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Mechanism of Action
Zolmitriptan binds with high affinity to human recombinant 5HT1D and 5-HT1B receptors, and moderate affinity for 5-HT1A receptors. The N-desmethyl metabolite also has high affinity for 5-HT1B/1D and moderate affinity for 5-HT1A receptors.
Migraines are likely due to local cranial vasodilatation and/or to the release of sensory neuropeptides (vasoactive intestinal peptide, substance P and calcitonin gene-related peptide) through nerve endings in the trigeminal system. The therapeutic activity of ZOMIG for the treatment of migraine headache is thought to be due to the agonist effects at the 5-HT1B/1D receptors on intracranial blood vessels (including the arterio-venous anastomoses) and sensory nerves of the trigeminal system which result in cranial vessel constriction and inhibition of pro-inflammatory neuropeptide release.
Absorption, Distribution, Metabolism, and Excretion
Zolmitriptan is well absorbed after oral administration for both ZOMIG tablets and the ZOMIG-ZMT orally disintegrating tablets. Zolmitriptan displays linear kinetics over the dose range of 2.5 to 50 mg.
The AUC and Cmax of zolmitriptan are similar following administration of ZOMIG tablets and ZOMIG-ZMT orally disintegrating tablets, but the Tmax is somewhat later with ZOMIG-ZMT, with a median Tmax of 3 hours for ZOMIG-ZMT orally disintegrating tablet compared with 1.5 hours for the ZOMIG tablet. The AUC, Cmax, and Tmax for the active N-desmethyl metabolite are similar for the two formulations.
During a moderate to severe migraine attack, mean AUC0-4 and Cmax for zolmitriptan, dosed as a ZOMIG tablet, were decreased by 40% and 25%, respectively, and mean Tmax was delayed by one-half hour compared to the same patients during a migraine free period.
Food has no significant effect on the bioavailability of zolmitriptan. No accumulation occurred on multiple dosing.
Mean absolute bioavailability is approximately 40%. The mean apparent volume of distribution is 7.0 L/kg. Plasma protein binding of zolmitriptan is 25% over the concentration range of 10- 1000 ng/mL.
Zolmitriptan is converted to an active N-desmethyl metabolite; the metabolite concentrations are about two-thirds that of zolmitriptan. Because the 5HT1B/1D potency of the metabolite is 2 to 6 times that of the parent compound, the metabolite may contribute a substantial portion of the overall effect after ZOMIG administration.
Total radioactivity recovered in urine and feces was 65% and 30% of the administered dose, respectively. About 8% of the dose was recovered in the urine as unchanged zolmitriptan. Indole acetic acid metabolite accounted for 31% of the dose, followed by N-oxide (7%) and N-desmethyl (4%) metabolites. The indole acetic acid and N-oxide metabolites are inactive.
Mean total plasma clearance is 31.5 mL/min/kg, of which one-sixth is renal clearance. The renal clearance is greater than the glomerular filtration rate suggesting renal tubular secretion.
In patients with severe hepatic impairment, the mean Cmax, Tmax, and AUC0-∞ of zolmitriptan were increased 1.5-fold, 2-fold (2 vs. 4 hours), and 3-fold, respectively, compared to subjects with normal hepatic function. Seven out of 27 patients experienced 20 to 80 mm Hg elevations in systolic and/or diastolic blood pressure after a 10 mg ZOMIG dose. Adjust the ZOMIG Dose in patients with moderate or severe hepatic impairment [see DOSAGE AND ADMINISTRATION and Use In Specific Populations].
Clearance of zolmitriptan was reduced by 25% in patients with severe renal impairment (Clcr ≥ 5 ≤ 25 mL/min) compared to subjects with normal renal function (Clcr > = 70 mL/min); no significant change in clearance was observed in patients with moderate renal impairment (Clcr ≥ 26 ≤ 50 mL/min).
Zolmitriptan pharmacokinetics in healthy elderly nonmigraineur volunteers (age 65–76 years) was similar to those in younger non-migraineur volunteers (age 18 - 39 years).
Mean plasma concentrations of zolmitriptan were up to 1.5fold higher in females than males.
Retrospective analysis of pharmacokinetic data between Japanese and Caucasians revealed no significant differences.
