Continuing Education Activity

Zolmitriptan is a medication used in the management and treatment of acute migraines. It is in the triptan class of drugs. Migraines are due to local cranial vasodilatation and the release of neuropeptides (calcitonin gene-related peptide, vasoactive intestinal peptide (VIP), and substance P) in the trigeminal system. Zolmitriptan is a selective 5-hydroxytryptamine 1B/1D receptor agonist with a weak affinity for the 5-HT 1A receptor subtypes. This activity describes the indications, action, and contraindications for zolmitriptan as a valuable agent in the treatment of acute migraines. In addition, this activity will highlight the mechanism of action, adverse event profile, toxicity, and other key factors (e.g., off-label uses, dosing, pharmacodynamics, pharmacokinetics, monitoring, relevant interactions) pertinent for members of the healthcare team in the treatment of patients with migraine and related conditions.

Objectives:

• Identify the mechanism of action of zolmitriptan.
• Describe the contraindications of zolmitriptan.
• Review the common adverse effects of zolmitriptan.
• Outline some interprofessional team strategies for improving care coordination and communication to advance zolmitriptan and improve outcomes.

Indications

FDA-approved Indications[1]

• Oral zolmitriptan
• Acute treatment of migraine with aura in adults 
• Acute treatment of migraine without aura in adults 
• Nasal spray zolmitriptan
• Acute migraine treatment in pediatric patients ages 12 and older and adults 

Off-label Clinical Uses[2]

• Acute treatment of cluster headaches (nasal spray)—Level A recommendation from the American Academy of Neurology.
• Acute treatment of menstrual migraine

Zolmitriptan is efficacious in the acute treatment of migraine headache pain and associated symptoms of nausea, vomiting, phonophobia, and photophobia.[1][3] Zolmitriptan was significantly more effective at helping patients achieve pain-free status at 2 hours, 3 hours, and 4 hours post-treatment compared to placebo.[4][5][6] In a multicenter, randomized placebo-controlled trial, 5 mg zolmitriptan nasal spray had a 2-hour headache response rate of 70.3%, significantly higher than the placebo group.[3]

Mechanism of Action

Migraines are due to local cranial vasodilatation and the release of neuropeptides (calcitonin gene-related peptide, vasoactive intestinal peptide (VIP), and substance P) in the trigeminal system. Zolmitriptan is a selective 5-hydroxytryptamine 1B/1D receptor agonist with a weak affinity for the 5-HT 1A receptor subtypes.[7] Its action on 5-HT 1B/1D receptors causes vasoconstriction in intracranial blood vessels; as well it can inhibit the release of pro-inflammatory neuropeptides from trigeminal perivascular nerve endings.[8] It crosses the blood-brain barrier as evidenced by the presence of radioactive [3H]-zolmitriptan labels within the cells of the trigeminal nucleus caudalis and nucleus tractus solitaries.[9]

Pharmacokinetics

Absorption: Zolmitriptan is rapidly absorbed after oral administration for zolmitriptan tablets and orally disintegrating tablets. Zolmitriptan exhibits linear kinetics over the dose range of 2.5 to 50 mg. Food has no substantial effect on the bioavailability of zolmitriptan. Zolmitriptan has a quick onset of action and is detected in the brain within 5 minutes of intranasal administration.[10] Zolmitriptan nasal spray is absorbed rapidly via the nasopharynx as explored in a Photon Emission Tomography (PET) study using 11C zolmitriptan. The mean comparative bioavailability of the nasal spray formulation is 102%, compared with the oral tablet (40%).

Distribution: The mean apparent volume of distribution is 7 L/kg. Plasma protein binding of zolmitriptan is 25%.[11][12]

Metabolism: Zolmitriptan is metabolized into three major metabolites by the human hepatic cytochrome P450 enzymes—primarily CYP1A2. Two-thirds of the parent compound breaks down into the active metabolite N-desmethyl-zolmitriptan (183C91). At the same time, the remaining one-third separates into the other two inactive metabolites: zolmitriptan N-oxide and an indole acetic acid derivative. Because the metabolite's 5HT1B/1D potency is 2 to 6 times that of the zolmitriptan, the metabolite ( N-desmethyl-zolmitriptan) contributes significantly to the overall effect after zolmitriptan administration. The pharmacokinetics of the N-desmethyl metabolite is similar to that of zolmitriptan for all nasal spray doses. The N-desmethyl metabolite is detected in plasma within 15 minutes, and peak plasma concentration is generally achieved by 3 hours after administration. A recent study revealed that CYP2D6 is the primary enzyme responsible for the metabolic activation of zolmitriptan. Zolmitriptan can be metabolized to an α,β-unsaturated imine intermediate by CYP2D6.[13]

