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NARAMIG TABLETS 2.5MG

Active substance(s): NARATRIPTAN HYDROCHLORIDE

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Naramig 2.5 mg film-coated tablets

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Tablets containing 2.5 mg of naratriptan as naratriptan hydrochloride.
For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Tablets

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Naramig Tablets are indicated for the acute treatment of migraine attacks with
or without aura.

4.2

Posology and method of administration
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.
Naramig Tablets are recommended as monotherapy for the acute treatment of
a migraine attack.
Naramig Tablets should not be used prophylactically.

Posology
Adults (18-65 years of age)
The recommended dose of Naramig Tablets is a single 2.5mg tablet.
The total dose should not exceed two 2.5mg tablets in any 24 hour period.
If symptoms of migraine should recur, following an initial response, a second
dose may be taken provided that there is a minimum interval of four hours
between the two doses.

If a patient does not respond to a first dose of Naramig Tablets a second dose
should not be taken for the same attack, as it is unlikely to be of benefit.
However Naramig Tablets may be used for subsequent migraine attacks.
Adolescents (12-17 years of age)
Efficacy of Naramig Tablets at single doses of 0.25, 1.0 and 2.5mg was not
demonstrated to be greater than placebo in a placebo-controlled study in
adolescents (12 to 17 years). Therefore, the use of Naramig Tablets in patients
under 18 years of age is not recommended.
Children (under 12 years of age)
There are 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.
Elderly (over 65 years of age)
The safety and effectiveness of naratriptan in individuals over age 65 have not
been evaluated and therefore, its use in this age group can not be
recommended. There is a moderate decrease in clearance with age (see
Pharmacokinetics).
Renal Impairment
Naramig should be used with caution in patients with renal impairment. The
maximum dose in any 24 hour treatment period is a single 2.5mg tablet. The
use of Naramig is contraindicated in patients with severe renal impairment
(creatinine clearance < 15mL/min)
(See Contraindications and Pharmacokinetics).
Hepatic Impairment
Naramig should be used with caution in patients with hepatic impairment. The
maximum dose in any 24 hour treatment period is a single 2.5mg tablet. The
use of Naramig is contraindicated in patients with severe hepatic impairment
(Child-Pugh grade C)
(See Contraindications and Pharmacokinetics).
Method of administration
Naramig Tablets should be swallowed whole with water.
4.3

Contraindications
Hypersensitivity to naratriptan or to any of the excipients listed in section 6.1.
As with other 5-hydroxytryptamine1 (5-HT1) receptor agonists naratriptan
should not be used in patients who have had a myocardial infarction or have
ischaemic heart disease, or Prinzmetal's angina/coronary vasospasm,
peripheral vascular disease or patients who have symptoms or signs consistent
with ischaemic heart disease.
Naratriptan should not be administered to patients with a history of
cerebrovascular accident (CVA) or transient ischaemic attack (TIA).
The use of naratriptan in patients with moderate or severe hypertension, and
mild uncontrolled hypertension is contraindicated.

The concomitant administration of ergotamine, derivatives or ergotamine
(including methysergide) or/and any triptan/5-hydroxytryptamine1 (5-HT1)
receptor agonist with naratriptan is contraindicated (see Section 4.5).
Naratriptan is contraindicated in patients with severely impaired renal
(creatinine clearance <15 ml/min) or hepatic function (Child-Pugh grade C).
4.4

Special warnings and precautions for use
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.
As with other acute migraine therapies, before treating headaches in patients
not previously diagnosed as migraineurs, and in migraineurs who present with
atypical symptoms, care should be taken to exclude other potentially serious
neurological conditions. It should be noted that migraineurs may be at risk of
certain cerebrovascular events (eg. CVA or TIA).
The safety and efficacy of naratriptan when administered during the aura
phase, prior to the onset of migraine headache, has yet to be established.
As with other 5-HT1 receptor agonists, naratriptan should not be given to
patients with risk factors for ischaemic heart disease, including those patients
who are heavy smokers or users of nicotine substitution therapy without prior
cardiovascular evaluation (see section 4.3). Special consideration should be
given to postmenopausal women and males over 40 with these risk factors.
These evaluations however, may not identify every patient who has cardiac
disease and, in very rare cases, serious cardiac events have occurred in patients
without underlying cardiovascular disease when 5-HT1 agonists have been
administered.
Following administration, naratriptan can be associated with transient
symptoms including chest pain andtightness which may be intense and involve
the throat (see section 4.8). Where such symptoms are thought to indicate
ischaemic heart disease, no further doses of naratriptan should be taken and
appropriate evaluation should be carried out (see section 4.8).
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, particularly during treatment
initiation, with dose increases, or with addition of another serotonergic
medication (see Section 4.5).
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.
Prolonged use of any type of painkiller for headaches can make them worse. If
this situation is experienced or suspected, medical advice should be obtained
and treatment should be discontinued. The diagnosis of MOH should be
suspected in patients who have frequent or daily headaches despite (or because
of) the regular use of headache medications.
Undesirable effects may be more common during concomitant use of triptans
and herbal preparations containing St John’s Wort (Hypericum perforatum).
This medicinal product contains anhydrous lactose, patients with rare
hereditary problems of galactose intolerance, the Lapp lactase deficiency or
glucose-galactose malabsorption should not take this medicine.
4.5

