Amerge Information
Amerge () Description
Amerge () Tablets contain naratriptan as the hydrochloride, which is a selective 5-hydroxytryptamine receptor subtype agonist. Naratriptan hydrochloride is chemically designated as N-methyl-3-(1-methyl-4-piperidinyl)-1H-indole-5-ethanesulfonamide monohydrochloride, and it has the following structure:
The empirical formula is CHNOS•HCl, representing a molecular weight of 371.93. Naratriptan hydrochloride is a white to pale yellow powder that is readily soluble in water. Each Amerge () Tablet for oral administration contains 1.11 or 2.78 mg of naratriptan hydrochloride equivalent to 1 or 2.5 mg of naratriptan, respectively. Each tablet also contains the inactive ingredients croscarmellose sodium; hypromellose; lactose; magnesium stearate; microcrystalline cellulose; triacetin; and titanium dioxide, iron oxide yellow (2.5-mg tablet only), and indigo carmine aluminum lake (FD&C Blue No. 2) (2.5-mg tablet only) for coloring.
Amerge () Clinical Pharmacology
Naratriptan binds with high affinity to 5-HT and 5-HT receptors and has no significant affinity or pharmacological activity at 5-HT receptor subtypes or at adrenergic α, α, or β; dopaminergic D or D; muscarinic; or benzodiazepine receptors.
The therapeutic activity of naratriptan in migraine is generally attributed to its agonist activity at 5-HT receptors. Two current theories have been proposed to explain the efficacy of 5-HT receptor agonists in migraine. One theory suggests that activation of 5-HT receptors located on intracranial blood vessels, including those on the arteriovenous anastomoses, leads to vasoconstriction, which is correlated with the relief of migraine headache. The other hypothesis suggests that activation of 5-HT receptors on sensory nerve endings in the trigeminal system results in the inhibition of pro-inflammatory neuropeptide release.
In the anesthetized dog, naratriptan has been shown to reduce the carotid arterial blood flow with little or no effect on arterial blood pressure or total peripheral resistance. While the effect on blood flow was selective for the carotid arterial bed, increases in vascular resistance of up to 30% were seen in the coronary arterial bed. Naratriptan has also been shown to inhibit trigeminal nerve activity in rat and cat. In 10 human subjects with suspected coronary artery disease (CAD) undergoing coronary artery catheterization, there was a 1% to 10% reduction in coronary artery diameter following subcutaneous injection of 1.5 mg of naratriptan.
Naratriptan tablets are well absorbed, with about 70% oral bioavailability. Following administration of a 2.5-mg tablet orally, the peak concentrations are obtained in 2 to 3 hours. After administration of 1- or 2.5-mg tablets, the C is somewhat (about 50%) higher in women (not corrected for milligram-per-kilogram dose) than in men. During a migraine attack, absorption was slower, with a T of 3 to 4 hours. Food does not affect the pharmacokinetics of naratriptan. Naratriptan displays linear kinetics over the therapeutic dose range.
The steady-state volume of distribution of naratriptan is 170 L. Plasma protein binding is 28% to 31% over the concentration range of 50 to 1,000 ng/mL.
Naratriptan is predominantly eliminated in urine, with 50% of the dose recovered unchanged and 30% as metabolites in urine. In vitro, naratriptan is metabolized by a wide range of cytochrome P450 isoenzymes into a number of inactive metabolites.
The mean elimination half-life of naratriptan is 6 hours. The systemic clearance of naratriptan is 6.6 mL/min/kg. The renal clearance (220 mL/min) exceeds glomerular filtration rate, indicating active tubular secretion. Repeat administration of naratriptan tablets does not result in drug accumulation.
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In normal volunteers, coadministration of single doses of naratriptan tablets and alcohol did not result in substantial modification of naratriptan pharmacokinetic parameters.
From population pharmacokinetic analyses, coadministration of naratriptan and fluoxetine, beta-blockers, or tricyclic antidepressants did not affect the clearance of naratriptan.
Naratriptan does not inhibit monoamine oxidase (MAO) enzymes and is a poor inhibitor of P450; metabolic interactions between naratriptan and drugs metabolized by P450 or MAO are therefore unlikely.
