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Mechanism of Action

Zolmitriptan binds with high affinity to human recombinant 5-HT_1D and 5-HT_1B receptors. Zolmitriptan exhibits modest affinity for 5-HT_1A receptors, but has no significant affinity (as measured by radioligand binding assays) or pharmacological activity at 5-HT₂, 5-HT₃, 5-HT₄, α₁-, α₂- or β₁-adrenergic; H₁, H₂, histaminic; muscarinic; D₁, or D₂ receptors. The N-desmethyl metabolite also has high affinity for 5-HT_1B/1D and modest affinity for 5-HT_1A receptors.

Current theories proposed to explain the etiology of migraine headache suggest that symptoms are 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 zolmitriptan for the treatment of migraine headache can most likely be attributed to the agonist effects at the 5-HT_1B/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.

Pharmacokinetics

Absorption

Zolmitriptan nasal spray is rapidly absorbed via the nasopharynx as detected in a Photon Emission Tomography (PET) study using ¹¹C zolmitriptan. Zolmitriptan was detected in plasma by 5 minutes and peak plasma concentration generally was achieved by 3 hours. The time at which maximum plasma concentrations were observed was similar after single (1 day) or multiple (4 day) nasal dosing. Plasma concentrations of zolmitriptan are sustained for 4 to 6 hours after dosing. Zolmitriptan displays linear kinetics after multiple doses of 2.5 mg, 5 mg, or 10 mg. The mean relative bioavailability of the nasal spray formulation is 102%, compared with the oral tablet.

Zolmitriptan and its active metabolite display dose proportionality after single or multiple dosing. Dose proportional increases in zolmitriptan and N-desmethyl metabolite Cmax and AUC were observed for 2.5 and 5 mg nasal spray doses. The pharmacokinetics for elimination of zolmitriptan and its active N-desmethyl metabolite are similar for all nasal spray dosages. The N-desmethyl metabolite is detected in plasma by 15 minutes and peak plasma concentration is generally achieved by 3 hours after administration.

Food has no significant effect on the bioavailability of zolmitriptan.

Distribution

Plasma protein binding of zolmitriptan is 25% over the concentration range of 10-1000 ng/mL. The mean (±SD) apparent volume of distribution for zolmitriptan nasal spray formulation is 8.4±3.3 L/kg.

Metabolism

Zolmitriptan is converted to an active N-desmethyl metabolite such that the metabolite concen-trations are about two-thirds that of zolmitriptan. Because the 5-HT_1B/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 zolmitriptan administration.

Excretion

The mean elimination half-life for zolmitriptan and its active N-desmethyl metabolite following nasal spray administration are approximately 3 hours, which is similar to the half-life values seen after oral tablet administration. The half-life values were similar for zolmitriptan and the N-desmethyl metabolite after single (1 day) and multiple (4 day) nasal dosing.

Mean total plasma clearance is 25.9 mL/min/kg, of which one-sixth is renal clearance. The renal clearance is greater than the glomerular filtration rate suggesting renal tubular secretion.

Special Populations

Age

The pharmacokinetics of oral zolmitriptan in healthy elderly non-migraineur volunteers (age 65–76 yrs) was similar to those in younger non-migraineur volunteers (age 18–39 yrs).

Gender

Mean plasma concentrations of orally administered zolmitriptan were up to 1.5-fold higher in females than males.

Renal Impairment

The effect of renal impairment on the pharmacokinetics of zolmitriptan nasal spray has not been evaluated. After orally dosing zolmitriptan, renal clearance was reduced by 25% in patients with severe renal impairment (Clcr ≥ 5 ≤ 25 mL/min) compared with the normal group (Clcr ≥ 70 mL/min); no significant change in renal clearance was observed in the moderately renally impaired group (Clcr ≥ 26 ≤ 50 mL/min).

Hepatic Impairment

The effect of hepatic disease on the pharmacokinetics of zolmitriptan nasal spray has not been evaluated. In severely hepatically impaired patients, the mean Cmax, Tmax, and AUC0-∞ of zolmitriptan dosed orally were increased 1.5, 2, and 3-fold, respectively, compared with normals. Seven out of 27 patients experienced 20 to 80 mm Hg elevations in systolic and/or diastolic blood pressure after a 10 mg dose. Because of the similarity in exposure, zolmitriptan tablets and nasal spray should have similar dosage adjustments and should be administered with caution in subjects with liver disease, generally using doses less than 2.5 mg. Doses lower than 5 mg can only be achieved through the use of an oral formulation [see DOSAGE AND ADMINISTRATION and Use in Specific Populations].

Hypertensive Patients

No differences in the pharmacokinetics of oral zolmitriptan or its effects on blood pressure were seen in mild to moderate hypertensive volunteers compared with normotensive controls.

Race

Retrospective analysis of pharmacokinetic data between Japanese and Caucasians revealed no significant differences for orally dosed zolmitriptan.

