Zolmitriptan

Zolmitriptan is a an Antimigraine Agent belonging to pharmacology class of Serotonin 5-HT1B, 1D Receptor Agonist Class.

Zolmitriptan can be used in the treatment of Migraine, moderate to severe, acute treatment.

Zolmitriptan is Well absorbed (oral); rapidly absorbed via the nasopharynx (intranasal). Absolute bioavailability: Approx 40%. Time to peak plasma concentration: 1.5 hours (tab); 3 hours (orodispersible tab; nasal spray) with Volume of distribution: 7 L/kg (oral); 8.4 L/kg (intranasal). Plasma protein binding: 25% and get Metabolised in the liver mainly into indole acetic acid, N-oxide, and N-desmethyl analogues; primary metabolism is mainly by CYP1A2. The active N-desmethyl metabolite undergoes further metabolism by MAO-A and get excreted Via urine (approx 60-65%; 8% as unchanged drug, 31% as indole acetic acid, 7% as N-oxide, and 4% as N-desmethyl metabolites); faeces (approx 30%, mainly as unchanged drug). Elimination half-life: 2.5-3 hours.

The common side effects associated with Zolmitriptan include MI, coronary vasospasm, angina pectoris, peripheral or gastrointestinal vascular ischaemia and infarction, splenic infarction, Raynaud syndrome.

Zolmitriptan is available in the form of tablets, Nasal Solution.

The molecule is available in India, USA, Japan, Germany.

Selective agonist for serotonin (5-HT1B and 5-HT1D receptors) in cranial arteries and sensory nerves of the trigeminal system; causes vasoconstriction and reduces inflammation associated with antidromic neuronal transmission correlating with relief of migraine.

The Tmax of Zolmitriptan Tablet: 1.5 hours; Orally-disintegrating tablet and nasal spray: 3 hours.

Onset of Action: Most patients have response to treatment within 2 hours.

Zolmitriptan is available in tablet, Nasal Solution

Tablet: May be broken in half to achieve a smaller initial dose

Orally-disintegrating tablet: Must be taken whole; do not break, crush, or chew. Place on tongue and allow to dissolve. Administration with liquid is not required.

Nasal spray: Blow nose gently prior to use. After removing protective cap, instill device into nostril. Block opposite nostril; breathe in gently through nose while pressing plunger of spray device. Breathe gently through mouth for 5-10 seconds.

Zolmitriptan can be used in the treatment of Migraine, moderate to severe, acute treatment.

Zolmitriptan is a selective agonist of serotonin (5-HT1B and 5-HT1D receptors) that are in sensory nerves and cranial arteries of the trigeminal system. This results in the constriction of cranial vessels and inhibition of pro-inflammatory neuropeptide release, leading to relief of migraine.

Zolmitriptan is approved for use in the following clinical indications

Migraine, moderate to severe, acute treatment:

Nasal inhalation: Acute treatment of migraine with or without aura in adults and pediatric patients ≥12 years.

Oral: Acute treatment of migraine with or without aura in adults.

Although not approved there have been certain off labelled uses documented for Zolmitriptan which includes:

Cluster headache, treatment; Menstrual migraines (short-term prevention).

Cluster headache, treatment (off-label): Nasal inhalation (available as a 2.5 or 5 mg dose per nasal sprayer) or oral: Usual dose: 5 to 10 mg at the onset of cluster headache (maximum single dose: 10 mg)

Menstrual migraine, prophylaxis (off-label use): Oral: 2.5 mg 2 to 3 times daily starting 2 days prior to the expected onset of menses and continued through to 5 days after the onset of menses (7 days total) .

Migraine, moderate to severe, acute treatment

Note: Do not use within 24 hours of an ergotamine preparation or a different triptan. Limit use to <10 days per month to avoid medication-overuse headache. Administration early in the course of a migraine attack, at the first sign of pain, may improve response to treatment. When attack is complicated by severe nausea or vomiting, a nonoral preparation may be more effective.

Oral: 2.5 mg as a single dose; if symptoms persist or return, may repeat dose after ≥2 hours. Maximum: 5 mg/dose; 10 mg per 24 hours.

Nasal inhalation: 2.5 to 5 mg as a single dose; if symptoms persist or return, may repeat dose after ≥2 hours. Maximum: 5 mg/dose; 10 mg per 24 hours (Ref). Note: Some experts recommend a large initial dose, as it may be more effective than multiple smaller doses.

Tablet, Nasal Solution

2.5 mg, 5 mg

Tablet

Dose Adjustment in Kidney impairment patient:

No dosage adjustment provided in manufacturer’s labeling; however, zolmitriptan clearance is reduced in patients with severe renal impairment (CrCl 5 to 25 mL/minute).