Smoking increased the clearance of naratriptan by 30%.
Amerge () Clinical Trials
The efficacy of Amerge () Tablets in the acute treatment of migraine headaches was evaluated in 6 randomized, double-blind, placebo-controlled studies of which 4 used the recommended dosing regimen and were conducted as outpatient trials. Three of these studies enrolled adult patients who were predominantly female (86%) and Caucasian (96%) with a mean age of 41 (range: 18 to 65). One study enrolled adolescents with a mean age of 14 (range: 12 to 17). In the adolescent study, 54% of the patients were female and 89% were Caucasian. In all studies, patients were instructed to treat at least 1 moderate to severe headache. Headache response, defined as a reduction in headache severity from moderate or severe pain to mild or no pain, was assessed up to 4 hours after dosing. Associated symptoms such as nausea, vomiting, photophobia, and phonophobia were also assessed. Maintenance of response was assessed for up to 24 hours postdose. A second dose of Amerge () Tablets or other medication was allowed 4 to 24 hours after the initial treatment for recurrent headache. The frequency and time to use of these additional treatments were also determined.
In all 3 trials in adults utilizing the recommended dosage regimen and outpatient use, the percentage of patients achieving headache response 4 hours after treatment, the primary outcome measure, was significantly greater among patients receiving Amerge () compared to those who received placebo. In all studies, response to 2.5 mg was numerically greater than response to 1 mg and in the largest of the 3 studies, there was a statistically significant greater percentage of patients with headache response at 4 hours in the 2.5-mg group compared to the 1-mg group. The results are summarized in Table 1.
In the single study in adolescents, there were no statistically significant differences between any of the treatment groups. The headache response rates at 4 hours (n) were 65% (n = 74), 67% (n = 78), and 64% (n = 70) for placebo, 1-mg, and 2.5-mg groups, respectively.
The estimated probability of achieving an initial headache response in adults over the 4 hours following treatment is depicted in Figure 1.
For patients with migraine-associated nausea, photophobia, and phonophobia at baseline, there was a lower incidence of these symptoms 4 hours following administration of 1- and 2.5-mg Amerge () Tablets compared to placebo.
Four to 24 hours following the initial dose of study treatment, patients were allowed to use additional treatment for pain relief in the form of a second dose of study treatment or other medication. The estimated probability of patients taking a second dose or other medication for migraine over the 24 hours following the initial dose of study treatment is summarized in Figure 2.
There is no evidence that doses of 5 mg provide a greater effect than 2.5 mg. There was no evidence to suggest that treatment with Amerge () was associated with an increase in the severity or frequency of migraine attacks. The efficacy of Amerge () Tablets was unaffected by presence of aura; gender, age, or weight of the patient; oral contraceptive use; or concomitant use of common migraine prophylactic drugs (e.g., beta-blockers, calcium channel blockers, tricyclic antidepressants). There was insufficient data to assess the impact of race on efficacy.
Amerge () Indications And Usage
Amerge () Tablets are indicated for the acute treatment of migraine attacks with or without aura in adults.
Amerge () Tablets are not intended for the prophylactic therapy of migraine or for use in the management of hemiplegic or basilar migraine (see CONTRAINDICATIONS). Safety and effectiveness of Amerge () Tablets have not been established for cluster headache, which is present in an older, predominantly male population.
Amerge () Warnings
Amerge () Tablets should only be used where a clear diagnosis of migraine has been established.
Because of the potential of this class of compounds (5-HT agonists) to cause coronary vasospasm, naratriptan should not be given to patients with documented ischemic or vasospastic coronary artery disease (CAD) (see CONTRAINDICATIONS). It is strongly recommended that 5-HT agonists (including naratriptan) not be given to patients in whom unrecognized CAD is predicted by the presence of risk factors (e.g., hypertension, hypercholesterolemia, smoker, obesity, diabetes, strong family history of CAD, female with surgical or physiological menopause, male over 40 years of age) unless a cardiovascular evaluation provides satisfactory clinical evidence that the patient is reasonably free of coronary artery and ischemic myocardial disease or other significant underlying cardiovascular disease. The sensitivity of cardiac diagnostic procedures to detect cardiovascular disease or predisposition to coronary artery vasospasm is modest, at best. If, during the cardiovascular evaluation, the patient’s medical history, electrocardiographic, or other investigations reveal findings indicative of, or consistent with, coronary artery vasospasm or myocardial ischemia, naratriptan should not be administered (see CONTRAINDICATIONS).
