PRODUCT INFORMATION NARAMIG TABLETS

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1 PRODUCT INFORMATION NARAMIG TABLETS NAME OF THE MEDICINE: 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. N CH 3 CH 3 NHSO 2 N H. HCl CAS REGISTRY NUMBER: DESCRIPTION: The molecular formula of naratriptan hydrochloride is C 17 H 25 N 3 O 2 S.HCl, the relative molecular mass is It takes the form of a white to pale yellow microcrystalline solid. Naratriptan hydrochloride is a non-polar drug (log D = -4) with a solubility in water of approximately 35 mg/ml at 25 C. PHARMACOLOGY: Pharmacology: Naratriptan has been shown to be a selective agonist for 5 hydroxytryptamine 1 (5-HT 1 ) receptors mediating vascular contraction. This receptor is found predominantly in intracranial (cerebral and dural) blood vessels. Naratriptan has high affinity for human cloned 5-HT 1B and 5-HT 1D receptors, the human 5-HT 1B receptor is thought to correspond to the vascular 5-HT 1 receptor mediating contraction of intracranial blood vessels. Naratriptan has little or no effect at other 5-HT receptor (5-HT 2, 5-HT 3, 5-HT 4 and 5-HT 7 ) 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 man, 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 anti-migraine action of naratriptan in humans. Pharmacokinetics: 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 in women and 5.4 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. Plasma protein binding is low (29%) and the volume of distribution is 170 litres. 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 Naramig tablets Issue No. 8R 1

2 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 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 PRECAUTIONS, Interactions other medicines). 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 DOSAGE and ADMINISTRATION and 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 DOSAGE and ADMINISTRATION and 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 PRECAUTIONS, Special Populations). CLINICAL TRIALS: Seven clinical studies were conducted in 3907 adult (18-65 years) migraine patients in which a total of 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 1. 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 1, 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 non-clinical 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. Naramig tablets Issue No. 8R 2

3 Table 1: Summary of Controlled Clinical Studies of 2.5 mg Naratriptan in Adult Migraine Patients Study Treatment n (Phase) Headache relief * Pain free ** % of Patients 24h overall efficacy # Recurrence ## 2h 4h 2h 4h 1 Placebo (II) Naratriptan a b Placebo (III) Naratriptan a 69 a 24 a 45 a 48 c 27 3 Placebo (III) Naratriptan Sumatriptan Placebo (III) Naratriptan a 66 a a 19 Sumatriptan a 76 ad a 36 5 Naratriptan (III) Sumatriptan e * Headache severity score from grade 3 or 2, pre-treatment, to grade 1 or 0, post-treatment. ** Headache severity score from grade 3 or 2, pre-treatment, to grade 0, post-treatment. # Headache relief by 4 hours without subsequent increase in headache severity or use of rescue medication within 24 hours. ## Headache relief by 4 hours (without use of rescue medication) with significant increase in headache severity between 4 and 24 hours. + oral sumatriptan, 100 mg tablet. a b c d e p<01, p<5 and p<05 vs placebo; p<5 and p=05 vs naratriptan. The study conducted in patients particularly susceptible to migraine recurrence (Table 1, Study 5), showed the incidence of headache recurrence 4 to 24 hours post-first dose was lower with naratriptan 2.5 mg tablets (45%) than with sumatriptan 100 mg tablets (57%, p< 05). 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<01), 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. Naramig tablets Issue No. 8R 3

4 INDICATIONS: Naramig tablets are indicated for the acute treatment of migraine attacks with or without aura. 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 5HT 1 receptor agonists. Severely impaired renal function (creatinine clearance < 15 ml/min). Severely impaired hepatic function (Child-Pugh grade C). PRECAUTIONS: 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 (eg. CVA or TIA). 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 (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 Interactions with Other Medicines). The concomitant administration of ergotamine, derivatives of ergotamine (including methysergide) and any triptan/5-ht1 agonist with naratriptan is not recommended. 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. Naramig tablets Issue No. 8R 4

5 Overuse of acute migraine treatments has been associated with the exacerbation of headache (medication overuse headache, MOH) in susceptible patients. Withdrawl of the treatment may be necessary. 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 ophthalmologic effects. Carcinogenesis, Mutagenesis and Impairment of Fertility 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 5mg. The rat studies revealed an increased incidence of benign thyroid follicular cell adenoma at the highest dose tested. 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. 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 pre-implantation 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 5mg (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: Pregnancy Category B3. Studies in rabbits showed that after oral administration, naratriptan and/or its metabolites readily crossed the placenta and was distributed widely in the fetuses. In rats treated during organogenesis with oral naratriptan, post-implantation loss was increased and there was an increase in the incidence of skeletal variations of the fetuses at 10mg/kg/day (greater than 10 times the exposure (based on AUC) attained in humans after the maximum recommended daily dose of 5mg) and pup survival measured at post-natal day 20 was reduced by treatment at 340mg/kg/day ( 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 5mg) and variations in the major blood vessels were seen at 30mg/kg/day (greater than 34 times the exposure (based on AUC) attained in humans after the maximum recommended daily dose of 5mg). 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 fetus. Use in Lactation: Naramig tablets Issue No. 8R 5