Drug Interactions

All drug interaction studies were performed in healthy volunteers using a single 10 mg dose of zolmitriptan and a single dose of the other drug except where otherwise noted. Eight drug interaction studies have been performed with zolmitriptan tablets and one study (xylometazoline) was performed with nasal spray.

Xylometazoline

An in vivo drug interaction study with ZOMIG (zolmitriptan nasal spray) Nasal Spray indicated that 1 spray (100 μL dose) of xylometazoline (0.1% w/v), a decongestant, administered 30 minutes prior to a 5 mg nasal dose of zolmitriptan did not alter the pharmacokinetics of zolmitriptan.

Fluoxetine

The pharmacokinetics of zolmitriptan, as well as its effect on blood pressure, were unaffected by 4 weeks of pre-treatment with oral fluoxetine (20 mg/day).

MAO Inhibitors

Following one week of administration of 150 mg bid moclobemide, 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 N-desmethyl metabolite of zolmitriptan [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS].

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.

Propranolol

Cmax and AUC of zolmitriptan 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 interactive effects on blood pressure or pulse rate following administration of propranolol with zolmitriptan.

Acetaminophen

A single 1 g dose of acetaminophen does not alter the pharmacokinetics of zolmitriptan and its N-desmethyl metabolite. However, zolmitriptan delayed the Tmax of acetaminophen by one hour.

Metoclopramide

A single 10 mg dose of metoclopramide had no effect on the pharmacokinetics of zolmitriptan or its metabolites.

Oral Contraceptives

Retrospective analysis of pharmacokinetic data across studies indicated that mean plasma concentrations of zolmitriptan were generally higher in females taking oral contraceptives compared with those not taking oral contraceptives. Mean Cmax and AUC of zolmitriptan were found to be higher by 30% and 50%, respectively, and Tmax was delayed by one-half hour in females taking oral contraceptives. The effect of zolmitriptan on the pharmacokinetics of oral contraceptives has not been studied.

Cimetidine

Following the administration of cimetidine, the half-life and AUC of a 5 mg dose of zolmitriptan and its active metabolite were approximately doubled [see DRUG INTERACTIONS].

Clinical Studies

The efficacy of ZOMIG (zolmitriptan nasal spray) Nasal Spray 5 mg in the acute treatment of migraine headache with or without aura was demonstrated in a randomized, outpatient, double-blind, placebo-controlled trial. 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 15, 30, 45 minutes and 1, 2, and 4 hours after dosing. Pain-free response rates and associated symptoms such as nausea, photophobia, and phonophobia were also assessed. A dose of escape medication was allowed 4 to 24 hours after the initial treatment for persistent and recurrent headache.

Of the 1372 patients treated in the study, 83% were female and 99% were Caucasian, with a mean age of 40.6 years (range 18 to 65 years).

The two hour headache response rates in patients treated with ZOMIG (zolmitriptan nasal spray) Nasal Spray were statistically significant among patients receiving ZOMIG (zolmitriptan nasal spray) Nasal Spray compared with placebo. There was a greater percentage of patients with a headache response at 2 hours in the higher dose groups. The headache response efficacy endpoints of the controlled clinical study, analyzed from the first attack data, are shown in Table 2.

Table 2: First Attack Data: Percentage of Patients with Headache Response to ZOMIG (zolmitriptan nasal spray) Nasal Spray (Mild or No Headache) 2 Hours Following Treatment
(N = number of randomized patients treating a migraine attack).
The 2 hour headache response was the primary end-point.

The estimated probability of achieving an initial headache response by 4 hours following treatment with ZOMIG (zolmitriptan nasal spray) Nasal Spray is depicted in Figure 1.

Figure 1: Estimated probability of achieving an initial headache response within 4 hours of initial treatment

Note: Figure 1 shows the Kaplan-Meier plot of the probability over time of obtaining headache response (moderate or severe headache improving to mild or no pain) following treatment with zolmitriptan nasal spray. The averages displayed are based on a placebo controlled, outpatient trial providing evidence of efficacy. Patients not achieving headache response or taking additional treatment prior to 4 hours were censored to 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 (zolmitriptan nasal spray) Nasal Spray as compared with 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 an escape medication within the 24 hours following the initial dose of study treatment

* This Kaplan-Meier plot is based on data obtained from the placebo controlled clinical trial.

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. It should be noted that the protocol did not allow remedication within 4 hours post dose.

The efficacy of ZOMIG (zolmitriptan nasal spray) was unaffected by presence of aura; presence of headache upon awakening, relationship to menses; gender, age or weight of the patient; or presence of pre-treatment nausea. The efficacy of ZOMIG (zolmitriptan nasal spray) Nasal Spray 5 mg was further supported by an interim analysis of another similarly designed trial. The 2 hour headache response rates for the first 210 subjects in that study for ZOMIG (zolmitriptan nasal spray) 5 mg and placebo were 70% and 47%, respectively (N=108 and 102, respectively, p=0.0006).

Last reviewed on RxList: 12/22/2008
This monograph has been modified to include the generic and brand name in many instances.