Dose Adjustment in Hepatic Patient:

Oral

Tablet:

Mild impairment: There is no dosage adjustment provided in the manufacturer’s labeling.

Moderate to severe impairment: Initial: 1.25 mg (maximum: 5 mg per 24 hours in severe impairment).

Orally disintegrating tablet:

Mild impairment: There is no dosage adjustment provided in the manufacturer’s labeling.

Moderate to severe impairment: Use is not recommended.

Nasal inhalation:

Mild impairment: No dosage adjustment necessary.

Moderate to severe impairment: Use is not recommended

• Dose Adjustment in Pediatric Patient:

Migraine: Children ≥12 years and Adolescents: Intranasal: Nasal inhalation:

Initial dose: 2.5 mg; may titrate as individual response may vary; maximum single dose: 5 mg/dose; Note: Administer at the onset of migraine headache.

Second dose: May repeat in 2 hours if the migraine headache has not resolved or returns after transient improvement; maximum daily dose: 10 mg/day.

The dietary restriction should be individualized as per patient requirements.

Zolmitriptan may be contraindicated in the following conditions:

Hypersensitivity to zolmitriptan or any component of the formulation; ischemic coronary artery disease (angina pectoris, history of myocardial infarction [MI], or documented silent ischemia); coronary artery vasospasm, including Prinzmetal variant angina, or other significant underlying cardiovascular disease; Wolff-Parkinson-White syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders; peripheral vascular disease; ischemic bowel disease; uncontrolled hypertension; recent use (within 24 hours) of treatment with another 5-HT₁ agonist, or an ergotamine-containing or ergot-type medication like dihydroergotamine or methysergide; history of stroke, transient ischemic attack, or history of hemiplegic migraine or migraine with brainstem aura; coadministration of monoamine oxidase A (MAO A) inhibitors or use of zolmitriptan within 2 weeks of discontinuation of MAO A inhibitor therapy.

Documentation of allergenic cross-reactivity for triptans is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.

The treating physician must closely monitor the patient and keep pharmacovigilance as follows

Concerns related to adverse effects:

• Cardiac events: Coronary artery vasospasm, transient ischemia, myocardial infarction, ventricular tachycardia/fibrillation, cardiac arrest, and death have been reported within a few hours of 5-HT₁ agonist administration; use is contraindicated in patients with ischemic or vasospastic coronary artery disease. Patients who experience sensations of chest pain/pressure/tightness or symptoms suggestive of angina following dosing should be evaluated for coronary artery disease or Prinzmetal's angina before receiving additional doses; if dosing is resumed and similar symptoms recur, monitor with ECG. Patients with Prinzmetal's variant angina, Wolff-Parkinson-White Syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders should not receive zolmitriptan.

• Cerebrovascular events: Cerebral/subarachnoid hemorrhage and stroke have been reported with 5-HT₁ agonist administration and some have resulted in fatalities. Do not administer to patients with a history of stroke or TIA; discontinue use if a cerebrovascular event occurs.

• Elevated blood pressure: Significant elevation in blood pressure, including hypertensive crisis, has also been reported on rare occasions in patients with and without a history of hypertension. Use is contraindicated in patients with uncontrolled hypertension.

• Vasospasm-related events: Peripheral vascular ischemia, gastrointestinal vascular ischemia and infarction (presenting with abdominal pain and bloody diarrhea), splenic infarction, and Raynaud syndrome have been reported with 5-HT₁ agonists. In patients who experience signs or symptoms suggestive of a vasospastic reaction following use of a 5-HT₁ agonist, rule out a vasospastic reaction before receiving additional doses.

• Visual effects: Rarely, partial vision loss and blindness (transient and permanent) have been reported with 5-HT₁ agonists.

There is no sufficient scientific evidence traceable regarding use and safety of Zolmitriptan in concurrent use with alcohol.

Zolmitriptan is present in breast milk.

Data related to the presence of 5-HT_1B/1D agonists (triptans) in breast milk is available from a study of 19 lactating women (6 weeks to 30 months postpartum) treated for migraine headaches. During the study, infants were fed previously expressed breast milk. Breast milk was sampled prior to and at intervals up to 24 hours after the dose in patients taking zolmitriptan 5 mg (nasal spray, n=1) or 2.5 mg (orally, n=3). Using the average breast milk concentration observed, authors of the study calculated the estimated exposure of zolmitriptan to the breastfed infant to be 0.6 mcg/kg/day, providing a relative infant dose (RID) of 0.7% based on the weight-adjusted maternal dose following use of the nasal spray. Following maternal use of oral zolmitriptan, the estimated exposure to the breastfed infant was calculated to be 0.2 to 1.5 mcg/kg/day (RID 0.8% to 5.3%). Using the maximum breast milk concentration, the RID of zolmitriptan was calculated to be 1.4% to 9.4%. The active metabolite of zolmitriptan was not included in the calculations (concentrations were near or below the limit of quantification). One patient was also taking propranolol for migraine headache prevention; her Cmax and AUC were higher than other patients taking zolmitriptan. A large interindividual variability among breast milk concentrations was found with all the triptans in the study, even when considering dose and dosage form (Amundsen 2021). In general, breastfeeding is considered acceptable when the RID is <10%.

