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Document: spc-doc_PL 22805-0034 change

• spc-doc_PL 20117-0222
• spc-doc_PL 22805-0034
• spc-doc_PL 30306-0297

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SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Naratriptan 2.5 mg Film- coated tablets

2    QUALITATIVE AND QUANTITATIVE    COMPOSITION

Each film-coated tablet contains 2.78 mg of Naratriptan hydrochloride equivalent to 2.5 mg Naratriptan.

Each film-coated tablet contains 94 mg of lactose.

For a full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Film-coated tablet

Green colored, capsule shaped, film coated tablets debossed with “N” on one side and plain on the other side.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Acute treatment of the headache phase of migraine attacks with or without aura. Naratriptan should not be used prophylactically.

4.2    Posology and method of administration

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

Adults (18 to 65 years)

The recommended dose of Naratriptan is 2.5 mg.

In case of recurrence of the symptoms of migraine 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 5 mg 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 it is unlikely to be of benefit. However, Naratriptan may be used for subsequent migraine attacks.

Adolescents (12 to 17 years)

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

Elderly (over 65 years)

The safety and effectiveness of Naratriptan in patients over 65 years have not been evaluated and therefore, its use in this age group cannot be recommended (see section 5.2).

Renal impairment

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

Children (under 12 years)

Naratriptan is not recommended for use in children under 12 years, since no data on the safety and efficacy are available.

Method of Administration

Naratriptan should be swallowed whole with water.

4.3 Contraindications

Hypersensitivity to naratriptan or to any of the excipients.

Previous history of myocardial infarction, ischaemic heart disease, Prinzmetal angina / coronary vasospasm, peripheral vascular disease and patients who have symptoms or signs consistent with ischaemic heart disease.

History of cerebrovascular accident (CVA) or transient ischemic attack (TIA).

Moderate to severe hypertension, mild uncontrolled hypertension.

Severely impaired renal (creatinine clearance <15 ml / min) or hepatic (Child-Pugh grade C) function.

Concurrent administration of ergotamine, ergotamine derivatives (including methysergide) and any triptan / 5-hydroxytryptamine1 (5-HTi)-receptor agonist with Naratriptan (see section 4.5).

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 (e.g. CVA or TIA).

The safety and efficacy of Naratriptan when administered during the aura phase before the onset of headache phase 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 a prior cardiovascular evaluation (see section 4.3). Special consideration should be given to postmenopausal women and men over 40 years of age with these risk factors. These evaluations however, may not identify every patient who has cardiac disease, and in rare cases, serious cardiac events have occurred in patients without underlying cardiovascular disease when 5-HT₁ agonists have been administered.

The administration of Naratriptan may be associated with transient symptoms including chest tightness and pain that 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 administered and appropriate evaluation should be carried out (see section 4.8).

Naratriptan contains a sulphonamide group and therefore there is a theoretical risk of hypersensitivity reactions 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-norepinephrine reuptake inhibitors (SNRIs). If concomitant treatment with Naratriptan and an SSRI or SNRI is clinically warranted, the patient should be monitored, particularly during treatment initiation, with dose increases, or with addition of another serotonergic medication (see section 4.5).

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 should be suspected in patients who have frequent or daily headaches despite (or due to) regular use of medications for headache.

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

4.5 Interaction with other medicinal products and other forms of interaction

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

Naratriptan did not inhibit the enzyme monoamine oxidase in vitro. Therefore, no in vivo studies were conducted for interaction with monoamine oxidase inhibitors.

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 drug interactions was found with beta-blockers, tricyclic antidepressants or selective serotonin reuptake inhibitors.

Oral contraceptives decrease the total clearance of Naratriptan by 30% and smoking increases the 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. Nevertheless, due to the safety profile of Naratriptan, inhibition of the secretion of Naratriptan 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 possiblity with co-administration of these and 5-HTj receptor agonist (see section 4.3).

At least 24 hours should elapse after the administration of Naratriptan before an ergotamine containing preparation or any triptan / 5-HTi receptor agonist is given. Conversely, at least 24 hours should elapse after the administration of an ergotamine containing preparation or any triptan / 5-HTi receptor agonist 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-norepinephrine reuptake inhibitors (SNRI) and triptans (see section 4.4).

The undesirable effects may be more common during concomitant use of triptans and herbal preparations containing St. John's Wort (Hypericum perforatum).

4.6 Pregnancy and lactation

Pregnancy

The safety of this medicinal product for use in human pregnancy has not been established.

Evaluation the experimental studies in animals does not indicate direct teratogenic effects. However, in rabbits, delays in the fetal ossification and possible effects on the viability of the embryos have been observed.

The administration of Naratriptan in pregnant women should only be considered if the expected benefit to the mother is greater than any possible risk to the foetus.