Interaction with other medicinal products and other forms of interaction
Serotonin syndrome (including altered mental status, autonomic instability and
neuromuscular abnormalities) has been reported following concomitant
treatment with triptans and SSRIs/SNRIs (see Section 4.4).
There is no evidence of a pharmacokinetic interaction with β-blockers,
tricyclic antidepressants, selective serotonin reuptake inhibitors, alcohol or
food.
Co-administration of naratriptan with ergotamine, dihydroergotamine, or
sumatriptan did not result in clinically significant effects on blood pressure,
heart rate or ECG or affect naratriptan exposure. However, an increased risk
of coronary vasospasm is a theoretical possibility and concomitant
administration with preparations containing ergotamine or another triptan/5HT1 receptor agonist is contraindicated (see section 4.3).
At least 24 hours should elapse after the administration of naratriptan before
an ergotamine-containing preparation or any triptan/5-HT1 receptor agonist is
given. Conversely, at least 24 hours should elapse after the administration of
an ergotamine-containing preparation before naratriptan is given.
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 Pharmacokinetics).
Oral contraceptives decrease the total clearance of naratriptan by 30%, and
smoking increases total clearance by 30%. But no dosing adjustments are
required.
Since 60% of naratriptan is excreted renally with active renal secretion
representing approximately 30% of total clearance, interactions might be

possible with other drugs that are also renally secreted. However due to the
safety profile of naratriptan, inhibition of naratriptan secretion is probably of
minor importance, while the possibility of naratriptan to inhibit other drugs
actively secreted should be considered

4.6

Fertility, pregnancy and Lactation
Pregnancy
Evaluation of experimental animal studies does not indicate any direct
teratogenic effects or harmful effects on peri- and postnatal development.
However, delays in foetal ossification and possible effects on embryo viability
have been observed in the rabbit.
Post-marketing data from prospective pregnancy registries have documented
the pregnancy outcomes in less than 60 women exposed to naratriptan. Due to
a small sample size no definitive conclusion can be drawn regarding the risk of
birth defects following exposure to naratriptan.
Because animal reproduction studies are not always predictive of human
response administration of naratriptan should only be considered if the
expected benefit to the mother is greater than any possible risk to the foetus.
Breast-feeding
Naratriptan and/or drug related metabolites are secreted into the milk of
lactating rats.
Transient effects in the pre and post-natal development of neonatal rats were
observed only at maternal exposures sufficiently in excess of maximum human
exposure. No studies have been conducted to determine the level of
transference of naratriptan into breast milk of nursing women. It is
recommended that infant exposure be minimised by avoiding breast-feeding
for 24 hours after treatment.

4.7

Effects on ability to drive and use machines

Drowsiness may occur as a result of migraine or its treatment with naratriptan.
Caution is recommended when skilled tasks are to be performed (e.g. driving or
operating machinery).
4.8
Undesirable effects
At therapeutic doses of naratriptan the incidence of side effects reported in
clinical trials was similar to placebo. Some of the symptoms may be part of
the migraine attack.
Undesirable effects are ranked under headings of frequency using the
following convention: Very common (≥1/10), common (≥1/100 and <1/10),

uncommon (≥1/1,000 and <1/100), rare (≥1/10,000 and <1/1,000) and very
rare (<1/10,000).
Immune system disorders
Rare:
Hypersensitivity
reactions
ranging
from
hypersensitivity to rare cases of anaphylaxis.

cutaneous

Nervous system disorders
Common:
Tingling. This is usually of short duration, may be severe and
may affect any part of the body including the chest or throat.
Dizziness and somnolence.
Eye disorders
Uncommon: Visual disturbance.
Cardiac disorders
Uncommon: Bradycardia, tachycardia, palpitations.
Very Rare:
Coronary artery vasospasm, transient ischaemic ECG changes,
angina and myocardial infarction (see sections 4.3 and 4.4).
Vascular disorders
Very rare:
Peripheral vascular ischaemia.
Gastrointestinal
Common:
Nausea and vomiting.
Rare:
Ischaemic colitis.
Skin and subcutaneous tissue disorders
Rare:
Rash, Urticaria, Pruritis, facial oedema
General disorders and administration site conditions:
The following symptoms are usually of short duration, may be severe and may
affect any part of the body including the chest or throat:
Common:
Sensations of heat, malaise/fatigue.
Uncommon: Pain, sensations of heaviness, pressure or tightness.
Investigations
Uncommon: Increase in blood pressure of approximately 5mmHg (systolic)
and 3 mmHg (diastolic) in a period of upto 12 hours after administration.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal
product is important. It allows continued monitoring of the benefit/risk balance
of the medicinal product. Healthcare professionals are asked to report any
suspected adverse reactions via the Yellow Card Scheme at:
www.mhra.gov.uk/yellowcard.
4.9