For patients with risk factors predictive of CAD, who are determined to have a satisfactory cardiovascular evaluation, it is strongly recommended that administration of the first dose of naratriptan take place in the setting of a physician’s office or similar medically staffed and equipped facility. Because cardiac ischemia can occur in the absence of clinical symptoms, consideration should be given to obtaining on the first occasion of use an electrocardiogram (ECG) during the interval immediately following administration of Amerge () Tablets, in these patients with risk factors.
It is recommended that patients who are intermittent long-term users of 5-HT agonists, including Amerge () Tablets, and who have or acquire risk factors predictive of CAD, as described above, undergo periodic cardiovascular evaluation as they continue to use Amerge () Tablets.
The systematic approach described above is intended to reduce the likelihood that patients with unrecognized cardiovascular disease will be inadvertently exposed to naratriptan.
Naratriptan can cause coronary artery vasospasm (see CLINICAL PHARMACOLOGY). Serious adverse cardiac events, including acute myocardial infarction, life-threatening disturbances of cardiac rhythm, and death have been reported within a few hours following the administration of 5-HT agonists. Considering the extent of use of 5-HT agonists in patients with migraine, the incidence of these events is extremely low.
In healthy volunteers, dose-related increases in systemic blood pressure have been observed after administration of up to 20 mg of oral naratriptan. At the recommended doses, the elevations are generally small, although an increase of systolic pressure of 32 mmHg was seen in 1 patient following a single 2.5-mg dose. The effect may be more pronounced in the elderly and hypertensive patients. A patient who was mildly hypertensive (the baseline blood pressure was 150/98) experienced a significant increase in blood pressure to 204/144 mmHg 225 minutes after administration of a 10-mg oral dose. Significant elevation in blood pressure, including hypertensive crisis, has been reported on rare occasions in patients receiving 5-HT agonists with and without a history of hypertension. Naratriptan is contraindicated in patients with uncontrolled hypertension (see CONTRAINDICATIONS).
An 18% increase in mean pulmonary artery pressure and an 8% increase in mean aortic pressure was seen following dosing with 1.5 mg of subcutaneous naratriptan in a study evaluating 10 subjects with suspected CAD undergoing cardiac catheterization.
Amerge () Precautions
Chest discomfort (including pain, pressure, heaviness, tightness) has been reported after administration of 5-HT agonists, including Amerge () Tablets. These events have not been associated with arrhythmias or ischemic ECG changes in clinical trials with Amerge () Tablets. Because naratriptan may cause coronary artery vasospasm, patients who experience signs or symptoms suggestive of angina following naratriptan should be evaluated for the presence of CAD or a predisposition to Prinzmetal variant angina before receiving additional doses of naratriptan, and should be monitored electrocardiographically if dosing is resumed and similar symptoms recur. Similarly, patients who experience other symptoms or signs suggestive of decreased arterial flow, such as ischemic bowel syndrome or Raynaud syndrome following naratriptan administration should be evaluated for atherosclerosis or predisposition to vasospasm (see CONTRAINDICATIONS and WARNINGS).
Amerge () Tablets should also be administered with caution to patients with diseases that may alter the absorption, metabolism, or excretion of drugs, such as impaired renal or hepatic function (see CLINICAL PHARMACOLOGY, CONTRAINDICATIONS, and DOSAGE AND ADMINISTRATION).
Care should be taken to exclude other potentially serious neurological conditions before treating headache in patients not previously diagnosed with migraine or who experience a headache that is atypical for them. There have been rare reports where patients received 5-HT agonists for severe headaches that were subsequently shown to have been secondary to an evolving neurologic lesion (see WARNINGS).