Pregnancy Category C

There are no adequate and well- controlled studies in pregnant women; therefore, Zolmitriptan should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In reproductive toxicity studies in rats and rabbits, oral administration of zolmitriptan to pregnant animals resulted in embryolethality and fetal abnormalities (malformations and variations) at clinically relevant exposures.

When zolmitriptan was administered to pregnant rats during the period of organogenesis at oral doses of 100, 400, and 1200 mg/kg/day (plasma exposures (AUCs) ≈280, 1100, and 5000 times the human AUC at the maximum recommended human dose (MRHD) of 10 mg/day), there was a dose-related increase in embryolethality. A no-effect dose for embryolethality was not established. When zolmitriptan was administered to pregnant rabbits during the period of organogenesis at oral doses of 3, 10, and 30 mg/kg/day (plasma AUCs ≈1, 11, and 42 times the human AUC at the MRHD), there were increases in embryolethality and in fetal malformations and variations. The no-effect dose for adverse effects on embryo-fetal development was associated with a plasma AUC similar to that in humans at the MRHD. When female rats were given zolmitriptan during gestation, parturition, and lactation at oral doses of 25, 100, and 400 mg/kg/day (plasma AUCs ≈70, 280, and 1100 times that in human at the MRHD), an increased incidence of hydronephrosis was found in the offspring. The no-effect dose was associated with a plasma AUC ≈280 times that in humans at the MRHD.

Increased risk of adverse effects with St. John’s wort.

The adverse reactions related to Zolmitriptan can be categorized as

• Common Adverse effects: MI, coronary vasospasm, angina pectoris, peripheral or gastrointestinal vascular ischemia and infarction, splenic infarction, Raynaud syndrome.
• Less Common Adverse effects: Nausea, vomiting, dry mouth, abdominal pain, dysphagia.
• Rare Adverse effects: significant elevation in blood pressure (including hypertensive crisis); partial vision loss, transient or permanent blindness; anaphylaxis or anaphylactoid reactions.

The clinically relevant drug interactions of Zolmitriptan is briefly summarized here

• Ergot-containing Drugs

Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because these effects may be additive, use of ergotamine containing or ergot-type medications (like dihydroergotamine or methysergide) and Zolmitriptan within 24 hours of each other is contraindicated.

• MAO-A Inhibitors

MAO-A inhibitors increase the systemic exposure of zolmitriptan and its active N-desmethyl metabolite. Therefore, the use of Zolmitriptan in patients receiving MAO-A inhibitors is contraindicated.

• 5-HT1B/1D agonists

Concomitant use of other 5-HT1B/1D agonists (including triptans) within 24 hours of Zolmitriptan treatment is contraindicated because the risk of vasospastic reactions may be additive.

• Selective Serotonin Reuptake Inhibitors and Serotonin Norepinephrine Reuptake Inhibitors

Cases of life-threatening serotonin syndrome have been reported during co-administration of triptans and selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs).

• Cimetidine

Following administration of cimetidine, the half-life and blood levels of zolmitriptan and its active N-desmethyl metabolite were approximately doubled. If cimetidine and Zolmitriptan are used concomitantly, limit the maximum single dose of Zolmitriptan to 2.5 mg, not to exceed 5 mg in any 24-hour period.

The common side of Zolmitriptan include the following

MI, coronary vasospasm, angina pectoris, peripheral or gastrointestinal vascular ischemia and infarction, splenic infarction, Raynaud syndrome.

Pregnancy Category C

There are no adequate and well- controlled studies in pregnant women; therefore, Zolmitriptan should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In reproductive toxicity studies in rats and rabbits, oral administration of zolmitriptan to pregnant animals resulted in embryolethality and fetal abnormalities (malformations and variations) at clinically relevant exposures.

