PRODUCT INFORMATION

NARAMIG TABLETS

NAME OF THE MEDICINE:

Naratriptan hydrochloride is the therapeutically active ingredient in Naramig tablets. The
chemical name of naratriptan hydrochloride is 2-[3-(1-Methyl-piperidin-4-yl)-1H-indol-5-yl]ethanesulphonic acid methylamide hydrochloride.
CH3
N
CH3NHSO2
N
H

. HCl

CAS REGISTRY NUMBER: 143388-64-1

DESCRIPTION:
The molecular formula of naratriptan hydrochloride is C17H25N3O2S.HCl, the relative molecular
mass is 371.9. It takes the form of a white to pale yellow microcrystalline solid. Naratriptan
hydrochloride is a non-polar drug (log D = -0.34) with a solubility in water of approximately
35 mg/mL at 25C.
PHARMACOLOGY:
Pharmacology:
Naratriptan has been shown to be a selective agonist for 5 hydroxytryptamine1 (5-HT1)
receptors mediating vascular contraction. This receptor is found predominantly in intracranial
(cerebral and dural) blood vessels. Naratriptan has high affinity for human cloned 5-HT1B and
5-HT1D receptors, the human 5-HT1B receptor is thought to correspond to the vascular 5-HT1
receptor mediating contraction of intracranial blood vessels. Naratriptan has little or no effect
at other 5-HT receptor (5-HT2, 5-HT3, 5-HT4 and 5-HT7) subtypes.
In animals, naratriptan selectively constricts the carotid arterial circulation. This circulation
supplies blood to the extracranial and intracranial tissues such as the meninges. In man,
dilatation and/or oedema formation in these vessels is thought to be the underlying
mechanism of migraine. In addition, experimental evidence suggests that naratriptan inhibits
trigeminal nerve activity. Both these actions may contribute to the anti-migraine action of
naratriptan in humans.
Pharmacokinetics:
Following oral administration, naratriptan is rapidly absorbed with maximum plasma
concentrations observed at 2-3 hours. After administration of a 2.5 mg naratriptan tablet Cmax
is approximately 8.3 ng/mL in women and 5.4 ng/mL in men. The oral bioavailability is 74% in
women and 63% in men, with no differences in efficacy and tolerability in clinical use.
Therefore a gender related dose adjustment is not required. Plasma protein binding is low
(29%) and the volume of distribution is 170 litres. The mean elimination half-life (t1/2) is 6
hours.
Mean clearance after intravenous administration is 470 mL/min in men and
380 mL/min in women. Renal clearance is similar in men and women (220 mL/min) and is
Naramig tablets Issue No. 8R

higher than the glomerular filtration rate suggesting that naratriptan is actively secreted in the
renal tubules. Naratriptan is predominantly excreted in the urine with 50% of the dose
recovered as unchanged naratriptan and 30% recovered as inactive metabolites. In-vitro
studies showed that the metabolism of naratriptan by cytochrome P450 isoenzymes is very
low and that no specific isoenzyme is involved. Consequently, significant metabolic drug
interactions with naratriptan are not anticipated (see PRECAUTIONS, Interactions other
medicines).
As renal excretion is the major route for the elimination of naratriptan, exposure to naratriptan
may be increased in patients with renal disease. A study in male and female patients with
renal impairment (creatinine clearance 18 to 115 mL/min; n=15) showed 80 % (approximate)
increase in t1/2 and 50 % (approximate) reduction in clearance when compared to healthy
subjects (n=8) (see DOSAGE and ADMINISTRATION and CONTRAINDICATIONS).
A study in male and female patients with hepatic impairment (Child-Pugh grade A or B, n=8)
demonstrated a 40 % (approximate) increase in t1/2 and a 30% (approximate) reduction in
clearance when compared to healthy subjects (n=8) (see DOSAGE and ADMINISTRATION
and CONTRAINDICATIONS).
The naratriptan AUC and Cmax were approximately 35 % lower in males compared to females
without differences in efficacy and tolerability in clinical use. Therefore a gender related dose
adjustment is not required.
In healthy elderly subjects (age 65 to 77 years, n=12), clearance was decreased by 26 %
when compared to healthy young subjects (age 24 to 44 years, n=12) (see PRECAUTIONS,
Special Populations).

