NARAMIG tablets

MIMS Revision Date: 01 November 2018

1 Name of Medicine

Naratriptan (as hydrochloride).

2 Qualitative and Quantitative Composition

Quantity of the active ingredient per tablet is naratriptan (as hydrochloride) 2.5 mg.
Excipients with known effect: lactose. For the full list of excipients, see Section 6.1 List of Excipients.
Naratriptan hydrochloride takes the form of a white to pale yellow microcrystalline solid. Naratriptan hydrochloride is a non-polar drug (log D = -0.34) with a solubility in water of approximately 35 mg/mL at 25°C.

3 Pharmaceutical Form

Naramig tablets are green, film-coated, D-shaped, biconvex tablets, plain on both sides. Each Naramig tablet contains 2.5 mg naratriptan base as the hydrochloride salt.

4 Clinical Particulars

4.1 Therapeutic Indications

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

4.2 Dose and Method of Administration

The recommended adult dose of oral Naramig is a single 2.5 mg tablet. If symptoms recur a second dose may be taken provided that there is a minimum interval of four hours between the two doses. The Naramig tablet should be swallowed whole with water.
The total daily dose should not exceed two 2.5 mg tablets in any 24 hour period.
Naramig tablets should be taken as early as possible after the onset of a migraine headache but they are effective if taken at a later stage.
If the patient does not respond to the first dose of Naramig tablets, it is unlikely that a second dose will be of benefit for the same attack. However, Naramig tablets may be used for subsequent migraine attacks.
Naramig should not be used prophylactically.
Renal impairment. The maximum total daily dose in adult patients with renal impairment is a single 2.5 mg tablet. The use of naratriptan is contraindicated in patients with severe renal impairment (creatinine clearance < 15 mL/min) (see Section 4.3 Contraindications).
Hepatic impairment. The maximum total daily dose in adult patients with hepatic impairment is a single 2.5 mg tablet. The use of naratriptan is contraindicated in patients with severe hepatic impairment (Child-Pugh grade C) (see Section 4.3 Contraindications).

4.3 Contraindications

Hypersensitivity to any component of the preparation.
A history of myocardial infarction.
Ischaemic heart disease.
Prinzmetal's angina/ coronary vasospasm.
Signs or symptoms consistent with ischaemic heart disease.
A history of cerebrovascular accident (CVA) or transient ischaemic attack (TIA).
Peripheral vascular disease.
Uncontrolled hypertension.
Concomitant use of other 5HT₁-receptor agonists.
Severely impaired renal function (creatinine clearance < 15 mL/min).
Severely impaired hepatic function (Child-Pugh grade C).

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.
Before treating headaches in patients not previously diagnosed as migraine patients, and in migraine patients who present with atypical symptoms, care should be taken to exclude other potentially serious neurological conditions. It should be noted that migraine patients may be at risk of certain cerebrovascular events (e.g. CVA or TIA).
Cardiac patients. 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.
Serotonin syndrome. 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 Interactions with Other Medicines and Other Forms of Interactions).
Naratriptan contains a sulfonamide 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.
Overuse of acute migraine treatments has been associated with the exacerbation of headache (medication overuse headache (MOH)) in susceptible patients. Withdrawal of the treatment may be necessary.
Ophthalmic effects. Because naratriptan binds to melanin, it could accumulate in melanin rich tissues (such as the eye) over time. However, no effects on the retina related to treatment with naratriptan were noted in any of the toxicity studies. Prescribers should be aware of the possibility of long-term ophthalmological effects.
Use in hepatic impairment. The liver plays a lesser role in the clearance of orally administered naratriptan. However, for patients with mild to moderate hepatic dysfunction, dosage adjustment is still recommended (see Section 4.2 Dose and Method of Administration). Naratriptan is contraindicated for patients with severe hepatic impairment (see Section 4.3 Contraindications).
Use in 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 (see Section 5 Pharmacological Properties; Section 5.2 Pharmacokinetic Properties). For patients with mild to moderate renal dysfunction, dosage adjustment is recommended (see Section 4.2 Dose and Method of Administration). Naratriptan is contraindicated for patients with severe renal impairment (see Section 4.3 Contraindications).
Use in the elderly. There is a moderate decrease in naratriptan clearance with age (see Section 5 Pharmacological Properties; Section 5.2 Pharmacokinetic Properties). The safety and efficacy of naratriptan in individuals over 65 years have not been established.
Paediatric use. Children. 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.
Adolescents. In a clinical trial in adolescents, a very high placebo response was observed. The efficacy of naratriptan in this population has therefore not been demonstrated.
Effects on laboratory tests. No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