No differences in the pharmacokinetics of zolmitriptan or its effects on blood pressure were seen in mild to moderate hypertensive volunteers compared with normotensive controls.
Drug Interaction Studies
All drug interaction studies were performed in healthy volunteers using a single 10 mg dose of ZOMIG and a single dose of the other drug except where otherwise noted.
Following one week of administration of moclobemide (150 mg twice daily), a specific MAO-A inhibitor, there was an increase of about 25% in both Cmax and AUC for zolmitriptan and a 3-fold increase in the Cmax and AUC of the active Ndesmethyl metabolite of zolmitriptan. MAO inhibitors are contraindicated in ZOMIG-treated patients [see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and DRUG INTERACTIONS].
Selegiline, a selective MAO-B inhibitor, at a dose of 10 mg/day for 1 week, had no effect on the pharmacokinetics of zolmitriptan and its metabolite.
Following the administration of cimetidine, the half-life and AUC of zolmitriptan (5 mg dose), and its active metabolite, were approximately doubled [see DOSAGE AND ADMINISTRATION, DRUG INTERACTIONS].
The pharmacokinetics of zolmitriptan, as well as its effect on blood pressure, were unaffected by 4 weeks of pretreatment with oral fluoxetine (20 mg/day).
Cmax and AUC of zolmitriptan were increased 1.5-fold after one week of dosing with propranolol (160 mg/day). Cmax and AUC of the N-desmethyl metabolite were reduced by 30% and 15%, respectively. There were no changes in blood pressure or pulse rate following administration of propranolol with ZOMIG.
A single 1 gram dose of acetaminophen did not alter the pharmacokinetics of zolmitriptan and its N-desmethyl metabolite. However, ZOMIG administration delayed the Tmax of acetaminophen by one hour.
A single 10 mg dose of metoclopramide had no effect on the pharmacokinetics of zolmitriptan or its metabolites.
Retrospective analysis of pharmacokinetic data across studies indicated that mean Cmax and AUC of zolmitriptan were increased by 30% and 50%, respectively, and Tmax was delayed by one-half hour in women taking oral contraceptives. The effect of ZOMIG on the pharmacokinetics of oral contraceptives has not been studied.
The efficacy of ZOMIG tablets in the acute treatment of migraine headaches was demonstrated in five randomized, double-blind, placebo-controlled studies (Studies 1, 2, 3, 4, and 5), of which two utilized the 1 mg dose, two utilized the 2.5 mg dose and four utilized the 5 mg dose. In Study 1, patients treated their headaches in a clinic setting. In the other studies, patients treated their headaches as outpatients. In Study 4, patients who had previously used sumatriptan were excluded, whereas in the other studies no such exclusion was applied.
Patients enrolled in these 5 studies were predominantly female (82%) and Caucasian (97%) with a mean age of 40 years (range 12-65). Patients were instructed to treat a 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 at 1, 2, and, in most studies, 4 hours after dosing. Associated symptoms such as nausea, photophobia, and phonophobia were also assessed. Maintenance of response was assessed for up to 24 hours post-dose. A second dose of ZOMIG tablets or other medication was allowed 2 to 24 hours after the initial treatment for persistent and recurrent headache. The frequency and time to use of these additional treatments were also recorded. In all studies, the effect of ZOMIG was compared to placebo in the treatment of a single migraine attack.
In all five studies, the percentage of patients achieving headache response 2 hours after treatment was significantly greater among patients who received ZOMIG tablets at all doses (except for the 1 mg dose in the smallest study) compared to those who received placebo. In Studies 1 and 3, there was a statistically significant greater percentage of patients with headache response at 2 hours in the higher dose groups (2.5 and/or 5 mg) compared to the 1 mg dose group. There were no statistically significant differences between the 2.5 and 5 mg dose groups (or of doses up to 20 mg) for the primary end point of headache response at 2 hours in any study. The results of these controlled clinical studies are summarized in Table 1.
Table 2 : Percentage of Patients with Headache Response
(Reduction in Headache Severity from Moderate or Severe Pain to Mild or No
Headache) 2 Hours Following Treatment in Studies 1 through 5
|Placebo||ZOMIG tablets 1 mg||ZOMIG tablets 2.5 mg||ZOMIG tablets 5 mg|
|Study 1a||16% (n=19)||27% (n=22)||NA||60%*# (n=20)|
|Study 2||19% (n=88)||NA||NA||66%* (n=179)|
|Study 3||34% (n=121)||50%* (n=140)||65%*# (n=260)||67%*# (n=245)|
|Study 4b||44% (n=55)||NA||NA||59%* (n=491)|
|Study 5||36% (n=92)||NA NA||62%* (n=178)||NA|
|n=number of patients randomized
*p < 0.05 in comparison with placebo.
