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Zomig (Zolmitriptan) - Description and Clinical Pharmacology

 
 



DESCRIPTION

ZOMIG® (zolmitriptan) Tablets and ZOMIG-ZMT® (zolmitriptan) Orally Disintegrating Tablets contain zolmitriptan, which is a selective 5-hydroxytryptamine 1B/1D (5-HT1B/1D) receptor agonist. Zolmitriptan is chemically designated as (S)-4-[[3-[2-(dimethylamino)ethyl]-1H-indol-5-yl]methyl]-2-oxazolidinone and has the following chemical structure:

The empirical formula is C­16­H­21­N­3­O­­2­, representing a molecular weight of 287.36. Zolmitriptan is a white to almost white powder that is readily soluble in water. ZOMIG Tablets are available as 2.5 mg (yellow) and 5 mg (pink) film coated tablets for oral administration. The film coated tablets contain anhydrous lactose NF, microcrystalline cellulose NF, sodium starch glycolate NF, magnesium stearate NF, hydroxypropyl methylcellulose USP, titanium dioxide USP, polyethylene glycol 400 NF, yellow iron oxide NF (2.5 mg tablet), red iron oxide NF (5 mg tablet), and polyethylene glycol 8000 NF.

ZOMIG-ZMT® Orally Disintegrating Tablets are available as 2.5 mg and 5.0 mg white uncoated tablets for oral administration. The orally disintegrating tablets contain mannitol USP, microcrystalline cellulose NF, crospovidone NF, aspartame NF, sodium bicarbonate USP, citric acid anhydrous USP, colloidal silicon dioxide NF, magnesium stearate NF and orange flavor SN 027512.

CLINICAL PHARMACOLOGY

Mechanism of Action:

Zolmitriptan binds with high affinity to human recombinant 5-HT1D and 5-HT1B receptors. Zolmitriptan exhibits modest affinity for 5-HT1A receptors, but has no significant affinity (as measured by radioligand binding assays) or pharmacological activity at 5-HT2, 5-HT3, 5-HT4, alpha1-, alpha2-, or beta1- adrenergic; H1, H2, histaminic; muscarinic; dopamine1, or dopamine2 receptors. The N-desmethyl metabolite also has high affinity for 5-HT1B/1D and modest 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 zolmitriptan for the treatment of migraine headache can most likely be attributed 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.

Clinical Pharmacokinetics and Bioavailability

Absorption:

Zolmitriptan is well absorbed after oral administration for both the conventional tablets and the 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 the orally disintegrating tablet compared with 1.5 hours for the conventional 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 conventional 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.

Distribution:

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- 1000ng/mL.

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, the metabolite may contribute a substantial portion of the overall effect after zolmitriptan administration.

Elimination:

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 31.5mL/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: Zolmitriptan pharmacokinetics in healthy elderly non-migraineur volunteers (age 65−76 yrs) were similar to those in younger non-migraineur volunteers (age 18 - 39 yrs).

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

Renal Impairment: Clearance of zolmitriptan was reduced by 25% in patients with severe renal impairment (Clcr ≥ 5 ≤ 25 mL/min) compared to 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: In severely hepatically impaired patients, the mean Cmax, Tmax, and AUC0-∞ of zolmitriptan were increased 1.5, 2 (2 vs 4 hr), and 3-fold, respectively, compared to 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. Zolmitriptan should be administered with caution in subjects with liver disease, generally using doses less than 2.5 mg (see WARNINGS and PRECAUTIONS).

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

Race:: Retrospective analysis of pharmacokinetic data between Japanese and Caucasians revealed no significant differences.

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.

Fluoxetine: 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).

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 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 to 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 PRECAUTIONS).

Clinical Studies:

The efficacy of ZOMIG Tablets in the acute treatment of migraine headaches was demonstrated in five randomized, double-blind, placebo controlled studies, of which 2 utilized the 1 mg dose, 2 utilized the 2.5 mg dose and 4 utilized the 5 mg dose; all studies used the marketed formulation. 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 postdose. 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 zolmitriptan 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 receiving ZOMIG Tablets at all doses (except for the 1 mg dose in the smallest study) compared to those who received placebo. In the two studies that evaluated the 1 mg dose, 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.

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.

Table 1: Percentage of Patients with Headache Response (Mild or no Headache) 2 Hours Following Treatment (n=number of patients randomized).

Placebo

ZOMIG

1.0 mg

ZOMIG

2.5 mg

ZOMIG

5 mg

Study 1 1

16%

(n=19)

27%

(n=22)

NA 2

60% 3 4

(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 4 5

44%

(n=55)

NA

NA

59%

(n=491)

Study 5

36%

(n=92)

NA

NA

62%

(n=178)

NA

1 This was the only study in which patients treated the headache in a clinic setting.
2 NA - not applicable
3 p<0.05 in comparison with placebo.
4 p<0.05 in comparison with 1 mg.
5 This was the only study where patients were excluded who had previously used sumatriptan.

The estimated probability of achieving an initial headache response by 4 hours following treatment is depicted in Figure 1.

Figure 1: Estimated Probability Of Achieving Initial Headache ResponseWithin 4 Hours*

Figure 1: Estimated Probability Of Achieving Initial Headache ResponseWithin 4 Hours*

*Figure 1 shows the Kaplan-Meier plot of the probability over time of obtaining headache response (no or mild pain) following treatment with zolmitriptan. The averages displayed are based on pooled data from 3 placebo controlled, outpatient trials providing evidence of efficacy (Trials 2, 3 and 5). 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 as compared to 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*

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*

*This Kaplan-Meier plot is based on data obtained in 3 placebo controlled clinical trials (Study 2, 3 and 5). 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 protocols did not allow remedication within 2 hours postdose.

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; pretreatment nausea, or concomitant use of common migraine prophylactic drugs.

ZOMIG-ZMT Orally Disintegrating Tablets

The efficacy of ZOMIG-ZMT 2.5 mg was demonstrated in a randomized, placebo-controlled trial 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 the study, 87% were female and 97% were Caucasian, with a mean age of 41 years (range 18-62). At 2 hours post-dosing response rates in patients treated with ZOMIG-ZMT 2.5 mg were 63% compared to 22% in the placebo group. The difference was statistically significant. The estimated probability of achieving an initial headache response by 2 hours following treatment with ZOMIG-ZMT Tablets is depicted in Figure 3.

Figure 3: Estimated Probability of Achieving Initial Headache Response by 2 Hours

Figure 3: Estimated Probability of Achieving Initial Headache Response by 2 Hours

Figure 3 shows the Kaplan-Meier plot of the probability over time of obtaining headache response (no or mild pain) following treatment with ZOMIG-ZMT Tablets or placebo. Patients 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 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

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 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. Remedication was allowed 2 hours post-dose, and unlike the conventional tablet, remedication prior to 4 hours was not discouraged.

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