For a given attack, if a patient has no response to the first dose of Amerge () , the diagnosis of migraine should be reconsidered before administration of a second dose.
Overuse of acute migraine treatments has been associated with the exacerbation of headache (medication overuse headache) in susceptible patients. Withdrawal of the treatment may be necessary.
See PATIENT INFORMATION at the end of the full prescribing information for the text of the separate leaflet provided for patients.
Patients should be cautioned about the risk of serotonin syndrome with the use of naratriptan or other triptans, especially during combined use with SSRIs or SNRIs.
In a study in which rats were dosed orally with 10, 60, or 340 mg/kg/day for 6 months, changes in the female reproductive tract including atrophic or cystic ovaries and anestrus were seen at the high dose. The exposure at the no-effect dose of 60 mg/kg was approximately 85 times the exposure in humans receiving the MRDD.
Pregnancy Category C. There are no adequate and well-controlled studies in pregnant women; therefore, naratriptan should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
To monitor fetal outcomes of pregnant women exposed to Amerge () , GlaxoSmithKline maintains a Naratriptan Pregnancy Registry. Healthcare providers are encouraged to register patients by calling (800) 336-2176.
In reproductive toxicity studies in rats and rabbits, oral administration of naratriptan was associated with developmental toxicity (embryolethality, fetal abnormalities, pup mortality, offspring growth retardation) at doses producing maternal plasma drug exposures as low as 11 and 2.5 times, respectively, the exposure in humans receiving the MRDD of 5 mg.
When pregnant rats were administered naratriptan during the period of organogenesis at doses of 10, 60, or 340 mg/kg/day, there was a dose-related increase in embryonic death, with a statistically significant difference at the highest dose, and incidences of fetal structural variations (incomplete/irregular ossification of skull bones, sternebrae, ribs) were increased at all doses. The maternal plasma exposures (AUC) at these doses were approximately 11, 70, and 470 times the exposure in humans at the MRDD. The high dose was maternally toxic, as evidenced by decreased maternal body weight gain during gestation. A no-effect dose for developmental toxicity in rats exposed during organogenesis was not established.
When doses of 1, 5, or 30 mg/kg/day were given to pregnant Dutch rabbits throughout organogenesis, the incidence of a specific fetal skeletal malformation (fused sternebrae) was increased at the high dose, and increased incidences of embryonic death and fetal variations (major blood vessel variations, supernumerary ribs, incomplete skeletal ossification) were observed at all doses (4, 20, and 120 times, respectively, the MRDD on a body surface area basis). Maternal toxicity (decreased body weight gain) was evident at the high dose in this study. In a similar study in New Zealand White rabbits (1, 5, or 30 mg/kg/day throughout organogenesis), decreased fetal weights and increased incidences of fetal skeletal variations were observed at all doses (maternal exposures equivalent to 2.5, 19, and 140 times exposure in humans receiving the MRDD), while maternal body weight gain was reduced at 5 mg/kg or greater. A no-effect dose for developmental toxicity in rabbits exposed during organogenesis was not established.
When female rats were treated with 10, 60, or 340 mg/kg/day during late gestation and lactation, offspring behavioral impairment (tremors) and decreased offspring viability and growth were observed at doses of 60 mg/kg or greater, while maternal toxicity occurred only at the highest dose. Maternal exposures at the no-effect dose for developmental effects in this study were approximately 11 times the exposure in humans receiving the MRDD.
Safety and effectiveness of Amerge () Tablets in pediatric patients (younger than 18 years) have not been established.
One randomized, placebo-controlled clinical trial evaluating oral naratriptan (0.25 to 2.5 mg) in pediatric patients aged 12 to 17 years evaluated a total of 300 adolescent migraineurs. This study did not establish the efficacy of oral naratriptan compared to placebo in the treatment of migraine in adolescents (see CLINICAL TRIALS). Adverse events observed in this clinical trial were similar in nature to those reported in clinical trials in adults.
The use of Amerge () Tablets in elderly patients is not recommended.
Naratriptan is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in elderly patients who have reduced renal function. In addition, elderly patients are more likely to have decreased hepatic function; they are at higher risk for CAD; and blood pressure increases may be more pronounced in the elderly. Clinical studies of Amerge () Tablets did not include patients over 65 years of age.
