Zolmitriptan

287.36

287.36

1806241-263-5

2FS66TH3YW

760383

DTXSID8045933

C47789

N02CC03|N - Nervous system

29349990

57.4

2.2

white to beige

1.217±0.06 g/cm3(Predicted)

136-141°C

563.3±38.0 °C(Predicted)

294.5±26.8 °C

1.620

Soluble in DMSO at 5mg/ml

Refrigerator

1.03E-12mmHg at 25°C

D22 -5.79° (c = 0.5 in methanol)

9.64

160.6 Ų [M+H]+ [CCS Type: TW, Method: Major Mix IMS/Tof Calibration Kit (Waters)]|159.7 Ų [M+H]+ [CCS Type: TW, Method: calibrated with polyalanine and drug standards]

NONH for all modes of transport

3

36/37/38-22

26-36

RQ2707000

Xi,Xn

P260, P261, P264, P270, P271, P280, P301+P312, P302+P352, P304+P340, P305+P351+P338, P309+P311, P312, P321, P330, P332+P313, P337+P313, P362, P403+P233, P405, P501

H302

|Warning|H302 (94.44%): Harmful if swallowed [Warning Acute toxicity, oral]|P260, P261, P264, P270, P271, P280, P301+P312, P302+P352, P304+P340, P305+P351+P338, P309+P311, P312, P321, P330, P332+P313, P337+P313, P362, P403+P233, P405, and P501|Aggregated GHS information provided by 18 companies from 5 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Toxicity information regarding zolmitriptan is not readily available. Patients experiencing an overdose are at an increased risk of severe adverse effects such as cardiovascular symptoms due to excessive vasoconstriction and activation of serotonergic receptors. Patients receiving a single 50 mg oral dose of zolmitriptan often experienced sedation. Symptomatic and supportive measures are recommended.

In large prospective controlled trials, the different triptans have not been associated with serum enzyme elevations or hepatotoxicity; however, the frequency of monitoring in most studies was limited and rates of ALT elevations not reported. There have been rare individual reports of cholestatic hepatitis after the use of triptans, largely associated with zolmitriptan. Typically, the onset of injury was within 1 to 2 weeks of taking several doses of the zolmitriptan for a protracted and severe migraine attack. Recurrent jaundice with intermittent therapy has also been reported (Case 1). The pattern of serum enzyme elevations was mixed or cholestatic, and recovery was complete within 1 to 2 months. Allergic manifestations (rash, fever, eosinophilia) were not present and autoantibodies did not develop.

Zolmitriptan and its active N-desmethyl metabolite remain approximately 25% bound to plasma proteins over a concentration range of 10-1000 ng/mL.

Zolmitriptan is indicated for the acute treatment of migraine with or without auras in patients aged 18 and over.|FDA Label

The triptans are a group of serotonin receptor agonists that are useful in the therapy of vascular headaches and migraine. The triptans are generally used in low doses for a limited period of time and have not been associated with serum enzyme elevations, but some have been implicated in rare instances of clinically apparent, acute cholestatic hepatitis.

Migraine Headache Agents

Zolmitriptan, like other triptans, is a serotonin (5-hydroxytryptamine; 5-HT) receptor agonist, with enhanced specificity for the 5-HT_1B and 5-HT_1D receptor subtypes. It is through the downstream effects of 5-HT_1B/1D activation that triptans are proposed to provide acute relief of migraines. Zolmitriptan is also a vasoconstrictor, leading to possible adverse cardiovascular effects such as myocardial ischemia/infarction, arrhythmias, cerebral and subarachnoid hemorrhage, stroke, gastrointestinal ischemia, and peripheral vasospastic reactions. In addition, chest/throat/neck/jaw pain, tightness, and/or pressure has been reported, along with the possibility of medication overuse headaches and serotonin syndrome. Patients with phenylketonuria should be advised that ZOMIG-ZMT contains phenylalanine.

Endogenous compounds and drugs that specifically stimulate SEROTONIN 5-HT1 RECEPTORS. Included under this heading are agonists for one or more of the specific 5-HT1 receptor subtypes. (See all compounds classified as Serotonin 5-HT1 Receptor Agonists.)