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 Special Warnings and Precautions for Use).
There is no evidence of a pharmacokinetic interaction between naratriptan and β-blockers, tricyclic antidepressants, selective serotonin reuptake inhibitors, alcohol or food.
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 Section 5 Pharmacological Properties; Section 5.2 Pharmacokinetic Properties).
Although there is no clear evidence, it is possible that an interaction may occur between serotonin 5-HT₁ agonists and the herbal remedy St John's wort (Hypericum perforatum), which may result in an increase in side effects.
The concomitant administration of ergotamine, derivatives of ergotamine (including methysergide) and any triptan/5-HT₁ agonist with naratriptan is not recommended.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility. A fertility study by the oral route of administration, during which male and female rats were dosed daily with naratriptan prior to and throughout the mating period, showed evidence of increased preimplantation loss and consequent reduction in litter size at doses producing plasma concentrations at least 50 times those attained in humans after the maximum recommended daily dose of 5 mg (based on AUC). In rats, oral doses of naratriptan of 340 mg/kg/day (greater than 500 times maximum anticipated clinical exposure based on AUC) led to testicular and epididymal atrophy in males, and an increase in the incidence of ovarian atrophy and follicular/ luteal cysts in females.
Use in pregnancy. (Category B3)
Studies in rabbits showed that after oral administration, naratriptan and/or its metabolites readily crossed the placenta and were distributed widely in the foetuses. In rats treated during organogenesis with oral naratriptan, postimplantation loss was increased and there was an increase in the incidence of skeletal variations of the foetuses at 10 mg/kg/day (greater than 10 times the exposure (based on AUC) attained in humans after the maximum recommended daily dose of 5 mg) and pup survival measured at postnatal day 20 was reduced by treatment at 340 mg/kg/day (approximately 700 times clinical exposure based on AUC). In rabbits, the incidences of variations of the fetal skeleton were increased by maternal treatment at 5 mg/kg/day (greater than 15 times the exposure (based on AUC) attained in humans after the maximum recommended daily dose of 5 mg) and variations in the major blood vessels were seen at 30 mg/kg/day (greater than 34 times the exposure (based on AUC) attained in humans after the maximum recommended daily dose of 5 mg).
There are no adequate and well controlled studies in pregnant women. Therefore, naratriptan should not be used in pregnancy unless the benefits to the mother outweigh the potential risk to the foetus.
Use in lactation. Naratriptan and/or its metabolites are secreted into the milk of lactating rats, reaching concentrations higher than those seen in maternal plasma. Therefore, breastfeeding should be discontinued for 24 hours after the administration of naratriptan.

4.7 Effects on Ability to Drive and Use Machines

Drowsiness may occur as a result of migraine or its treatment with naratriptan. Caution is recommended when skilled tasks are to be performed (e.g. driving or operating machinery).

4.8 Adverse Effects (Undesirable Effects)

Table 1 contains integrated data from six placebo controlled studies and two uncontrolled studies of naratriptan tablets in adult migraine patients.

Interim 6 month results of an open label study showed that naratriptan was well tolerated over six months of treatment. Of the attacks that were treated with one and two doses of oral naratriptan 2.5 mg, adverse events were associated with 17% and 15% of attacks, respectively. The incidence of adverse events over the second three month period was lower than that for the first three month period, regardless of whether patients treated the migraine with a single dose or with two doses of naratriptan tablets 2.5 mg. The incidence of adverse events was similar for patients who treated a high frequency of attacks (> 18 attacks in six months) and for patients who treated fewer attacks (≤ 18 attacks in six months). The incidence of adverse events is shown in Table 2.
The following adverse reactions are usually of short duration, may be severe and may affect any part of the body including the chest or throat: pain, sensations of tingling and heat (commonly reported); sensations of heaviness, pressure or tightness (uncommonly reported).
Nausea and vomiting commonly occurred but the relationship to naratriptan is not clear since the incidence was similar or greater with placebo.
There have been rare reports of ischaemic colitis.
Hypersensitivity reactions ranging from cutaneous hypersensitivity to rare cases of anaphylaxis have been reported.
Somnolence has been rarely reported.
Coronary artery vasospasm, transient ischaemic ECG changes, angina and myocardial infarction have been reported very rarely (see Section 4.3 Contraindications and Section 4.4 Special Warnings and Precautions for Use).
Peripheral vascular ischaemia has been reported very rarely.
Reporting suspected adverse effects. Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.

