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Pharmacodynamic properties Pharmacotherapeutic group: 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, 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 2.5 mg 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. Pharmacokinetic properties Absorption 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 8.3ng/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%). The mean elimination half-life (t1/2) is 6 hours. Metabolism and Elimination 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. 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. 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. 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. 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.

Each tablet contains 2.5 mg of naratriptan (as naratriptan hydrochloride).

Naratriptan is indicated for the acute treatment of migraine attacks with or without aura.

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 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. Naratriptan is contraindicated in patients with severely impaired renal (creatinine clearance < 15 ml/min) or hepatic function (Child-Pugh grade C).

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 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: 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 Vascular disorders Very rare: Peripheral vascular ischaemia. Gastrointestinal Common: Nausea and vomiting. Rare: Ischaemic colitis.  Skin and subcutaneous tissue disorders Rare: Rash, Uticaria, 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 up to 12 hours after administration.

Serotonin syndrome (including altered mental status, autonomic instability and neuromuscular abnormalities) has been reported following concomitant treatment with triptans and SSRIs/SNRIs. 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. At least 24 hours should elapse after the administration of naratriptan before an ergotaminecontaining 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. 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.

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

Posology Naratriptan is recommended as monotherapy for the acute treatment of a migraine attack. Naratriptan should not be used prophylactically. Naratriptan should be swallowed whole with water. Adults (18-65 years of age) The recommended dose of Naratriptan is a single 2.5 mg tablet. The total dose should not exceed two 2.5 mg 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 Naratriptan a second dose should not be taken for the same attack, as it is unlikely to be of benefit. However Naratriptan may be used for subsequent migraine attacks. Adolescents (12-17 years of age) Efficacy of Naratriptan at single doses of 0.25, 1.0 and 2.5 mg was not demonstrated to be greater than placebo in a placebo-controlled study in adolescents (12 to 17 years). Therefore, the use of Naratriptan 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 efficacy of naratriptan in individuals over age 65 has not yet been established and therefore, its use in this age group cannot be recommended. There is a moderate decrease in clearance with age.  Renal Impairment Naratriptan should be used with caution in patients with renal impairment. The maximum dose in any 24-hour treatment period is a single 2.5 mg tablet. The use of Naratriptan is contraindicated in patients with  severe renal impairment (creatinine clearance < 15 ml/min). Hepatic Impairment Naratriptan should be used with caution in patients with hepatic impairment. The maximum dose in any 24-hour treatment period is a single 2.5 mg tablet. The use of Naratriptan is contraindicated in patients with  severe hepatic impairment (Child-Pugh grade C).