CLINICAL TRIALS:
Seven clinical studies were conducted in 3907 adult (18-65 years) migraine patients in which
a total of 15283 attacks were treated with placebo, naratriptan tablets or sumatriptan tablets.
Naratriptan tablets were used to treat at least one attack in 3204 adult patients.
The primary efficacy parameters, for adult migraine patients treated with placebo, naratriptan
tablets 2.5 mg or sumatriptan tablets 100 mg, in Phase II or Phase III studies are summarised
in Table 1.
In studies that included sumatriptan 100 mg as comparator or control medication, naratriptan
tablets 2.5 mg were shown to have lower incidence of recurrence but of similar 24 hour overall
efficacy (Table 1, Studies 3, 4 and 5). Analysis of the secondary endpoints (migraine
associated symptoms at 4 hours (nausea, photophobia or phonophobia), clinical disability at 4
hours or use of rescue medication within 24 hours) indicated that naratriptan tablets 2.5 mg
were effective when compared to placebo.
Five Phase III studies were conducted in adults in a non-clinical setting of doses of naratriptan
tablets ranging from 0.1 mg to 2.5 mg in which patients were allowed to continue taking
migraine prophylactic medication. Two of these studies included special objectives: a trial in
patients with a high incidence of migraine recurrence (history of recurrence in >50% of
successfully treated attacks) and a long term (12 month) efficacy and safety study.

Naramig tablets Issue No. 8R

Table 1:

Summary of Controlled Clinical Studies of 2.5 mg Naratriptan in Adult

Migraine Patients

Study
(Phase)

Treatment

1
(II)

Placebo
Naratriptan

122
127

2h
30
40

4h
34
a
60

2h
11
18

2
(III)

Placebo
Naratriptan

602
586

26
a
51

33
a
69

3
(III)

Placebo
Naratriptan
+
Sumatriptan

91
87
98

31
52
60

4
(III)

Placebo
Naratriptan
+
Sumatriptan

107
209
240

5
(III)

Naratriptan
+
Sumatriptan

225
225

% of Patients

24h
overall
efficacy#

Recurrence##

4h
20
b
33

22
43

38
28

7
a
24

15
a
45

19
c
48

36
27

39
63
80

14
27
34

22
45
52

22
48
44

36
17
44

22
a
50
a
59

27
a
66
ad
76

5
21
32

12
43
57

21
a
52
a
52

10
19
36

76
84

43
56

39
34

45
e
57

Headache
relief*

Pain
free**

* Headache severity score from grade 3 or 2, pre-treatment, to grade 1 or 0, post-treatment.

** Headache severity score from grade 3 or 2, pre-treatment, to grade 0, post-treatment.
# Headache relief by 4 hours without subsequent increase in headache severity or use of rescue
medication within 24 hours.
## Headache relief by 4 hours (without use of rescue medication) with significant increase in headache
severity between 4 and 24 hours.
+
oral sumatriptan, 100 mg tablet.
a
b
c
d
e
p<0.001, p<0.05 and p<0.005 vs placebo; p<0.05 and p=0.005 vs naratriptan.

The study conducted in patients particularly susceptible to migraine recurrence (Table 1,

Study 5), showed the incidence of headache recurrence 4 to 24 hours post-first dose was
lower with naratriptan 2.5 mg tablets (45%) than with sumatriptan 100 mg tablets (57%, p<
0.005). Fewer patients took the second dose when initially administered oral naratriptan
2.5 mg (40%) when compared to the oral sumatriptan 100 mg group (57%, p<0.001), and the
median time to onset of recurrence was longer (12.5 hours versus 10.5 hours, for naratriptan
and sumatriptan, respectively).
Interim 6 month data from the open label, 12 month safety study of naratriptan, demonstrated
the 2.5 mg tablet was efficacious and well tolerated in the acute treatment of migraine. A total
of 7709 attacks were treated. Headache relief (at 4 hours) occurred in 68% of all attacks, and
in 66% and 70% of attacks during 0 to 3 months and >3 to 6 months, respectively. For
patients treating <18 attacks during 6 months, headache relief was similar (62%) to patients
treating >18 attacks during the same period (70%).
There have been no adequate investigations of the safety and efficacy of naratriptan in
patients younger than 18 years or older than 65 years.