Excretion: Zolmitriptan has an elimination half-life of about three hours; it is primarily excreted by renal elimination; its clearance is greater than the glomerular filtration rate, indicating some renal tubular secretion of the drug.[14][15]

Administration

Formulations: Zolmitriptan is available as an oral tablet, orally-disintegrating tablet, and nasal spray—all of which are available in 2.5 mg or 5 mg doses. The maximum recommended daily dose is 10 mg for adults and pediatric patients ages 12 to 17.[16] Zolmitriptan can be taken with food and water or in a fasting state without altering its clinical effect.[11] This is beneficial for those whose migraines can strike at any time, day or night.

Specific Patient Population

Hepatic Impairment: Due to decreased metabolism, there was a prolonged half-life and elevated plasma levels of zolmitriptan that could cause more peripheral vasoconstrictive effects such as elevated blood pressure.[17] Hepatic enzymes metabolize zolmitriptan, and consequently, people with severe hepatic impairment should have a reduced daily intake because it has been demonstrated that this condition can alter the pharmacokinetics of zolmitriptan, such as decreased metabolism.[11] According to the manufacturer's labeling, after oral zolmitriptan administration, zolmitriptan blood concentrations are raised in patients with moderate to severe hepatic impairment. A marked elevation in blood pressure was observed in some of these patients. Therefore, reduce the zolmitriptan dose and administer it with caution in patients with moderate or severe hepatic impairment.

Renal Impairment: According to the manufacturer's labeling, clearance of zolmitriptan is reduced by 25% in patients with severe renal impairment; no significant change in clearance was observed in patients with moderate renal impairment. Consider dose adjustment in severe renal impairment.

Pregnancy Considerations: According to the manufacturer's labeling, there is a lack of data regarding the developmental risk of using zolmitriptan in pregnancy. Additionally, in reproductive studies in rats and rabbits, oral administration of zolmitriptan to pregnant animals resulted in fetal malformations at clinically relevant exposures. Consequently, consider alternative drugs for the management of migraine during pregnancy.

Breastfeeding Considerations: Preliminary evidence suggests that zolmitriptan levels in breastmilk are low. Amounts ingested by the infant are small and unlikely to affect the nursing infant, especially if the infant is older than two months. But it is important to note that concurrent use of prophylactic propranolol might substantially increase the zolmitriptan dose received by the breastfed infant.[18]

Adverse Effects

• The most common adverse effect in healthy individuals is dysgeusia, particularly with the nasal spray, which is most likely due to the route of the drug's administration. Other minor adverse events that have been documented with intranasal zolmitriptan use are nasal passage irritation, dizziness, throat irritation, and fatigue. Additionally, Phase 1 trials of the Real Life Intranasal Zolmitriptan Exposure (REALIZE) study demonstrated that side effects did not cause participants to discontinue the medication.[19] The Treatment of Acute Migraine Headache in Adolescents (TEENZ) was a double-blind, randomized control trial composed of over 700 pediatric participants. Its results further substantiate the trend in adverse events reported in the REALIZE trial, with dysgeusia being the most frequent adverse event.[4]

• Cardiovascular adverse drug reactions include increased systolic blood pressure in the elderly and increased diastolic blood pressure in both the elderly and young people. Additionally, there is the side effect of a dose-related increase in sedation.[14]

• There is a risk of headaches caused by medication withdrawal or medication overuse.[20]

• Zolmitriptan has a weak affinity for 5-HT 1A receptors; these receptors have implications for the development of serotonin syndrome. The constellation of autonomic and neuromuscular symptoms that comprise the serotonin syndrome can occur in response to the activation of central and peripheral 5-hydroxytryptamine receptors—mainly the 5-HT 1A and 2A receptors subtypes.[7]

• Risk in patients with phenylketonuria: Zolmitriptan orally disintegrating tablets contain phenylalanine (a component of aspartame). Phenylalanine is harmful to patients with phenylketonuria (PKU). However, zolmitriptan tablets do not contain phenylalanine. (manufacturer's labeling)

• Postmarketing case report of transient myopia and increased intraocular pressures in a woman who had been using increasing amounts of zolmitriptan for over a year.[21]

• Hepatotoxicity: Rare individual reports of cholestatic hepatitis after using zolmitriptan. Typically, the onset of injury was within 1 to 2 weeks of taking several doses of the zolmitriptan for a long and severe migraine attack.[22]

