Naramig Tablets 2.5mg

Tablets containing 2.5mg of naratriptan as naratriptan hydrochloride.

Tablets

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

Naramig Tablets are recommended as monotherapy for the acute treatment of a migraine attack.

Naramig Tablets should not be used prophylactically.

Naramig Tablets should be swallowed whole with water.

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).

Hypersensitivity to any component of the preparation.

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 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 or hepatic function.

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).

As with other 5-HT1 receptor agonists, 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 (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 (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 thissituation 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).

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/5-HT1 receptor agonist is contraindicated (see section 4.3).

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).

The safe use of naratriptan in pregnant women has not been established. Evaluation of experimental animal studies does not indicate any direct teratogenic effects or harmful effects on peri- and postnatal development.

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.

Naratriptan and/or drug related metabolites are secreted into the milk of lactating rats. Caution should be exercised when considering administration of naratriptan to nursing women.

Caution is recommended in patients performing skilled tasks (e.g. driving or operating machinery) as drowsiness may occur as a result of migraine. Drowsiness was no more apparent with naratriptan than with placebo in clinical trials.

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 cutaneous hypersensitivity to rare cases of anaphylaxis.

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 drowsiness.

Eye disorders

Uncommon: Visual disturbance.

Cardiac disorders

Uncommon: Bradycardia, tachycardia, palpitations.

Very Rare: Coronary artery vasospasm, transient ischaemic ECG changes, angina and myocardial infarction have been reported very rarely (see Contraindications and Warnings and Precautions).

Vascular disorders

Very rare: Peripheral vascular ischaemia.

Gastrointestinal

Common: Nausea and vomiting.

Rare: Ischaemic colitis.

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: Pain, sensations of heat. Malaise/fatigue.

Uncommon: Sensations of heaviness, pressure or tightness.

There is limited experience of accidental overdosage with naratriptan. However, there is no evidence to suggest that overdose is associated with adverse events other than those described above (see section 4.8 Undesirable Effects).

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.

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-HT_1B and 5-HT_1D receptors, the human 5-HT_1B 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, 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.

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.

Absorption, distribution, metabolism and elimination

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.

Naratriptan is distributed in a volume of 170L. Plasma protein binding is low (29%).

The mean elimination half-life (t_1/2) is 6 hours.

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 Interactions).

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 t_1/2 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 t_1/2 and an approximately 30% reduction in clearance (See Posology and method of administration).

No clinically relevant findings were observed in preclinical studies.

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)

None reported

36 months

Store below 30°C.

2, 4, 6 or 12 tablets in a double foil blister pack

Not all pack sizes may be marketed

None

Glaxo Wellcome UK Ltd, trading as GlaxoSmithKline UK

Stockley Park West,

Uxbridge,

Middlesex. UB11 1BT

PL 10949/0273

28 April 2002

29 October 2008

POM