Naramig tablets Issue No. 8R

INDICATIONS:
Naramig tablets are indicated for the acute treatment of migraine attacks with or without aura.

CONTRAINDICATIONS:
Hypersensitivity to any component of the preparation.
A history of myocardial infarction.
Ischaemic heart disease.
Prinzmetal's angina/coronary vasospasm.
Signs or symptoms consistent with ischaemic heart disease.
A history of cerebrovascular accident (CVA) or transient ischaemic attack (TIA).
Peripheral vascular disease.
Uncontrolled hypertension.
Concomitant use of other 5HT1 receptor agonists.
Severely impaired renal function (creatinine clearance < 15 mL/min).
Severely impaired hepatic function (Child-Pugh grade C).

PRECAUTIONS:
Naratriptan should only be used where there is a clear diagnosis of migraine.
Naratriptan is not indicated for use in the management of hemiplegic, basilar or
ophthalmoplegic migraine.
Before treating headaches in patients not previously diagnosed as migraine patients, and in
migraine patients who present with atypical symptoms, care should be taken to exclude other
potentially serious neurological conditions. It should be noted that migraine patients may be
at risk of certain cerebrovascular events (eg. CVA or TIA).
Naratriptan should not be given to patients in whom unrecognised cardiac disease is likely
without a prior evaluation for underlying cardiovascular disease. Such patients include
postmenopausal women, males over 40 and patients with risk factors for coronary artery
disease.
If symptoms consistent with ischaemic heart disease occur appropriate evaluation should be
carried out.
Serotonin syndrome (including altered mental status, autonomic instability and neuromuscular
abnormalities) has been reported following concomitant treatment with triptans and selective
serotonin reuptake inhibitors (SSRIs)/serotonin noradrenaline reuptake inhibitors (SNRIs). If
concomitant treatment with naratriptan and an SSRI/SNRI is clinically warranted, appropriate
observation of the patient is advised (see Interactions with Other Medicines).
The concomitant administration of ergotamine, derivatives of ergotamine (including
methysergide) and any triptan/5-HT1 agonist with naratriptan is not recommended.
Naratriptan contains a sulphonamide component therefore there is a theoretical risk of a
hypersensitivity reaction in patients with known hypersensitivity to sulphonamides.
The recommended dose of naratriptan should not be exceeded.
Naramig tablets Issue No. 8R

