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Zomig Nasal Spray

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Zomig Nasal Spray

Zomig Nasal Spray

CLINICAL PHARMACOLOGY

Mechanism of Action

Zolmitriptan binds with high affinity to human recombinant 5-HT1D 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.

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 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.

Pharmacokinetics

Absorption

Zolmitriptan nasal spray is rapidly absorbed via the nasopharynx as detected in a Photon Emission Tomography (PET) study using 11C zolmitriptan. The mean relative bioavailability of the nasal spray formulation is 102%, compared with the oral tablet. 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 days) nasal dosing. Plasma concentrations of zolmitriptan are sustained for 4 to 6 hours after dosing. Zolmitriptan and its active N-desmethyl metabolite display linear kinetics after single or multiple doses of ZOMIG nasal spray over the dose range of 0.1 to 10 mg.

The pharmacokinetics of the N-desmethyl metabolite are similar to that of zolmitriptan 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 apparent volume of distribution for zolmitriptan nasal spray formulation is 8.4 L/kg.

Metabolism

Zolmitriptan is converted to an active N-desmethyl metabolite such that 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.

Excretion

The mean elimination half-life for zolmitriptan and N-desmethyl metabolite following single or multiple nasal spray administration are approximately 3 hours, similar to the half-life values seen after oral tablet administration.

In a study with orally administered zolmitriptan, total radioactivity recovered in urine and feces was 65% and 30% of the administered dose, respectively. In urine, unchanged zolmitriptan and N-desmethyl metabolite accounted for 8% and 4% of the dose, respectively, whereas the inactive indole acetic acid and N-oxide metabolites accounted for 31% and 7% of the dose, respectively.

Mean total plasma clearance for zolmitriptan nasal spray 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 orally administered zolmitriptan in healthy elderly nonmigraineur volunteers (age 65-76 yrs) was similar to those in younger non-migraineur volunteers (age 18-39 yrs).

Sex

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

Race

There are no significant difference in the pharmacokinetics of orally administered zolmitriptan in Japanese and Caucasians.

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 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 patients with severe hepatic impairment, the mean Cmax, Tmax, and AUC of zolmitriptan dosed orally 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.[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.

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 Nasal Spray indicated that 1 spray (100μL 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 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 N-desmethyl metabolite of zolmitriptan [see CONTRAINDICATIONS 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.

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 1g 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 Cmax and AUC of zolmitriptan were 30% and 50% higher, respectively, and Tmax was delayed by one-half hour in females taking oral contraceptives compared to females not 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. A dosage adjustment is therefore required [see DRUG INTERACTIONS].

Clinical Studies

The efficacy of ZOMIG Nasal Spray 2.5 and 5 mg in the acute treatment of migraine headache with or without aura was demonstrated in Study 1, a randomized, outpatient, double-blind, placebo-controlled trial.

In Study 1, 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.

In Study 1, of the patients taking zolmitriptan 2.5 or 5 mg, 83% were female and 99% were Caucasian, with a mean age of 41 years (range 18 to 65 years).

The two hour headache response rates in patients treated with ZOMIG Nasal Spray were significantly higher among patients receiving ZOMIG Nasal Spray at all doses, compared with placebo (see Table 2).

Table 2: First Attack Data: Percentage of Patients with Headache, Response to ZOMIG Nasal Spray (Mild or No Headache) 2 Hours Following Treatment in Study 1

PLACEBO
(N=218)
n/%
ZOMIG2.5 mg
(N=219)
n/%
ZOMIG5 mg
(N=228)
n/%
67/31% 121/55%* 157/69%*
*p < 0.001 in comparison with placebo
N= number of patients evaluated at 2 hours
n= number (%) of patients with headache response at 2 h

The estimated probability of achieving an initial headache response following treatment with ZOMIG Nasal Spray is depicted in Figure 1.

Figure 1: Estimated probability of achieving an initial headache response after treatment in Study 1

Estimated probability of achieving an initial headache response after treatment in Study 1 - Illustration

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 estimates 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 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 in Study 1

Estimated probability of patients taking an escape medication within the 24 hours following the initial dose of study treatment in Study 1 - Illustration

*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 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 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 5 mg and placebo were 70% and 47%, respectively (N=108 and 102, respectively, p=0.0006).

Last reviewed on RxList: 9/30/2013
This monograph has been modified to include the generic and brand name in many instances.

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