Amerge () Adverse Reactions
Serious cardiac events, including some that have been fatal, have occurred following the use of 5-HT agonists. These events are extremely rare and most have been reported in patients with risk factors predictive of CAD. Events reported have included coronary artery vasospasm, transient myocardial ischemia, myocardial infarction, ventricular tachycardia, and ventricular fibrillation (see CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS).
The most common adverse events were paresthesias, dizziness, drowsiness, malaise/fatigue, and throat/neck symptoms, which occurred at a rate of 2% and at least 2 times placebo rate. Since patients treated only 1 to 3 headaches in the controlled clinical trials, the opportunity for discontinuation of therapy in response to an adverse event was limited. In a long-term, open-label study where patients were allowed to treat multiple migraine attacks for up to 1 year, 15 patients (3.6%) discontinued treatment due to adverse events.
Table 2 lists adverse events that occurred in 5 placebo-controlled clinical trials of approximately 1,752 exposures to placebo and Amerge () Tablets in adult migraine patients. The events cited reflect experience gained under closely monitored conditions of clinical trials in a highly selected patient population. In actual clinical practice or in other clinical trials, these frequency estimates may not apply, as the conditions of use, reporting behavior, and the kinds of patients treated may differ. Only events that occurred at a frequency of 2% or more in the group treated with Amerge () Tablets 2.5 mg and were more frequent in that group than in the placebo group are included in Table 2. From this table, it appears that many of these adverse events are dose related.
One event (vomiting) present in more than 1% of patients receiving Amerge () Tablets occurred more frequently on placebo than on naratriptan 2.5 mg.
Amerge () Tablets are generally well tolerated. Most adverse reactions were mild and transient.
The incidence of adverse events in placebo-controlled clinical trials was not affected by age or weight of the patients, duration of headache prior to treatment, presence of aura, use of prophylactic medications, or tobacco use. There was insufficient data to assess the impact of race on the incidence of adverse events.
In the paragraphs that follow, the frequencies of less commonly reported adverse clinical events are presented. Because the reports include events observed in open and uncontrolled studies, the role of Amerge () Tablets in their causation cannot be reliably determined. Furthermore, variability associated with adverse event reporting, the terminology used to describe adverse events, etc., limit the value of the quantitative frequency estimates provided. Event frequencies are calculated as the number of patients reporting an event divided by the total number of patients (n = 3,557) exposed to oral naratriptan doses up to 10 mg. All reported events are included except those already listed in the previous table, those too general to be informative, and those not reasonably associated with the use of the drug. Events are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse events are those occurring in at least 1/100 patients, infrequent adverse events are those occurring in 1/100 to 1/1,000 patients, and rare adverse events are those occurring in fewer than 1/1,000 patients.
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The following section enumerates potentially important adverse events that have occurred in clinical practice and that have been reported spontaneously to various surveillance systems. The events enumerated represent reports arising from both domestic and nondomestic use of naratriptan. These events do not include those already listed in the ADVERSE REACTIONS section above. Because the reports cite events reported spontaneously from worldwide postmarketing experience, frequency of events and the role of naratriptan in their causation cannot be reliably determined.
Amerge () Drug Abuse And Dependence
In one clinical study enrolling 12 subjects, all of whom had experience using oral opiates and other psychoactive drugs, Amerge () Tablets produced less intense subjective responses ordinarily associated with many drugs of abuse than did codeine (30 to 90 mg).
Amerge () Overdosage
A patient who was mildly hypertensive experienced a significant increase in blood pressure after administration of a 10-mg dose starting at 30 minutes (baseline value of 150/98 to 204/144 mmHg 225 minutes). This event resolved after treatment with antihypertensive therapy. Oral administration of 25 mg of naratriptan in 1 healthy young male subject increased blood pressure from 120/67 mmHg pretreatment up to 191/113 mmHg at approximately 6 hours postdose and resulted in adverse events including lightheadedness, tension in the neck, tiredness, and loss of coordination. Blood pressure returned to near baseline by 8 hours after dosing without any pharmacological intervention.