Overdose

Administration of a high dose of 25 mg naratriptan in one healthy male subject
increased blood pressure by up to 71 mmHg and resulted in adverse events
including light-headedness, tension in the neck, tiredness and a loss of coordination. Blood pressure returned to baseline by 8 hours after dosing without
other pharmacological intervention.
It is unknown what effect haemodialysis or peritoneal dialysis has on the
plasma concentrations of naratriptan.
Treatment
If overdosage with naratriptan occurs, the patient should be monitored for at
least 24 hours and standard supportive treatment applied as required.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
Mechanism of action
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.
Pharmacodynamic effect
In animals, naratriptan selectively constricts the carotid arterial circulation.
This circulation supplies blood to the extracranial and intracranial tissues such
as the meninges, and dilatation and/or oedema formation in these vessels is
thought to be the underlying mechanism of migraine in man. 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.
Clinical efficacy and safety
In man, a meta-analysis of BP recordings in 15 studies showed that the
population average maximum increases in systolic and diastolic blood pressure
after a 2.5mg dose of naratriptan tablets would be less than 5mmHg and
3mmHg respectively. The blood pressure response was unaffected by age,
weight, hepatic or renal impairment.

5.2

Pharmacokinetic properties
Absorption
Following oral administration, naratriptan is rapidly absorbed with maximum
plasma concentrations observed at 2-3 hours. After administration of a 2.5mg

naratriptan tablet Cmax is approximately 8.3ng/mL (95% Cl: 6.5 to
10.5ng/mL) in women and 5.4ng/mL (95% Cl: 4.7 to 6.1ng/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.
Distribution
Naratriptan is distributed in a volume of 170L. Plasma protein binding is low
(29%).
Biotransformation
Mean clearance after intravenous administration was 470mL/min in men and
380mL/min in women. Renal clearance is similar in men and women at
220mL/min and is 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
naratriptan was metabolised by a wide range of cytochrome P450 isoenzymes.
Consequently significant metabolic drug interactions with naratriptan are not
anticipated (see section 4.5).
Elimination
The mean elimination half-life (t1/2) is 6 hours.
Special Patient Populations
Elderly
In healthy elderly subjects (n=12), clearance was decreased by 26% when
compared to healthy young subjects (n=12) in the same study (See Posology
and method of administration).
Gender
The naratriptan AUC and Cmax were approximately 35% lower in males
compared to females however, with no differences in efficacy and tolerability
in clinical use.
Therefore a gender related dose adjustment is not required (see Posology and
method of administration).
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.
In a study in male and female renally impaired patients (creatinine clearance
18 to 115mL/min; n=15) matched for sex, age and weight with healthy
subjects (n=8), renally impaired patients had an approximately 80% increase

in t1/2 and an approximately 50% reduction in clearance (See Posology and
method of administration).
Hepatic impairment
The liver plays a lesser role in the clearance of orally administered naratriptan.
In a study in male and female hepatically impaired patients (Child-Pugh grade
A or B n=8) matched for sex, age and weight with healthy subjects who
received oral naratriptan, hepatically impaired patients had an approximately
40% increase in t1/2 and an approximately 30% reduction in clearance (See
Posology and method of administration).
5.3

Preclinical safety data
No clinically relevant findings were observed in preclinical studies.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Tablet core
Microcrystalline cellulose
Anhydrous lactose
Croscarmellose sodium
Magnesium stearate
Film-coat
Methylhydroxypropylcellulose
Titanium dioxide (E171)
Triacetin
Iron oxide yellow (E172)
Indigo carmine aluminium lake (E132)

6.2

Incompatibilities
None reported

6.3

Shelf life
36 months

6.4

Special precautions for storage
Store below 30°C.

6.5

Nature and contents of container

2, 4, 6 or 12 tablets in a double foil blister pack or child-resistant foil blister
pack.
Not all pack sizes may be marketed

6.6

Special precautions for disposal
No special requirements for disposal.

7

MARKETING AUTHORISATION HOLDER
Glaxo Wellcome UK Ltd, trading as GlaxoSmithKline UK
Stockley Park West,
Uxbridge,
Middlesex UB11 1BT

8

MARKETING AUTHORISATION NUMBER(S)
PL 10949/0273

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
28/04/2007 / 26/03/2002

10

DATE OF REVISION OF THE TEXT
25/08/2016

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