Overuse of acute migraine treatments has been associated with the exacerbation of
headache (medication overuse headache, MOH) in susceptible patients. Withdrawl of the
treatment may be necessary.
Because naratriptan binds to melanin, it could accumulate in melanin-rich tissues (such as the
eye) over time. However, no effects on the retina related to treatment with naratriptan were
noted in any of the toxicity studies. Prescribers should be aware of the possibility of long term
ophthalmologic effects.
Carcinogenesis, Mutagenesis and Impairment of Fertility
In carcinogenicity studies, rats and mice were given naratriptan by oral gavage for 104 weeks.
Plasma concentrations in rats and mice receiving the highest doses were at least 100 times
greater than the exposure (based on AUC) attained in humans after the maximum
recommended daily dose of 5mg. The rat studies revealed an increased incidence of benign
thyroid follicular cell adenoma at the highest dose tested.
Naratriptan showed no evidence of genotoxicity in a series of assays for gene mutations
(bacteria, yeast and mouse lymphoma cells). Tests for chromosomal damage in human
lymphocytes in vitro and micronucleus formation in vivo, showed that naratriptan was not
clastogenic. However, naratriptan underwent nitrosation at acidic pH in vitro to yield a product
or products which were bacterial mutagens. After oral administration of naratriptan to rats
maintained on a high nitrite diet, nitroso derivatives of naratriptan were detected in the
stomach. However, this did not increase the potential toxicity or carcinogenicity of naratriptan.
A fertility study by the oral route of administration, during which male and female rats were
dosed daily with naratriptan prior to and throughout the mating period, showed evidence of
increased pre-implantation loss and consequent reduction in litter size at doses producing
plasma concentrations at least 50 times those attained in humans after the maximum
recommended daily dose of 5mg (based on AUC). In rats, oral doses of naratriptan of 340
mg/kg/day (greater than 500 times maximum anticipated clinical exposure based on AUC) led
to testicular and epididymal atrophy in males, and an increase in the incidence of ovarian
atrophy and follicular/luteal cysts in females.
Use in Pregnancy: Pregnancy Category B3.
Studies in rabbits showed that after oral administration, naratriptan and/or its metabolites
readily crossed the placenta and was distributed widely in the fetuses. In rats treated during
organogenesis with oral naratriptan, post-implantation loss was increased and there was an
increase in the incidence of skeletal variations of the fetuses at 10mg/kg/day (greater than 10
times the exposure (based on AUC) attained in humans after the maximum recommended
daily dose of 5mg) and pup survival measured at post-natal day 20 was reduced by treatment
at 340mg/kg/day (700 times clinical exposure based on AUC). In rabbits, the incidences of
variations of the fetal skeleton were increased by maternal treatment at 5 mg/kg/day (greater
than 15 times the exposure (based on AUC) attained in humans after the maximum
recommended daily dose of 5mg) and variations in the major blood vessels were seen at
30mg/kg/day (greater than 34 times the exposure (based on AUC) attained in humans after
the maximum recommended daily dose of 5mg).
There are no adequate and well-controlled studies in pregnant women. Therefore naratriptan
should not be used in pregnancy unless the benefits to the mother outweigh the potential risk
to the fetus.
Use in Lactation:

Naramig tablets Issue No. 8R

Naratriptan and/or its metabolites are secreted into the milk of lactating rats, reaching
concentrations higher than those seen in maternal plasma. Therefore, breast feeding should
be discontinued for 24 hours after the administration of naratriptan.
Renal Impairment:
Renal excretion is the major route for the elimination of naratriptan. Accordingly exposure to
naratriptan may be increased in patients with renal disease (see PHARMACOLOGY,
Pharmacokinetics). For patients with mild to moderate renal dysfunction, dosage adjustment
is recommended (See DOSAGE and ADMINISTRATION). Naratriptan is contraindicated for
patients with severe renal impairment (See CONTRAINDICATIONS).
Hepatic Impairment:
The liver plays a lesser role in the clearance of orally administered naratriptan. However for
patients with mild to moderate hepatic dysfunction, dosage adjustment is still recommended
(See DOSAGE and ADMINISTRATION). Naratriptan is contraindicated for patients with
severe hepatic impairment (See CONTRAINDICATIONS).
Effects on Ability to Drive and Use Machines:
Caution is recommended in patients performing skilled tasks (e.g. driving or operating
machinery) as drowsiness may occur as a result of migraine.
Interactions with Other Medicines:
Serotonin syndrome (including altered mental status, autonomic instability and neuromuscular
abnormalities) has been reported following concomitant treatment with triptans and
SSRIs/SNRIs (see PRECAUTIONS).
There is no evidence of a pharmacokinetic interaction between naratriptan and -blockers,
tricyclic antidepressants, selective serotonin reuptake inhibitors, alcohol or food.
Naratriptan does not inhibit monoamine oxidase enzymes; therefore interactions with
monoamine oxidase inhibitors are not anticipated. In addition, the limited metabolism of
naratriptan and the wide range of cytochrome P450 isoenzymes involved suggest that
significant drug interactions with naratriptan are unlikely (see PHARMACOLOGY,
Pharmacokinetics).
Although there is no clear evidence, it is possible that an interaction may occur between
serotonin 5-HT1 agonists and the herbal remedy St John's Wort (hypericum perforatum),
which may result in an increase in side effects.
Special Populations:
Children:
There is no data available on the use of naratriptan in children under 12 years of age therefore
its use in this age group is not recommended.
Adolescents:
In a clinical trial in adolescents, a very high placebo response was observed. The efficacy of
naratriptan in this population has therefore not been demonstrated.
Patients over 65 Years:
There is a moderate decrease in naratriptan clearance with age (see PHARMACOLOGY,
Pharmacokinetics). The safety and efficacy of naratriptan in individuals over 65 years has
not been established.