Zolmitriptan tablets have a mean absolute oral bioavailability of approximately 40%, with food having no effect on the rate or extent of absorption. The dosing kinetics are linear over a range of 2.5 to 50 mg with 75% of the eventual C_max being attained within 1 hour of dosing. The median T_max for the tablet form is 1.5 hours, while for the orally disintegrating tablet form, it is 3 hours. The AUC across studies was in the range of 84.4-173.8 ng/mL*h while the C_max was between 16 and 25.2 ng/mL. Zolmitriptan administered as a nasal spray is detected in the plasma within 2-5 minutes, compared to 10-15 minutes for the tablet form; the faster kinetics likely reflect fast absorption across the nasal mucosa. The bioavailability compared to the tablet is 102%, and plasma zolmitriptan concentration is maintained for 4-6 hours after intranasal delivery. The active N-desmethyl metabolite of zolmitriptan has a mean plasma concentration that is roughly two-thirds of zolmitriptan, regardless of dosage route or concentration.|Zolmitriptan is primarily excreted in urine (approximately 65%) and feces (approximately 30%). Within urine, the most common form is the indole acetic acid metabolite (31%), followed by the N-oxide (7%), and N-desmethyl (4%) metabolites; the majority of zolmitriptan recovered in feces remains unchanged.|Zolmitriptan has a volume of distribution between 7 and 8.4 L/kg.|Zolmitriptan has a clearance of 31.5 mL/min/kg for oral tablets and 25.9 mL/min/kg for nasal administration; one-sixth of the clearance is renal.

Zolmitriptan is metabolized in the liver, and studies using cytochrome P450 inhibitors like [cimetidine] suggest that it is likely metabolized by CYP1A2, as well as by monoamine oxidase (MAO). Zolmitriptan metabolism results in three major metabolites: an active N-desmethyl metabolite (183C91) as well as inactive N-oxide (1652W92) and indole acetic acid (2161W92) metabolites.|Zolmitriptan has known human metabolites that include N-Desmethylzolmitriptan and Zolmitriptan N-oxide.

Zolmitriptan has a mean elimination half-life of approximately three hours, while its active N-desmethyl metabolite has a slightly longer (approximately 3.5 hours) half-life.

Migraines are complex physiological events characterized by unilateral throbbing headaches combined with photophobia and other aversions to sensory input. Migraine attacks are generally divided into phases: the premonitory phase, which typically involves irritability, fatigue, yawning, and stiff neck; the headache phase, which lasts for between four and 72 hours; and the postdrome phase, which lasts for up to a day following resolution of pain and whose symptoms are similar to those of the premonitory phase. In addition, neurological deficits, collectively termed migraine aura, may precede the headache phase. The underlying pathophysiology of migraines is a matter of active research but involves both neurological and vascular components. The head pain associated with migraine is thought to be a consequence of activation of the nociceptive nerves comprising the trigeminocervical complex (TCC). Terminals of nociceptive nerves that innervate the dura matter release vasoactive peptides, such as calcitonin gene-related peptide (CGRP), resulting in cranial vasodilation. Finally, when present, migraine aura appears to correlate with a transient wave(s) of cortical depolarization, termed cortical spreading depression (CSD). Triptans, including zolmitriptan, are proposed to act in three ways. The main mechanism is through modulation of nociceptive nerve signalling in the central nervous system through 5-HT_1B/1D receptors throughout the TCC and associated areas of the brain. In addition, triptans can enhance vasoconstriction, both through direct 5-HT_1B-mediated dilation of cranial blood vessels, as well as through 5-HT_1D-mediated suppression of CGRP release. Although triptans are classically described solely in terms of their effects on 5-HT_1B/1D receptors, they also act as 5-HT_1F agonists as well. This 5-HT subtype is also found throughout the TCC, but is not present appreciably in cerebral vasculature; the significance of triptan-mediated 5-HT_1F activation is currently not well described. Additionally, CSD that initiates in the ipsilateral parietal region may exert its effects in a manner that relies on 5-HT_1B/1D receptor activation, suggesting that triptans may have some effect on CSD-mediated symptoms.

311C90

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