Lactation

Naratriptan and/or its metabolites are excreted in 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 the breast milk of lactating women. It is recommended that infant exposure be minimized by avoiding breast-feeding for 24 hours after treatment.

4.7 Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed. Caution is advised in patients who perform skilled tasks (e.g., driving or handling machinery) as drowsiness or other symptoms may occur during a migraine attack.

Undesirable effects

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

The frequency data on adverse reactions are based on the following convention:

•    Common: >1/100 to <1/10,

•    Uncommon: >1/1,000 to <1/100,

•    Rare: >1/10,000 to <1/1,000 and

•    Very rare: <1/10,000

•    Not known (cannot be estimated from the available data)

System Organ Class	Adverse drug reactions	Frequency
Immune system disorders	Anaphylaxis	Rare
Nervous system disorders	Tingling sensation, dizziness, drowsiness	Common
Eye disorders	Visual disturbances	Uncommon
Cardiac disorders	Bradycardia, tachycardia, palpitations	Uncommon
	Coronary artery vasospasm, transient ischaemic ECG changes, angina pectoris, myocardial infarction	Very rare
Vascular disorders	Peripheral vascular ischaemia.	Very rare
Gastrointestinal disorders	Nausea, vomiting	Common
	Ischaemic colitis	Rare
Skin and subcutaneous tissue disorders	Rash, urticaria, pruritus, facial edema	Rare
Musculoskeletal, connective tissue and bone disorders	Heaviness (usually transient, may be intense and can affect any part of the body, including chest and throat)	Uncommon
General disorders and administration site conditions	Sensations of heat, malaise/fatigue	Common
	Pain, sensation of pressure or tightness. These side effects are usually transient, may be intense and affect any part of the body, including the chest and throat	Uncommon
Investigations	Increase in blood pressure of approximately 5 mmHg (systolic) and 3 mmHg (diastolic) in a period of up to 12 hours after administration	Uncommon

4.9 Overdose

Administration of a high dose of 25 mg Naratriptan in a healthy male subject, increased blood pressure by up to 71 mmHg, and resulted in adverse events including dizziness, tension in the neck, fatigue and loss of co-ordination. Blood pressure returned to baseline after 8 hours of the administration without any 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.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group:    analgesics; antimigraine preparations; Selective

serotonin (5 HT1) agonists,

ATC code: N02CC02.

Naratriptan has been shown to be a selective agonist for 5 hydroxytryptamine1 (5-HT1) receptors mediating vascular contraction. Naratriptan has high affinity for human cloned 5-HT_JB and 5-HT_m receptors. The 5-HT_JB receptor is thought to correspond to the vascular 5-HTj 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 constricts the carotid arterial circulation. In addition, experimental evidence suggests that Naratriptan inhibits trigeminal nerve activity. These two mechanisms probably contribute to the antimigraine action of Naratriptan in humans.

In clinical studies, the onset of efficacy is from one hour and peak efficacy is reached in four hours. The initial efficacy of Naratriptan 2.5 mg was slightly lower than sumatriptan100 mg. However, the efficacy over 24 hours was similar for both active substances and the incidence of adverse events in clinical trials was slightly lower after administration of Naratriptan 2.5 mg than administering sumatriptan 100 mg. No studies have been performed comparing Naratriptan 2.5 mg and sumatriptan 50 mg.

5.2 Pharmacokinetic properties

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, C_max is approximately 8.3 ng/ml (95 % confidence interval: 6.5 to 10.5 ng/ml) in women and 5.4 ng/ml (95% confidence interval: 4.7 to 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-specific dose adjustment is not required.

The plasma protein binding of Naratriptan is low (29 %), the distribution volume is 170 liters.

The mean elimination half-life (t _1/2) is 6 hours.

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 drug interactions with Naratriptan are not anticipated (see section 4.5).

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

Special patient 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 values of AUC and C_max of Naratriptan 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 to 115 ml/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 section 4.2).

Hepatic impairment

The liver plays a limited role in the clearance of orally administered Naratriptan. In a study of male and female hepatically impaired patients (Child-Pugh class 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 ti/₂ and an approximately 30 % reduction in clearance (see section 4.2).

5.3 Preclinical safety data

Non-clinical effects in single and repeated dose toxicity studies were observed only at exposures sufficiently in excess of maximum human exposure.

A standard battery of genotoxicity tests showed no genotoxic potential observed for Naratriptan.

In the carcinogenicity studies with rats and mice, no tumours were observed relevant to clinical use.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Tablet core:

Cellulose microcrystalline Lactose anhydrous Croscarmellose sodium Magnesium stearate

Film-coating:

Hypromellose 6 cp (E464)

Titanium dioxide (E171)

Triacetin

Iron oxide yellow (E172)

FD&C blue #2/indigo carmine aluminium lake (E132)

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

22/02/2011

10    DATE OF REVISION OF THE TEXT

22/02/2011