ADVERSE EFFECTS:
Naramig tablets Issue No. 8R

Table 2 contains integrated data from six placebo-controlled studies and two uncontrolled
studies of naratriptan tablets in adult migraine patients.
Table 2.

Common adverse events (frequency > 2.0 %) regardless of attributability,

reported in 8 clinical studies in adult migraine patients.

425

Placebo
+
Placebo
#
177

Naratriptan
2.5 mg +
Naratriptan
#
700

Sumatriptan
100 mg +
Sumatriptan
#
249

482
(34%)

166
(39%)

38
(21%)

215
(31%)

89
(36%)

1.0
1.2
0.3
0.0
0.3
0.3

1.7
0.9
1.3
0.8
0.9
0.5

2.8
1.6
3.3
4.0
2.6
3.3

0.6
0.0
0.0
0.6
0.0
0.0

1.9
0.7
1.0
0.3
0.3
0.3

3.2
2.8
2.4
2.0
0.8
1.6

CHEST DISCOMFORT
Chest pressure/heaviness

0.8

1.0

1.6

0.6

0.4

2.4

EYE
Photophobia

2.0

0.7

0.2

0.0

0.3

0.0

GASTROINTESTINAL
Nausea
Vomiting

6.1
9.7

7.3
4.3

6.3
2.1

5.1
6.2

6.1
4.6

7.6
1.2

MUSCULOSKELETAL
Musculoskeletal pain

0.8

1.8

3.3

0.6

1.6

2.0

1.7
0.9
2.3

2.6
3.5
1.1

2.8
2.3
0.5

0.0
0.0
0.6

1.9
2.4
0.3

3.2
1.6
0.8

1.0

3.8

8.5

0.0

4.0

5.2

Placebo

Naratriptan
2.5 mg

Sumatriptan
100 mg

782

1415

Number of patients with

any adverse event

235
(30%)

CHARACTERISTIC
SENSATIONS
Warm-hot sensation
Paraesthesiae
Feeling of heaviness
Feeling of tightness
Pressure sensation
Numbness

Number of patients

NEUROLOGICAL
Dizziness
Drowsiness and
sleepiness
Migraines
NON-SITE SPECIFIC
Malaise and fatigue
#

Patients that have taken an optional second dose of identical study medication for recurrence 4 to 24 hours after the first dose.

Interim 6 month results of an open-label study showed that naratriptan was well tolerated over
six months of treatment. Of the attacks that were treated with one and two doses of oral
naratriptan 2.5 mg, adverse events were associated with 17 % and 15 % of attacks
respectively. The incidence of adverse events over the second three month period was lower
than that for the first three month period, regardless of whether patients treated the migraine
with a single dose or with two doses of naratriptan tablets 2.5 mg. The incidence of adverse
events was similar for patients who treated a high frequency of attacks (>18 attacks in six
months) and for patients who treated fewer attacks (< 18 attacks in six months). The
incidence of adverse events is shown below:

Naramig tablets Issue No. 8R

Table 3.

Common adverse events (frequency > 2.0 %) regardless of attributability,

reported in an open-label study of naratriptan in adult migraine patients.
Naratriptan 2.5 mg
404

Naratriptan 2.5 mg +
Naratriptan 2.5 mg
#
341

190
(47%)

131
(38%)

CARDIOVASCULAR
Palpitations

2.0

1.5

CHARACTERISTIC
SENSATIONS
Warm-hot sensation
Feeling of heaviness
Paraesthesiae

3.7
2.5
2.2

2.6
1.8
1.5

CHEST DISCOMFORT
Chest pain and discomfort
Chest pressure/heaviness

2.7
2.2

2.1
0.6

GASTROINTESTINAL
Nausea
Hyposalivation
Vomiting

10.1
2.9
2.7

8.5
2.3
0.9

2.7
1.5

2.1
2.1

NEUROLOGICAL
Drowsiness and sleepiness
Dizziness
Headaches
Vertigo

8.4
3.5
2.7
2.2

4.1
2.1
1.8
0.9

NON-SITE SPECIFIC
Malaise and fatigue

6.2

6.5

Number of patients
Number of patients with
any adverse event

MUSCULOSKELETAL
Musculoskeletal pain
Muscle stiffness, tightness
and rigidity

Patients that have taken an optional second dose of identical study medication for recurrence 4 to 24 hours after the first dose.

