- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
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 ImpairmentNaramig 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 ImpairmentNaramig 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 administrationNaramig Tablets should be swallowed whole with water.
PregnancyEvaluation 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-feedingNaratriptan 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.
|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 somnolence.|
|Uncommon:||Bradycardia, tachycardia, palpitations.|
|Very Rare:||Coronary artery vasospasm, transient ischaemic ECG changes, angina and myocardial infarction (see sections 4.3 and 4.4).|
|Very rare:||Peripheral vascular ischaemia.|
|Common:||Nausea and vomiting.|
|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.|
|Uncommon:||Increase in blood pressure of approximately 5mmHg (systolic) and 3 mmHg (diastolic) in a period of upto 12 hours after administration.|
TreatmentIf overdosage with naratriptan occurs, the patient should be monitored for at least 24 hours and standard supportive treatment applied as required.
Mechanism of actionNaratriptan 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 effectIn 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 safetyIn 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.
AbsorptionFollowing 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.
DistributionNaratriptan is distributed in a volume of 170L. Plasma protein binding is low (29%).
BiotransformationMean 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).
EliminationThe mean elimination half-life (t1/2) is 6 hours.
Special Patient Populations
ElderlyIn 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).
GenderThe 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 impairmentRenal 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 impairmentThe 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).
Tablet coreMicrocrystalline celluloseAnhydrous lactoseCroscarmellose sodiumMagnesium stearate
Film-coatMethylhydroxypropylcelluloseTitanium dioxide (E171)TriacetinIron oxide yellow (E172)Indigo carmine aluminium lake (E132)
Not all pack sizes may be marketed
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