Another subject experienced asymptomatic ischemic ECG changes likely due to coronary artery vasospasm approximately 2 hours following a 7.5-mg oral dose.
The elimination half-life of naratriptan is about 6 hours (see CLINICAL PHARMACOLOGY), and therefore monitoring of patients after overdose with Amerge () Tablets should continue for at least 24 hours or while symptoms or signs persist. There is no specific antidote to naratriptan. Standard supportive treatment should be applied as required. If the patient presents with chest pain or other symptoms consistent with angina pectoris, ECG monitoring should be performed for evidence of ischemia. It is unknown what effect hemodialysis or peritoneal dialysis has on the serum concentrations of naratriptan.
Amerge () Dosage And Administration
In controlled clinical trials, single doses of 1 and 2.5 mg of Amerge () Tablets taken with fluid were effective for the acute treatment of migraines in adults. A greater proportion of patients had headache response following a 2.5-mg dose than following a 1-mg dose (see CLINICAL TRIALS). Individuals may vary in response to doses of Amerge () Tablets. The choice of dose should therefore be made on an individual basis, weighing the possible benefit of the 2.5-mg dose with the potential for a greater risk of adverse events. If the headache returns or if the patient has only partial response, the dose may be repeated once after 4 hours, for a maximum dose of 5 mg in a 24-hour period. There is evidence that doses of 5 mg do not provide a greater effect than 2.5 mg.
The safety of treating, on average, more than 4 headaches in a 30-day period has not been established.
Amerge () How Supplied
Amerge () Tablets 1 and 2.5 mg of naratriptan (base) as the hydrochloride. Amerge () Tablets, 1 mg, are white, D-shaped, film-coated tablets debossed with “GX CE3” on one side in blister packs of 9 tablets (NDC 0173-0561-00). Amerge () Tablets, 2.5 mg, are green, D-shaped, film-coated tablets debossed with “GX CE5” on one side in blister packs of 9 tablets (NDC 0173-0562-00).
This product's prescribing information may have been updated. Please refer to www.gsk.com for the most current version.
GlaxoSmithKline
Research Triangle Park, NC 27709
©2010, GlaxoSmithKline. All rights reserved.
February 2010
AMG:2PI
Amerge () Patient Information
The following wording is contained in a separate leaflet provided for patients.
Read this leaflet carefully before you start to take Amerge () Tablets. Keep the leaflet for reference because it gives you a summary of important information about Amerge () Tablets.
Read the leaflet that comes with each refill of your prescription because there may be new information.
This leaflet does not have all the information about Amerge () Tablets. Ask your healthcare provider for more information or advice.
Amerge () is a kind of medicine called a triptan. You should take it only if you have a prescription.
Amerge () is used to relieve your migraine. It is used to prevent attacks or reduce the number of attacks you have. Use Amerge () only to treat an actual migraine attack.
The decision to use Amerge () Tablets is one that you and your healthcare provider should make together, based on your personal needs and health.
Remember, if you answered to any of the above questions, then talk with your healthcare provider about it.
Amerge () , IMITREX, and PAXIL are registered trademarks of GlaxoSmithKline. The other brands listed are trademarks of their respective owners and are not trademarks of GlaxoSmithKline. The makers of these brands are not affiliated with and do not endorse GlaxoSmithKline or its products.
GlaxoSmithKline
Research Triangle Park, NC 27709
©2010, GlaxoSmithKline. All rights reserved.
February 2010
AMG:2PIL
Amerge () Principal Display Panel
9 Tablets
R only
Each tablet contains 1 mg of naratriptan as the hydrochloride.
Store at controlled room temperature, 20 to 25C (68 to 77F) (see USP).
GlaxoSmithKline
Research Triangle Park, NC 27709
Made in Singapore
©2007, GlaxoSmithKline
Amerge () Principal Display Panel
9 Tablets
R only
Each tablet contains 2.5 mg of naratriptan as the hydrochloride.
Store at controlled room temperature, 20 to 25C (68 to 77F) (see USP).
GlaxoSmithKline
Research Triangle Park, NC 27709
Made in Singapore
