NARAVERG

Film-coated tablet.

Green, biconvex, round, film-coated tablets debossed “NT 2.5” on one side and plain on the other.

Acute treatment of the headache phase of migraine attacks with or without aura.

Naratriptan should be taken as early as possible after the onset of a migraine headache but it is effective if taken at a later stage.

Naratriptan should not be used prophylactically. Posology

Adults (18-65 years of age)

The recommended dose of naratriptan is a single 2.5mg tablet.

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. The total dose should not exceed two 2.5mg tablets in any 24-hour period.

If a patient does not respond to the first dose of naratriptan, a second dose should not be taken for the same attack as no benefit has been shown. Naratriptan may be used for subsequent migraine attacks.

Special populations

Adolescents (12-17 years of age)

In a clinical trial in adolescents, a very high placebo response was observed. The efficacy of naratriptan in this population has not been demonstrated and its use cannot be recommended.

Children (under 12 years of age)

Naratriptan is not recommended for use in children below 12 years due to a lack of data on safety and efficacy.

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 cannot be recommended.

Renal impairment

The maximum total daily dose in patients with mild or moderate renal impairment is a single 2.5mg tablet. The use of naratriptan is contraindicated in patients with severe renal impairment (see sections 4.3 and 5.2).

Hepatic impairment

The maximum total daily dose in patients with mild or moderate hepatic impairment is a single 2.5mg tablet. The use of naratriptan is contraindicated in patients with severe hepatic impairment (see sections 4.3 and 5.2).

Method of administration

The tablets should be swallowed whole with water.

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 (e.g. 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 and tightness 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).

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.

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) or serotonin noradrenaline reuptake inhibitors (SNRIs). If concomitant treatment with naratriptan and an SSRI or SNRI is clinically warranted, appropriate observation of the patient is advised, particularly during treatment initiation, with dose increases, or with addition of another serotonergic agent (see section 4.5).

Adverse events may be more common during concomitant use of triptans and herbal preparations containing St John’s Wort (Hypericum perforatum).

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 medication-overuse headache (MOH) should be suspected in patients who have frequent or daily headaches despite (or because of) the regular use of headache products.

This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Clinical studies did not reveal any interaction with alcohol or food.

Naratriptan did not inhibit monoamine oxidase enzymes in vitro. Therefore in vivo interaction studies with monoamine oxidase inhibitors were not performed.

From in vitro studies it has been concluded that a wide range of cytochrome P450 isoenzymes are involved in the limited metabolism of naratriptan. Therefore significant metabolic drug interactions involving specific cytochrome P450 enzymes are unlikely (see section 5.2).

In clinical studies no evidence of interaction was found with β-blockers, tricyclic antidepressants or selective serotonin reuptake inhibitors.

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 excretion representing approximately 30% of total clearance, interactions might be possible with other substances 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 inhibiting other actively secreted substances should be considered.

There are limited data on interactions with ergotamine, ergotamine-containing preparations, dihydroergotamine (DHE) or sumatriptan. The increased risk of coronary vasospasm is a theoretical possibility with co-administrations of these and 5-HT₁ receptor agonists (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.

There have been reports describing patients with symptoms compatible with serotonin syndrome (including altered mental status, autonomic instability and neuromuscular abnormalities) following the use of selective serotonin reuptake inhibitors (SSRIs) or serotonin noradrenaline reuptake inhibitors (SNRIs) and triptans (see section 4.4).

No studies on the effects on the ability to drive and use machines have been performed.

Caution is recommended in patients performing skilled tasks (e.g. driving or operating machinery) as drowsiness and other symptoms may occur during a migraine attack.

Some of the symptoms reported as adverse events may be part of the migraine attack.

Adverse events/reactions are ranked under headings of frequency using the following convention: common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000).