4.9 Overdose

Administration of a high dose of naratriptan 25 mg in one healthy male subject increased systolic blood pressure by up to 71 mmHg and resulted in adverse events that included lightheadedness, tension in the neck, tiredness and a loss of coordination. 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 concentration 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.
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action. Naratriptan has been shown to be a selective agonist for 5-hydroxytryptamine₁ (5HT₁) receptors mediating vascular contraction. This receptor is found predominantly in intracranial (cerebral and dural) blood vessels. Naratriptan has high affinity for human cloned 5HT_1B and 5HT_1D receptors. The human 5HT_1B receptor is thought to correspond to the vascular 5HT₁ receptor mediating contraction of intracranial blood vessels. Naratriptan has little or no effect at other 5HT receptor (5HT₂, 5HT₃, 5HT₄ and 5HT₇) subtypes.
In animals, naratriptan selectively constricts the carotid arterial circulation. This circulation supplies blood to the extracranial and intracranial tissues such as the meninges. In humans, dilatation and/or oedema formation in these vessels is thought to be the underlying mechanism of migraine. In addition, experimental evidence suggests that naratriptan inhibits trigeminal nerve activity. Both these actions may contribute to the antimigraine action of naratriptan in humans.
Clinical trials. Seven clinical studies were conducted in 3907 adult (18-65 years) migraine patients in which a total of 15,283 attacks were treated with placebo, naratriptan tablets or sumatriptan tablets. Naratriptan tablets were used to treat at least one attack in 3204 adult patients.
The primary efficacy parameters for adult migraine patients treated with placebo, naratriptan tablets 2.5 mg or sumatriptan tablets 100 mg in phase II or phase III studies are summarised in Table 3.
In studies that included sumatriptan 100 mg as comparator or control medication, naratriptan tablets 2.5 mg were shown to have lower incidence of recurrence but of similar 24 hour overall efficacy (Table 3, Studies 3, 4 and 5). Analysis of the secondary endpoints (migraine associated symptoms at 4 hours (nausea, photophobia or phonophobia), clinical disability at 4 hours or use of rescue medication within 24 hours) indicated that naratriptan tablets 2.5 mg were effective when compared to placebo.
Five phase III studies were conducted in adults in a nonclinical setting of doses of naratriptan tablets ranging from 0.1 mg to 2.5 mg in which patients were allowed to continue taking migraine prophylactic medication. Two of these studies included special objectives: a trial in patients with a high incidence of migraine recurrence (history of recurrence in ≥ 50% of successfully treated attacks) and a long-term (12 month) efficacy and safety study.

The study conducted in patients particularly susceptible to migraine recurrence (see Table 3, Study 5), showed the incidence of headache recurrence 4 to 24 hours postfirst dose was lower with naratriptan 2.5 mg tablets (45%) than with sumatriptan 100 mg tablets (57%, p < 0.005). Fewer patients took the second dose when initially administered oral naratriptan 2.5 mg (40%) when compared to the oral sumatriptan 100 mg group (57%, p < 0.001), and the median time to onset of recurrence was longer (12.5 hours versus 10.5 hours, for naratriptan and sumatriptan, respectively).
Interim 6 month data from the open label, 12 month safety study of naratriptan demonstrated the 2.5 mg tablet was efficacious and well tolerated in the acute treatment of migraine. A total of 7709 attacks were treated. Headache relief (at 4 hours) occurred in 68% of all attacks, and in 66% and 70% of attacks during 0 to 3 months and > 3 to 6 months, respectively. For patients treating ≤ 18 attacks during 6 months, headache relief was similar (62%) to patients treating > 18 attacks during the same period (70%).
There have been no adequate investigations of the safety and efficacy of naratriptan in patients younger than 18 years or older than 65 years.

