Naratriptan Information
Naratriptan () Description
Naratriptan () tablets USP contain Naratriptan () as the hydrochloride, which is a selective 5-hydroxytryptamine receptor subtype agonist. Naratriptan () hydrochloride is chemically designated as -methyl-3-(1-methyl-4-piperidinyl)-1-indole-5-ethanesulfonamide monohydrochloride, and it has the following structure:
CHNOS•HCl M.W. 371.93
Naratriptan () hydrochloride is a white to pale yellow powder that is readily soluble in water. Each Naratriptan () tablet USP 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 these inactive ingredients: croscarmellose sodium, FD&C Blue #1 Aluminum Lake, hydroxypropyl cellulose, iron oxide black, iron oxide yellow, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol-part. hydrolyzed, talc, and titanium dioxide.
Naratriptan () 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. , 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.
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.
Naratriptan () Clinical Trials
The efficacy of Naratriptan () 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 Naratriptan () 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 Naratriptan () tablets 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 .
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 .
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 Naratriptan () 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 .
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 Naratriptan () tablets was associated with an increase in the severity or frequency of migraine attacks. The efficacy of Naratriptan () 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.
Naratriptan () Indications And Usage
Naratriptan () tablets are indicated for the acute treatment of migraine attacks with or without aura in adults.
Naratriptan () tablets are not intended for the prophylactic therapy of migraine or for use in the management of hemiplegic or basilar migraine (see ). Safety and effectiveness of Naratriptan () tablets have not been established for cluster headache, which is present in an older, predominantly male population.
Naratriptan () Warnings
Naratriptan () 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, or 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 Naratriptan () tablets, in these patients with risk factors.
It is recommended that patients who are intermittent long-term users of 5-HT agonists, including Naratriptan () tablets, and who have or acquire risk factors predictive of CAD, as described above, undergo periodic cardiovascular evaluation as they continue to use Naratriptan () tablets.
The systematic approach described above is intended to reduce the likelihood that patients with unrecognized cardiovascular disease will be inadvertently exposed to Naratriptan () .
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 ).
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.
Naratriptan () Precautions
Chest discomfort (including pain, pressure, heaviness, tightness) has been reported after administration of 5-HT agonists, including Naratriptan () tablets. These events have not been associated with arrhythmias or ischemic ECG changes in clinical trials with Naratriptan () 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 and ).
Naratriptan () 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 , , and ).
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 ).
For a given attack, if a patient has no response to the first dose of Naratriptan () tablets, the diagnosis of migraine should be reconsidered before administration of a second dose.
Safety and effectiveness of Naratriptan () 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 ). Adverse events observed in this clinical trial were similar in nature to those reported in clinical trials in adults.
The use of Naratriptan () 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 Naratriptan () tablets did not include patients over 65 years of age.
Naratriptan () 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.
One event (vomiting) present in more than 1% of patients receiving Naratriptan () tablets occurred more frequently on placebo than on Naratriptan () 2.5 mg.
Naratriptan () 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.
Naratriptan () Drug Abuse And Dependence
In one clinical study enrolling 12 subjects, all of whom had experience using oral opiates and other psychoactive drugs, Naratriptan () tablets produced less intense subjective responses ordinarily associated with many drugs of abuse than did codeine (30 to 90 mg).
Naratriptan () 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 ), and therefore monitoring of patients after overdose with Naratriptan () 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 () .
Naratriptan () Dosage And Administration
In controlled clinical trials, single doses of 1 and 2.5 mg of Naratriptan () 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 ). Individuals may vary in response to doses of Naratriptan () tablets USP. 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.
Naratriptan () How Supplied
Naratriptan () tablets USP are available as:
1 mg – light gray, D-shaped, film-coated tablets, debossed with “93” on one side of the tablet, and “8522” on the other side of the tablet, in unit-of-use blisters of 9.
2.5 mg – green, D-shaped, film-coated tablets, debossed with “93” on one side of the tablet, and “8523” on the other side of the tablet, in unit-of-use blisters of 9.
Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].
Manufactured In Canada By:
Toronto, Canada M1B 2K9
Manufactured For:
Sellersville, PA 18960
Rev. A 8/2010
The following wording is contained in a separate leaflet provided for patients.
Naratriptan () Information For The Patient
Please read this leaflet carefully before you take Naratriptan () tablets USP. This leaflet provides a summary of the information available about your medicine. Please do not throw away this leaflet until you have finished your medicine. You may need to read this leaflet again. This leaflet does not contain all the information on Naratriptan () tablets USP. For further information or advice, ask your doctor or pharmacist.
The name of your medicine is Naratriptan () tablets USP. It can be obtained only by prescription from your doctor. The decision to use Naratriptan () tablets USP is one that you and your doctor should make jointly, taking into account your individual preferences and medical circumstances. If you have risk factors for heart disease (such as high blood pressure, high cholesterol, obesity, diabetes, smoking, strong family history of heart disease, or you are postmenopausal or a male over 40), you should tell your doctor, who should evaluate you for heart disease in order to determine if Naratriptan () tablets USP are appropriate for you. The majority of those who have taken Naratriptan () tablets USP have not experienced any significant side effects. Rarely, deaths and/or serious heart problems have been reported with this class of medicines; in all but a few instances, however, these deaths and/or serious heart problems occurred in people with heart disease and it was not clear whether these medicines were a contributing factor.
Naratriptan () tablets USP are intended to relieve your migraine, but not to prevent or reduce the number of attacks you experience. Use Naratriptan () tablets USP only to treat an actual migraine attack.
If the answer to any of the following questions is or if you do not know the answer, then please discuss it with your doctor before you use Naratriptan () tablets USP.
Remember, if you answered to any of the above questions, then discuss it with your doctor.
Do not use Naratriptan () tablets USP if you are pregnant, think you might be pregnant, are trying to become pregnant, or are not using adequate contraception, unless you have discussed this with your doctor.
For adults, the usual dose is a single tablet taken whole with fluids. It may be given at any time after the headache starts. For an individual attack, if you have no response to the first tablet, do not take a second tablet without first talking to your doctor. If you need more relief due to a partial response or return of your headache after the first tablet, a second tablet may be taken, but not sooner than 4 hours following the first tablet. Do not take more than a total of 2 Naratriptan () tablets USP in any 24 hour period. If you have kidney or liver disease, take as directed by your doctor.
If you have taken more medicine than you have been told, contact either your doctor, hospital emergency department, or nearest poison control center immediately.
All brand names listed are the registered trademarks of their respective owners and are not trademarks of Teva Pharmaceuticals USA.
Manufactured In Canada By:
Toronto, Canada M1B 2K9
Manufactured For:
Sellersville, PA 18960
Rev. A 8/2010
Naratriptan () Principal Display Panel
Naratriptan () TABLETS USP
1 mg*
*
PHARMACIST: Please dispense the patient information leaflet with the drug product.
Rx only
9 TABLETS (1 BLISTER CARD)
TEVA
Naratriptan () Principal Display Panel
Naratriptan () TABLETS USP
2.5 mg*
*
PHARMACIST: Please dispense the patient information leaflet with the drug product.
Rx only
9 TABLETS (1 BLISTER CARD)
TEVA
