"Nov. 13, 2012 -- Women who get migraines are more likely than those who don't to develop small areas of tissue changes in their brains, a new study shows. At the same time, these changes do not seem to affect the women's thinking or memory."...
Mechanism of Action
Naratriptan binds with high affinity to 5-HT1D and 5-HT1B receptors and has no significant affinity or pharmacological activity at 5-HT2-4 receptor subtypes or at adrenergic α1, α2, or β; dopaminergic D1 or D2; muscarinic; or benzodiazepine receptors.
The therapeutic activity of naratriptan in migraine is generally attributed to its agonist activity at 5-HT1D/1B receptors. Two current theories have been proposed to explain the efficacy of 5-HT1D/1B receptor agonists in migraine. One theory suggests that activation of 5-HT1D/1B 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-HT1D/1B 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 Cmax 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 Tmax 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.
Age: A small decrease in clearance (approximately 26%) was observed in healthy elderly subjects (65 to 77 years) compared to younger patients, resulting in slightly higher exposure (see PRECAUTIONS).
Race: The effect of race on the pharmacokinetics of naratriptan has not been examined.
Renal Impairment: Clearance of naratriptan was reduced by 50% in patients with moderate renal impairment (creatinine clearance, 18 to 39 mL/min) compared to the normal group. Decrease in clearances resulted in an increase of mean half-life from 6 hours (healthy) to 11 hours (range, 7 to 20 hours). The mean Cmax increased by approximately 40%. The effects of severe renal impairment (creatinine clearance, ≤ 15 mL/min) on the pharmacokinetics of naratriptan has not been assessed (see CONTRAINDICATIONS and DOSAGE AND ADMINISTRATION).
Hepatic Impairment: Clearance of naratriptan was decreased by 30% in patients with moderate hepatic impairment (Child-Pugh grade A or B). This resulted in an approximately 40% increase in the half-life (range, 8 to 16 hours). The effects of severe hepatic impairment (Child-Pugh grade C) on the pharmacokinetics of naratriptan have not been assessed (see CONTRAINDICATIONS and DOSAGE AND ADMINISTRATION).
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.
Oral Contraceptives: Oral contraceptives reduced clearance by 32% and volume of distribution by 22%, resulting in slightly higher concentrations of naratriptan. Hormone replacement therapy had no effect on pharmacokinetics in older female patients.
Smoking increased the clearance of naratriptan by 30%.
The efficacy of AMERGE (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 AMERGE (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 AMERGE (naratriptan) 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.
Table 1: Percentage of Adult Patients With Headache Response
(Mild or No Headache) 4 Hours Following Treatment
|Placebo||AMERGE 1.0 mg||AMERGE 2.5 mg|
|Study 1||34% (n = 122)||50%* (n = 117)||60%* (n = 127)|
|Study 2||27% (n = 104)||52%* (n = 208)||66%*† (n = 199)|
|Study 3||32% (n = 169)||54%* (n = 166)||65%* (n = 167)|
|*p < 0.05 in comparison with placebo.
†p < 0.05 in comparison with 1 mg.
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.
Comparisons of drug performance based upon results obtained in different clinical trials are never reliable. Because studies are conducted at different times, with different samples of patients, by different investigators, employing different criteria and/or different interpretations of the same criteria, under different conditions (dose, dosing regimen, etc.), quantitative estimates of treatment response and the timing of response may be expected to vary considerably from study to study.
The estimated probability of achieving an initial headache response in adults over the 4 hours following treatment is depicted in Figure 1.
Figure 1: Estimated Probability of Achieving Initial Headache
Response Within 4 Hours*
* The figure shows the probability over time of obtaining headache response (no or mild pain) following treatment with AMERGE (naratriptan) Tablets. The averages displayed are based on pooled data from the 3 controlled clinical trials providing evidence of efficacy (Studies 1, 2, and 3). In this Kaplan-Meier plot, patients not achieving response within 240 minutes were censored at 240 minutes.
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 (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 Figure 2.
Figure 2: Estimated Probability of Patients Taking a Second
Dose of AMERGE (naratriptan) Tablets or Other Medication for Migraine Over the 24 Hours Following
the Initial Dose of Study Treatment*
* Kaplan-Meier plot based on data obtained in the 3 controlled clinical trials (Studies 1, 2, and 3) providing evidence of efficacy with patients not using additional treatments censored at 24 hours. The plot also includes patients who had no response to the initial dose. Remedication was discouraged prior to 4 hours postdose.
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 (naratriptan) was associated with an increase in the severity or frequency of migraine attacks. The efficacy of AMERGE (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.
Last reviewed on RxList: 9/3/2010
This monograph has been modified to include the generic and brand name in many instances.
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