#p < 0.05 in comparison with 1 mg.
a Study 1 was the only study in which patients treated the headache in a clinic setting.
b Study 4 was the only study where patients were excluded who had previously used sumatriptan.
NA - not applicable
The estimated probability of achieving an initial headache response by 4 hours following treatment in pooled Studies 2, 3, and 5 is depicted in Figure 1.
Figure 1 : Estimated Probability of Achieving Initial
Headache Response (Reduction in Headache Severity from Moderate or Severe Pain
to Mild or No Headache) Within 4 Hours of Treatment in Pooled Studies 2, 3, and
*In this Kaplan-Meier plot, the averages displayed are based on pooled data from 3 placebo controlled, outpatient trials. Patients not achieving headache response or taking additional treatment prior to 4 hours were censored at 4 hours.
For patients with migraine associated photophobia, phonophobia, and nausea at baseline, there was a decreased incidence of these symptoms following administration of ZOMIG tablets as compared with placebo.
Two 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 : The Estimated Probability Of Patients Taking A
Second Dose Or Other Medication For Migraines Over The 24 Hours Following The
Initial Dose Of Study Treatment in Pooled Studies 2, 3, and 5*
*In this Kaplan-Meier plot,patients not using additional treatments were censored at 24 hours. The plot includes both patients who had headache response at 2 hours and those who had no response to the initial dose. The studies did not allow taking additional doses of study medication within 2 hours post-dose.
The efficacy of ZOMIG was unaffected by presence of aura; duration of headache prior to treatment; relationship to menses; gender, age, or weight of the patient; pre-treatment nausea or concomitant use of common migraine prophylactic drugs.
ZOMIG-ZMT Orally Disintegrating Tablets
The efficacy of ZOMIG-ZMT 2.5 mg orally disintegrating tablets was demonstrated in a randomized, placebo-controlled trial (Study 6) that was similar in design to the trials of ZOMIG tablets. Patients were instructed to treat a moderate to severe headache. Of the 471 patients treated in Study 6, 87% were female and 97% were Caucasian, with a mean age of 41 years (range 18-62).
At 2 hours post-dosing, there was a statistically significant greater percentage of patients treated with ZOMIG-ZMT 2.5 mg with a headache response (reduction in headache severity from moderate or severe pain to mild or no headache) compared to patients treated with placebo (63% vs. 22%). The estimated probability of achieving an initial headache response by 2 hours following treatment with ZOMIG-ZMT orally disintegrating tablets is depicted in Figure 3.
Figure 3 : Estimated Probability of Achieving Initial
Headache Response (Reduction in Headache Severity from Moderate or Severe Pain
to Mild or No Headache) Within 2 Hours in Study 6*
*In this Kaplan-Meier plotpatients taking additional treatment or not achieving headache response prior to 2 hours were censored at 2 hours.
For patients with migraine-associated photophobia, phonophobia and nausea at baseline, there was a decreased incidence of these symptoms following administration of ZOMIG-ZMT as compared to placebo.
Two to 24 hours following the initial dose of study treatment, patients were allowed to use additional treatment 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 in Study 6 is summarized in Figure 4.
Figure 4 : The Estimated Probability of Patients Taking a Second Dose or Other Medication for Migraines Over the 24 Hours Following The Initial Dose of Study Treatment in Study 6*
* In this Kaplan-Meier plot, patients not taking additional treatments were censored at 24 hours. The plot includes both patients who had headache response at 2 hours and those who had no response to the initial dose. Taking another dose of study medication was allowed 2 hours post-dose in Study 6. In contrast to studies of ZOMIG tablets (Studies 1, 2, 3, 4, and 5),
Study 6 allowed re-dosing of ZOMIG-ZMT oral disintegrating tablets prior to 4 hours.
Last reviewed on RxList: 10/1/2012
This monograph has been modified to include the generic and brand name in many instances.
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