The following adverse reactions are usually of short duration, may be severe and may affect
any part of the body including the chest or throat:

Pain, sensations of tingling and heat (commonly reported).

sensations of heaviness, pressure or tightness (uncommonly reported).

Nausea and vomiting commonly occurred but the relationship to naratriptan is not clear since
the incidence was similar or greater with placebo.
There have been rare reports of ischaemic colitis.
Hypersensitivity reactions ranging from cutaneous hypersensitivity to rare cases of
anaphylaxis have been reported.
Coronary artery vasospasm, transient ischaemic ECG changes, angina and myocardia
infarctions have been reported very rarely (see Contraindications and Precautions).
Peripheral vascular ischaemia has been reported very rarely.

Naramig tablets Issue No. 8R

DOSAGE AND ADMINISTRATION:

The recommended adult dose of oral Naramig is a single 2.5 mg tablet. If symptoms recur a
second dose may be taken provided that there is a minimum interval of four hours between
the two doses. The Naramig tablet should be swallowed whole with water.
The total daily dose should not exceed two 2.5 mg tablets in any 24 hour period.
Naramig tablets should be taken as early as possible after the onset of a migraine headache
but they are effective if taken at a later stage.
If the patient does not respond to the first dose of Naramig tablets, it is unlikely that a second
dose will be of benefit for the same attack. However Naramig tablets may be used for
subsequent migraine attacks.
Naramig should not be used prophylactically.
Renal Impairment:
The maximum total daily dose in adult patients with renal impairment is a single 2.5 mg tablet.
The use of naratriptan is contraindicated in patients with severe renal impairment (creatinine
clearance < 15 mL/min) (see CONTRAINDICATIONS).
Hepatic Impairment:
The maximum total daily dose in adult patients with hepatic impairment is a single 2.5 mg
tablet. The use of naratriptan is contraindicated in patients with severe hepatic impairment
(Child-Pugh grade C) (see CONTRAINDICATIONS).

OVERDOSAGE:
Administration of a high dose of 25 mg naratriptan in one healthy male subject increased
systolic blood pressure by up to 71 mmHg and resulted in adverse events that included lightheadedness, tension in the neck, tiredness and a loss of co-ordination. Blood pressure
returned to baseline by 8 hours after dosing without other pharmacological intervention.
It is unknown what effect
concentration of naratriptan.

haemodialysis

or peritoneal dialysis has on the plasma

Treatment:
If overdosage with naratriptan occurs, the patient should be monitored for at least 24 hours
and standard supportive treatment applied as required.
Contact the Poisons Information Centre (telephone 131126) for advice on overdose
management.

PRESENTATION AND STORAGE CONDITIONS:

Naramig is available as a 2.5 mg strength tablet.
Naramig tablets are green, film-coated, D-shaped, biconvex tablets engraved with GX CE5
on one face and blank on the other. Each tablet contains 2.5 mg naratriptan base as the
hydrochloride salt.

Naramig tablets Issue No. 8R

The tablets also contain: anhydrous lactose, microcrystalline cellulose (460), croscarmellose
sodium, magnesium stearate (572), Opadry Green OY-S-21027.
Packs contain 2, 4 or 6 tablets in foil blisters. Store below 30C.

NAME AND ADDRESS OF THE SPONSOR:

GlaxoSmithKline Australia Pty Ltd
1061 Mountain Highway
Boronia Victoria 3155

POISON SCHEDULE OF THE MEDICINE:

S4- Prescription Only Medicine

Date of TGA Approval: June 3, 1998

Date of most recent amendment: 25 June 2007

Issue No. 8

Naramig tablets Issue No. 8R

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