Drug-Drug Interactions

• Cimetidine, a CYP1A2 inhibitor, increases zolmitriptan and 183C91 in the systemic circulation, therefore increasing the body's exposure to its vasoconstrictive action; this indicates the need to reduce the total daily dose of zolmitriptan in those taking such inhibitors.[15]

• Zolmitriptan did not demonstrate significant interactions with acetaminophen or metoclopramide, which are often part of a regimen to treat headache symptoms.[23]

• Oral contraceptive use in female study participants did not significantly impact the efficacy or tolerability of the medicine.[11]

Contraindications

• Known hypersensitivity to zolmitriptan (increased risk of angioedema and anaphylaxis)

• Zolmitriptan is contraindicated in cerebrovascular or cardiovascular disease patients because 5-HT 1B receptors are present in coronary arteries. Such conditions include myocardial infarction, prinzmetal angina, stroke, TIA(transient ischemic attack), and peripheral vascular disease.[24]

• Coronary artery disease (history of myocardial infarction, Prinzmetal angina, angina pectoris) 

• Wolff-Parkinson-White Syndrome (WPW) or arrhythmias associated with other cardiac accessory conduction pathway disorders

• Ischemic bowel disease

• Uncontrolled hypertension

• Hemiplegic or basilar migraine since these patients are at a higher risk of stroke.[24][20]

Monitoring

For patients with multiple cardiovascular risk factors, administer the first zolmitriptan dose in a medically-supervised setting and perform an electrocardiogram (EKG) following zolmitriptan administration. For high-risk patients using zolmitriptan for the long term, perform a periodic cardiovascular evaluation. Clinicians should monitor blood pressure in all patients taking zolmitriptan because of its vasoconstrictive properties—especially those with hepatic impairment. Some signs that can indicate elevated blood pressure are headaches and palpitations.[17]

Toxicity

In pediatric cases, zolmitriptan toxicity did not result in life-threatening complications; common signs of toxicity were tachycardia, dyspnea, and vomiting.[25] In adults, overdoses of zolmitriptan have resulted in hypertension, tachycardia, and drowsiness.[26] There have been two reported cases of liver toxicity with zolmitriptan.[27] There is the risk of medication overuse headache, which is avoidable when the patients receive education on the proper administration of their medications.[20] It is important to note that there is no specific antidote to zolmitriptan. In cases of severe overdose, establish and maintain a patent airway, breathing, and circulation.

Enhancing Healthcare Team Outcomes

Headache is a widespread neurologic complaint. Health care providers can create an effective treatment plan when they partner with their patients to elucidate the qualities of that headache experience better. Triptans have the highest efficacy when taken at the beginning of the headache phase, not the prodrome. Patients who received education on their medication use reported a greater understanding of the circumstances for treating their headache pain and contraindications.[28]

Furthermore, providers must consider the ability of patients to afford the medication due to variations in medication coverage by health insurers. Zolmitriptan is the generic formulation of two branded products. Generics are more likely to be covered by commercial and government health insurers, while brand triptans are more likely to be covered by commercial insurers. Insurance plans can limit the formulation type and require meeting step therapy criteria before covering individual formulations.[29]

Recommendations

In 2006, the FDA issued an alert about serotonin syndrome associated with the concomitant use of triptan drugs with SSRIs or SNRIs; however, many have been skeptical of the actual prevalence of this adverse event [30]. For instance, JAMA Neurology published a secondary data analysis of electronic health record data that evaluated outcomes of patients who had been co-prescribed triptans with SSRIs or SNRIs. Of 19,017 patients, 17 were suspected cases, and two were definite cases that met diagnostic criteria.[30] Also, a review of the 29 cases used by the FDA as the basis for the alert found that only seven cases met Sternbach criteria, but no instances met the hunter criteria. Though precipitation of serotonin syndrome appears rare, it is important to be aware of the possibility, given the severity of the condition.[31]

The American Headache Society and the American Academy of Neurology provide evidence-based guidelines on headache treatment that health care providers can use to guide their decisions on treatment. Though the FDA may not currently approve zolmitriptan for the treatment of cluster headaches, the American Academy of Neurology has a Level A recommendation for using both oral and intranasal zolmitriptan for the acute treatment of cluster headaches. Multiple healthcare providers are involved in managing the patient with headaches on zolmitriptan therapy. Hence, clinicians (MDs, DOs, PAs, NPs), specialists, pharmacists, nursing staff, and other healthcare providers should collaborate closely. An interprofessional team approach improves efficacy, minimizes adverse drug reactions related to zolmitriptan therapy, and improves patient outcomes. [Level 5]