6 Naratriptan and/or its metabolites are secreted into the milk of lactating rats, reaching concentrations higher than those seen in maternal plasma. Therefore, breast feeding should be discontinued for 24 hours after the administration of naratriptan. 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 PHARMACOLOGY, Pharmacokinetics). For patients with mild to moderate renal dysfunction, dosage adjustment is recommended (See DOSAGE and ADMINISTRATION). Naratriptan is contraindicated for patients with severe renal impairment (See CONTRAINDICATIONS). 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 DOSAGE and ADMINISTRATION). Naratriptan is contraindicated for patients with severe hepatic impairment (See CONTRAINDICATIONS). Effects on Ability to Drive and Use Machines: Caution is recommended in patients performing skilled tasks (e.g. driving or operating machinery) as drowsiness may occur as a result of migraine. Interactions with Other Medicines: Serotonin syndrome (including altered mental status, autonomic instability and neuromuscular abnormalities) has been reported following concomitant treatment with triptans and SSRIs/SNRIs (see PRECAUTIONS). 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 PHARMACOLOGY, Pharmacokinetics). Although there is no clear evidence, it is possible that an interaction may occur between serotonin 5-HT 1 agonists and the herbal remedy St John's Wort (hypericum perforatum), which may result in an increase in side effects. Special Populations: Children: There is 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. Patients over 65 Years: There is a moderate decrease in naratriptan clearance with age (see PHARMACOLOGY, Pharmacokinetics). The safety and efficacy of naratriptan in individuals over 65 years has not been established. ADVERSE EFFECTS: Naramig tablets Issue No. 8R 6

7 Table 2 contains integrated data from six placebo-controlled studies and two uncontrolled studies of naratriptan tablets in adult migraine patients. Table 2. Common adverse events (frequency > 2.0 %) regardless of attributability, reported in 8 clinical studies in adult migraine patients. Placebo Naratriptan Sumatriptan Placebo Naratriptan Sumatriptan 2.5 mg 100 mg mg mg + Placebo Naratriptan Sumatriptan Number of patients # 700 # 249 # Number of patients with any adverse event CHARACTERISTIC SENSATIONS Warm-hot sensation Paraesthesiae Feeling of heaviness Feeling of tightness Pressure sensation Numbness 235 (30%) (34%) (39%) 38 (21%) 215 (31%) 89 (36%) CHEST DISCOMFORT Chest pressure/heaviness EYE Photophobia GASTROINTESTINAL Nausea Vomiting MUSCULOSKELETAL Musculoskeletal pain NEUROLOGICAL Dizziness Drowsiness and sleepiness Migraines NON-SITE SPECIFIC Malaise and fatigue # Patients that have taken an optional second dose of identical study medication for recurrence 4 to 24 hours after the first dose 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 below: Naramig tablets Issue No. 8R 7

8 Table 3. Common adverse events (frequency > 2.0 %) regardless of attributability, reported in an open-label study of naratriptan in adult migraine patients. Naratriptan 2.5 mg Naratriptan 2.5 mg + Naratriptan 2.5 mg Number of patients # Number of patients with any adverse event 190 (47%) 131 (38%) CARDIOVASCULAR Palpitations CHARACTERISTIC SENSATIONS Warm-hot sensation Feeling of heaviness Paraesthesiae CHEST DISCOMFORT Chest pain and discomfort Chest pressure/heaviness GASTROINTESTINAL Nausea Hyposalivation Vomiting MUSCULOSKELETAL Musculoskeletal pain Muscle stiffness, tightness and rigidity NEUROLOGICAL Drowsiness and sleepiness Dizziness Headaches Vertigo NON-SITE SPECIFIC Malaise and fatigue # Patients that have taken an optional second dose of identical study medication for recurrence 4 to 24 hours after the first dose. 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. Coronary artery vasospasm, transient ischaemic ECG changes, angina and myocardia infarctions have been reported very rarely (see Contraindications and Precautions). Peripheral vascular ischaemia has been reported very rarely. Naramig tablets Issue No. 8R 8

9 DOSAGE AND 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 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 CONTRAINDICATIONS). OVERDOSAGE: Administration of a high dose of 25 mg naratriptan 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 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 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. Contact the Poisons Information Centre (telephone ) for advice on overdose management. PRESENTATION AND STORAGE CONDITIONS: Naramig is available as a 2.5 mg strength tablet. Naramig tablets are green, film-coated, D-shaped, biconvex tablets engraved with GX CE5 on one face and blank on the other. Each tablet contains 2.5 mg naratriptan base as the hydrochloride salt. Naramig tablets Issue No. 8R 9

10 The tablets also contain: anhydrous lactose, microcrystalline cellulose (460), croscarmellose sodium, magnesium stearate (572), Opadry Green OY-S Packs contain 2, 4 or 6 tablets in foil blisters. Store below 30 C. NAME AND ADDRESS OF THE SPONSOR: GlaxoSmithKline Australia Pty Ltd 1061 Mountain Highway Boronia Victoria 3155 POISON SCHEDULE OF THE MEDICINE: S4- Prescription Only Medicine Date of TGA Approval: June 3, 1998 Date of most recent amendment: 25 June 2007 Issue No. 8 Naramig tablets Issue No. 8R 10