that its impact should be minimal.
Age: The pharmacokinetics
of oral sumatriptan in
the elderly (mean age: 72 years, 2 males and 4 females) and in patients
with migraine (mean age: 38 years, 25 males and 155 females) were
similar to that in healthy male
subjects (mean age: 30 years). Intranasal sumatriptan has not been
evaluated for age differences
(see PRECAUTIONS, Geriatric
Use.)
Race: The systemic
clearance and Cmax
of sumatriptan were similar in black
(n=34) and Caucasian
(n=38) healthy male subjects.
Intranasal sumatriptan has not been evaluated for race
differences.
Drug Interactions
Treatment with MAOIs generally leads to an increase of sumatriptan
plasma levels (see CONTRAINDICATIONS
and PRECAUTIONS).
MOAI interaction studies have not been performed with intranasal
sumatriptan. Due to gut
and hepatic metabolic
first-pass effects, the increase of systemic exposure after coadministration
of an MAO-A inhibitor
with oral sumatriptan is
greater than after coadministration
of the MAOI with subcutaneous
sumatriptan. The effects of an MAOI on systemic
exposure after intranasal
sumatriptan would be expected to be greater than the effect
after subcutaneous
sumatriptan but smaller than the effect
after oral sumatriptan
because only swallowed drug would be subject
to first-pass effects.
In a study of 14 healthy females, pretreatment
with an MAO-A inhibitor decreased the clearance
of subcutaneous
sumatriptan. Under the conditions of this experiment, the result
was a twofold increase in the area
under the sumatriptan plasma
concentration
´ time curve
(AUC), corresponding
to a 40% increase in elimination
half-life. This interaction was not evident with an MAO-B inhibitor.
A small study evaluating the effect
of pretreatment
with an MAO-A inhibitor on the bioavailability from a 25-mg oral
sumatriptan tablet resulted
in an approximately sevenfold increase in systemic
exposure.
Xylometazoline: An
in vivo drug interaction
study indicated that three drops
of xylometazoline (0.1% w/v), a decongestant, administered 15 minutes
prior to a 20-mg nasal
dose of sumatriptan did
not alter the pharmacokinetics
of sumatriptan.
CLINICAL STUDIES
The efficacy of sumatriptan nasal
spray in the acute treatment
of migraine headaches was demonstrated in eight randomized, double-blind,
placebo-controlled studies, of which five used the recommended dosing
regimen and used the
marketing formulation. Patients enrolled in these five studies were
predominantly female (86%) and Caucasian
(95%), with a mean age
of 41 (range of 18 to 65). 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 up to 2 hours after dosing. Associated
symptoms such as nausea, photophobia, and phonophobia
were also assessed. Maintenance of response
was assessed for up to 24 hours postdose. A second dose
of sumatriptan nasal spray
or other medication
was allowed 2 to 24 hours after the initial
treatment for recurrent
headache. The frequency and time
to use of these additional treatments were also determined. In all
studies, doses of 10 and 20 mg
were compared to placebo
in the treatment of one to three migraine
attacks. Patients received doses as a single spray into one nostril.
In two studies, a 5-mg dose
was also evaluated.
In all five trials utilizing the market formulation and recommended
dosage regimen, the percentage of patients achieving headache
response 2 hours after treatment
was significantly greater among patients receiving sumatriptan nasal
spray at all doses (with one exception) compared to those who received
placebo. In four of the five
studies, there was a statistically greater percentage of patients
with headache response
at 2 hours in the 20-mg group
when compared to the lower dose
groups (5 and 10 mg). There were no statistically significant
differences between the 5- and 10-mg dose groups in any study. The
results from the five controlled clinical trials are summarized
in TABLE 7. Note that, in general, comparisons of results obtained
in studies conducted under different conditions by different investigators
with different samples of patients are ordinarily unreliable for
purposes of quantitative
comparison.
| TABLE 7 Percentage of Patients
with Headache Response (No or Mild Pain) 2 Hours Following
Treatment |
| |
|
Sumatriptan Nasal Spray |
| |
Placebo |
5 mg |
10 mg |
20 mg |
| Study 1 |
25% (n=63) |
49%* (n=121) |
46%* (n=112) |
64%*†‡ (n=118) |
| Study 2 |
25% (n=138) |
Not applicable |
44%* (n=273) |
55%*‡ (n=277) |
| Study 3 |
35% (n=100) |
Not applicable |
54%* (n=106) |
63%* (n=202) |
| Study 4 |
29% (n=112) |
Not applicable |
43% (n=106) |
62%*†(n=215) |
| Study 5§ |
36% (n=198) |
45%* (n=296) |
53%* (n=291) |
60%*‡(n=286) |
| * P<0.05 in comparison
with placebo. |
| ‡ P<0.05 in comparison
with 10 mg. |
| † P<0.05 in comparison
with 5 mg. |
| § Data are for attack
1 only of multiattack study for comparison. |
For patients with migraine-associated nausea, photophobia, and phonophobia
at baseline, there was a lower incidence
of these symptoms at 2 hours following administration of sumatriptan
nasal spray compared to
placebo.
Two to 24 hours following the initial
dose of study treatment,
patients were allowed to use additional treatment
for pain relief
in the form of a second
dose of study treatment
or other medication. The estimated probability of patients taking
a second dose or other
medication for migraine
over the 24 hours following the initial
dose of study treatment
was 76%, 68%, and 62% for 5 mg, 10 mg, and 20 mg
of sumatriptan nasal spray,
respectively, and 78% for placebo. Also included are patients who
had no response to
the initial dose. No
remedication was allowed within 2 hours postdose.
There is evidence
that doses above 20 mg do
not provide a greater effect than 20 mg. There was no evidence
to suggest that treatment
with sumatriptan nasal spray was associated with an increase in
the severity of recurrent headaches. The efficacy of sumatriptan
nasal spray was unaffected
by presence of aura; duration
of headache prior to
treatment; gender, age, or weight of the patient; or concomitant
use of common migraine
prophylactic drugs
(e.g., beta-blockers, calcium
channel blockers, tricyclic
antidepressants). There were insufficient data to assess the impact
of race on efficacy.
ANIMAL PHARMACOLOGY
Corneal Opacities: Dogs receiving oral
sumatriptan developed corneal opacities and defects in the corneal
epithelium. Corneal opacities were seen at the lowest dosage
tested, 2 mg/kg per day,
and were present after 1 month of treatment. Defects in the corneal
epithelium were noted
in a 60-week study. Earlier examinations for these toxicities were
not conducted and no-effect doses were not established; however,
the relative exposure at the lowest dose
tested was approximately five times the human exposure after a 100-mg
oral dose
or three times the human
exposure after a 6-mg
subcutaneous dose or 22 times the human
exposure after a single
20-mg intranasal
dose. There is evidence
of alterations in corneal appearance
on the first day of intranasal
dosing to dogs. Changes were noted at the lowest dose
tested, which was approximately two times the maximum
single human intranasal
dose of 20 mg on a mg/m2
basis.
top