When zolmitriptan was administered to pregnant rats during the period of organogenesis at oral doses of 100, 400, and 1200 mg/kg/day (plasma exposures (AUCs) ≈280, 1100, and 5000 times the human AUC at the maximum recommended human dose (MRHD) of 10 mg/day), there was a dose-related increase in embryolethality. A no-effect dose for embryolethality was not established. When zolmitriptan was administered to pregnant rabbits during the period of organogenesis at oral doses of 3, 10, and 30 mg/kg/day (plasma AUCs ≈1, 11, and 42 times the human AUC at the MRHD), there were increases in embryolethality and in fetal malformations and variations. The no-effect dose for adverse effects on embryo-fetal development was associated with a plasma AUC similar to that in humans at the MRHD. When female rats were given zolmitriptan during gestation, parturition, and lactation at oral doses of 25, 100, and 400 mg/kg/day (plasma AUCs ≈70, 280, and 1100 times that in human at the MRHD), an increased incidence of hydronephrosis was found in the offspring. The no-effect dose was associated with a plasma AUC ≈280 times that in humans at the MRHD.

Labor and Delivery

There is no FDA guidance on use of Zolmitriptan during labor and delivery.

Nursing Mothers

It is not known whether zolmitriptan is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from Zolmitriptan , a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. In rats, oral dosing with zolmitriptan resulted in levels in milk up to 4 times higher than in plasma.

Pediatric Use

The safety and effectiveness in pediatric patients have not been established. Therefore, Zolmitriptan is not recommended for use in patients under 18 years of age.

One randomized, placebo-controlled clinical trial of Zolmitriptan tablets (2.5, 5 and 10 mg) evaluated 696 pediatric patients (aged 12-17 years) with migraines. This study did not demonstrate the efficacy of Zolmitriptan compared to placebo in the treatment of migraine in adolescents. Adverse reactions in the adolescent patients treated with Zolmitriptan were similar in nature and frequency to those reported in clinical trials in adults treated with Zolmitriptan . Zolmitriptan has not been studied in pediatric patients less than 12 years old.

In the post-marketing experience with triptans, including Zolmitriptan , there were no additional adverse reactions seen in pediatric patients that were not seen in adults.

Geriatric Use

Clinical studies of Zolmitriptan did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

A cardiovascular evaluation is recommended for geriatric patients who have other cardiovascular risk factors (e.g., diabetes, hypertension, smoking, obesity, strong family history of coronary artery disease) prior to receiving Zolmitriptan ,

The pharmacokinetics of zolmitriptan were similar in geriatric patients (aged > 65 years) compared to younger patients.

Gender

There is no FDA guidance on the use of Zolmitriptan with respect to specific gender populations.

Race

There is no FDA guidance on the use of Zolmitriptan with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Zolmitriptan in patients with renal impairment.

Hepatic Impairment

After oral Zolmitriptan administration, zolmitriptan blood levels were increased in patients with moderate to severe hepatic impairment, and significant elevation in blood pressure was observed in some of these patients. Therefore, adjust the Zolmitriptan dose and administer with caution in patients with moderate or severe hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Zolmitriptan in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Zolmitriptan in patients who are immunocompromised.

Signs and Symptoms

There is no experience with acute overdose of Zolmitriptan. Clinical study subjects who received single 50 mg oral doses of Zolmitriptan commonly experienced sedation.

Management

There is no specific antidote to Zolmitriptan . In cases of severe intoxication, intensive care procedures are recommended, including establishing and maintaining a patent airway, ensuring adequate oxygenation and ventilation, and monitoring and support of the cardiovascular system.

The elimination half-life of Zolmitriptan is 3 hours; therefore, monitor patients after overdose with Zolmitriptan for at least 15 hours or until symptoms or signs resolve. It is unknown what effect hemodialysis or peritoneal dialysis has on the plasma concentrations of zolmitriptan.

Pharmacodynamics:

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.

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 Zolmitriptan 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: Well absorbed (oral); rapidly absorbed via the nasopharynx (intranasal). Absolute bioavailability: Approx 40%. Time to peak plasma concentration: 1.5 hours (tab); 3 hours (orodispersible tab; nasal spray).

Distribution: Volume of distribution: 7 L/kg (oral); 8.4 L/kg (intranasal). Plasma protein binding: 25%.

Metabolism: Metabolized in the liver mainly into indole acetic acid, N-oxide, and N-desmethyl analogues; primary metabolism is mainly by CYP1A2. The active N-desmethyl metabolite undergoes further metabolism by MAO-A.

Excretion: Via urine (approx 60-65%; 8% as unchanged drug, 31% as indole acetic acid, 7% as N-oxide, and 4% as N-desmethyl metabolites); faeces (approx 30%, mainly as unchanged drug). Elimination half-life: 2.5-3 hours.

1. https://www.uptodate.com/contents/Zolmitriptan -drug-information?search=Zolmitriptan &source=panel_search_result&selectedTitle=1~148&usage_type=panel&kp_tab=drug_general&display_rank=1#F154338
2. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/022352s017lbl.pdf
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4. https://www.mims.com/india/drug/info/Zolmitriptan ?type=full&mtype=generic#mechanism-of-action