5.2 Pharmacokinetic Properties

Absorption. Following oral administration, naratriptan is rapidly absorbed with maximum plasma concentrations observed at 2-3 hours. After administration of a naratriptan 2.5 mg tablet C_max is approximately 8.3 nanogram/mL in women and 5.4 nanogram/mL in men.
Distribution. 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. Plasma protein binding is low (29%) and the volume of distribution is 170 L. The mean elimination half-life (t_1/2) is 6 hours. Mean clearance after intravenous administration is 470 mL/min in men and 380 mL/min in women. Renal clearance is similar in men and women (220 mL/min) and is higher than the glomerular filtration rate suggesting that naratriptan is actively secreted in the renal tubules.
Metabolism. In vitro studies showed that the metabolism of naratriptan by cytochrome P450 isoenzymes is very low and that no specific isoenzyme is involved. Consequently, significant metabolic drug interactions with naratriptan are not anticipated (see Section 4.4 Special Warnings and Precautions for Use and Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Excretion. Naratriptan is predominantly excreted in the urine with 50% of the dose recovered as unchanged naratriptan and 30% recovered as inactive metabolites.
As renal excretion is the major route for the elimination of naratriptan, exposure to naratriptan may be increased in patients with renal disease. A study in male and female patients with renal impairment (creatinine clearance 18 to 115 mL/min, n = 15) showed 80% (approximate) increase in t_1/2 and 50% (approximate) reduction in clearance when compared to healthy subjects (n = 8) (see Section 4.2 Dose and Method of Administration and Section 4.3 Contraindications).
A study in male and female patients with hepatic impairment (Child-Pugh grade A or B, n = 8) demonstrated a 40% (approximate) increase in t_1/2 and a 30% (approximate) reduction in clearance when compared to healthy subjects (n = 8) (see Section 4.2 Dose and Method of Administration and Section 4.3 Contraindications).
The naratriptan AUC and C_max were approximately 35% lower in males compared to females without differences in efficacy and tolerability in clinical use. Therefore a gender related dose adjustment is not required.
In healthy elderly subjects (age 65 to 77 years, n = 12), clearance was decreased by 26% when compared to healthy young subjects (age 24 to 44 years, n = 12) (see Section 4.4 Special Warnings and Precautions for Use).

5.3 Preclinical Safety Data

Genotoxicity. Naratriptan showed no evidence of genotoxicity in a series of assays for gene mutations (bacteria, yeast and mouse lymphoma cells). Tests for chromosomal damage in human lymphocytes in vitro and micronucleus formation in vivo showed that naratriptan was not clastogenic. However, naratriptan underwent nitrosation at acidic pH in vitro to yield a product or products which were bacterial mutagens. After oral administration of naratriptan to rats maintained on a high nitrite diet, nitroso derivatives of naratriptan were detected in the stomach. However, this did not increase the potential toxicity or carcinogenicity of naratriptan.
Carcinogenicity. In carcinogenicity studies, rats and mice were given naratriptan by oral gavage for 104 weeks. Plasma concentrations in rats and mice receiving the highest doses were at least 100 times greater than the exposure (based on AUC) attained in humans after the maximum recommended daily dose of 5 mg. The rat studies revealed an increased incidence of benign thyroid follicular cell adenoma at the highest dose tested.

6 Pharmaceutical Particulars

6.1 List of Excipients

Excipients included in the dosage form are: lactose, microcrystalline cellulose, croscarmellose sodium, magnesium stearate and Opadry Green OY-S-21027 (ARTG No 3062).

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

3 years from date of manufacture.

6.4 Special Precautions for Storage

Store below 30°C.

6.5 Nature and Contents of Container

PA/Al/PVC/Al blisters packs contain 2, 4 or 6 tablets - also available in a 2 starter pack.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Naratriptan hydrochloride is the therapeutically active ingredient in Naramig tablets. The chemical name of naratriptan hydrochloride is 2-[3-(1-Methyl-piperidin-4-yl)-1H-indol-5-yl]- ethanesulphonic acid methylamide hydrochloride. Molecular formula: C₁₇H₂₅N₃O₂S. HCl. Molecular weight: 371.93.
Chemical structure.

CAS number. 143388-64-1.

7 Medicine Schedule (Poisons Standard)

S4.

Date of First Approval

03 June 1998

Date of Revision

25 June 2018

Summary Table of Changes