Immune system disorders

Rare: Anaphylaxis

Nervous system disorders

Common: Sensations of tingling, dizziness, drowsiness

Eye disorders

Uncommon: Visual disturbance

Cardiac disorders

Uncommon: Bradycardia, tachycardia, palpitations

Very rare: Coronary artery vasospasm, angina, myocardial infarction

Vascular disorders

Very rare: Peripheral vascular ischaemia

Gastrointestinal disorders

Common: Nausea, vomiting

Rare: Ischaemic colitis

Skin and subcutaneous tissue disorders

Rare: Rash, urticaria, pruritis, facial oedema

Musculoskeletal and connective tissue disorders

Uncommon: Sensations of heaviness (usually transient, may be intense and can affect any part of the body, including the chest and throat)

General disorders and administration site disorders

Common: Sensations of heat, malaise/fatigue

Uncommon: Pain, sensations of pressure or tightness. These symptoms are usually transient, may be intense and can affect any part of the body, including the chest and throat

Investigations

Uncommon: Increase in blood pressure of approximately 5 mmHg (systolic) and 3 mmHg (diastolic) in a period of up to 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 HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: http://www.hpra.ie/; E-mail: medsafety@hpra.ie

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 co-ordination. 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 overdose with naratriptan occurs, the patient should be monitored for at least 24 hours and standard supportive treatment applied as required.

Absorption

Following oral administration, naratriptan is absorbed with maximum plasma concentrations observed at 2-3 hours. After administration of a 2.5mg naratriptan tablet C_max is approximately 8.3 ng/ml (95% confidence interval: 6.5-10.5 ng/ml) in women and 5.4 ng/ml (95% confidence interval: 4.7-6.1 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.

Distribution

Naratriptan is distributed in a volume of 170 litres.

Plasma protein binding is low (29%).

Biotransformation

Mean clearance after intravenous administration was 470 ml/min in men and 380 ml/min in women. Renal clearance is similar in men and women at 220 ml/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 is metabolised by a wide range of cytochrome P450 isoenzymes. Consequently, significant metabolic interactions with naratriptan are not anticipated (see section 4.5).

Naratriptan does not inhibit cytochrome P450 enzymes. Whether naratriptan has any inducing potential on human isoenzymes is unknown, however it was not shown to produce significant changes in the expression of hepatic cytochrome P450 isoforms in rats.

Elimination

The mean elimination half-life (t_½) is 6 hours.

Special populations

Elderly

In healthy elderly subjects (n=12), clearance was decreased by 26% and AUC was increased by 30% when compared to healthy young subjects (n=12) in the same study (see section 4.2).

Gender

The naratriptan AUC and C_max were approximately 35% lower in males compared to females, possibly due to the concomitant use of oral contraceptives, however, with no differences in efficacy and tolerability in clinical use. Therefore, a gender-related dose adjustment is not required (see section 4.2).

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 18-115ml/min; n=15) matched for sex, age and weight with healthy subjects (n=8), renally impaired patients had an approximately 80% increase in t_½ and an approximately 50% reduction in clearance (see section 4.2).

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_½ and an approximately 30% reduction in clearance (see section 4.2).

Preclinical effects in single and repeat dose toxicity studies were observed only at exposures sufficiently in excess of maximum human exposure.

A standard battery of genotoxicity tests did not indicate any genotoxic potential of naratriptan.

No tumours relevant to clinical use were found in mouse and rat carcinogenicity studies.

Core:

Lactose, anhydrous

Cellulose, microcrystalline

Silica, colloidal anhydrous

Crosscarmellose sodium

Magnesium stearate

Coating:

Hypromellose (E464)

Titanium dioxide (E171)

Lactose, monohydrate

Macrogol 3350

Triacetin

Quinoline yellow aluminium lake (E104)

Indigo carmine aluminium lake (E132)

Iron oxide, yellow (E172)

Not applicable.

3years

OPA/aluminium/PVC-aluminium blisters.

Pack sizes:

2, 4, 6, 12 film-coated tablets and hospital packs of 18 or 50 film-coated tablets.

Not all pack sizes may be marketed.

Teva Pharma B.V.

Date of first authorisation: 16 May 2008

Date of last renewal: 6 February 2012

No special requirements.