Zomig Nasal Spray

— THERAPEUTIC CATEGORIES —
  • Migraine and headache
PAGE CONTENTS
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  • Generic Name & Formulations
  • Indications
  • Dosage and Administration
  • Contraindications
  • Boxed Warnings
  • Warnings/Precautions
  • Pharmacokinetics
  • Interactions
  • Adverse Reactions
  • Clinical Trials
  • Note
  • Patient Counseling

    • Zomig Nasal Spray Generic Name & Formulations

    Legal Class

    Rx

    General Description

    Zolmitriptan 2.5mg, 5mg; per spray.

    Pharmacological Class

    Selective 5-HT1B/1D receptor agonist.

    See Also

    How Supplied

    Tabs, ZMT tabs 2.5mg—6; Tabs, ZMT tabs 5mg—3; Single-dose sprayer—6

    How Supplied

    The Zomig Nasal Spray device is a blue-colored plastic device with a gray protection cap, labeled to indicate the nominal dose. Each Zomig Nasal Spray device administers a single dose of Zomig. Zomig Nasal Spray is supplied as a clear to pale yellow solution of zolmitriptan, buffered to a pH 5.0. Each Zomig Nasal Spray device contains 2.5 mg or 5 mg of zolmitriptan in a 100 µL unit dose aqueous buffered solution containing citric acid, anhydrous, USP, disodium phosphate dodecahydrate USP and purified water USP.

    • 2.5 mg Zomig Nasal Spray is supplied in boxes of 6 single-use nasal spray units.
    • 5 mg Zomig Nasal Spray is supplied in boxes of 6 single-use nasal spray units.

    Storage

    Store Zomig Nasal Spray at controlled room temperature, 20-25°C (68-77°F) [see USP].

    Manufacturer

    Amneal Pharmaceuticals

    Generic Availability

    Tabs (YES); ZMT tabs, sprayer (NO)

    Mechanism of Action

    The therapeutic activity of zolmitriptan is thought to be due to the agonist effects at the 5HT1B/1D receptors on intracranial blood vessels and sensory nerves of the trigeminal system which results in cranial vessel constriction and inhibition of pro-inflammatory neuropeptide release.

    Zomig Nasal Spray Indications

    Indications

    Acute treatment of migraine with or without aura. 

    Limitations of Use

    Use only after a clear diagnosis of migraine has been established. Not indicated for the prevention of migraine attacks. Safety and effectiveness of Zomig have not been established for cluster headache. Nasal Spray: also, not recommended in patients with moderate to severe hepatic impairment.

    Zomig Nasal Spray Dosage and Administration

    Prior to Treatment Evaluations

    Prior to treatment, perform a cardiovascular evaluation in triptan-naïve patients who have multiple cardiovascular risk factors (eg, increased age, diabetes, hypertension, smoking, obesity, strong family history of CAD).

    Adult

    Initially 2.5mg once; max single dose: 5mg. If headache returns, may repeat once after 2 hrs; max 10mg/day. Reevaluate if no response after 1st dose. The safety of treating an average of more than 4 headaches in a 30-day period has not been established. Moderate to severe hepatic impairment: not recommended; use alternate formulation. Concomitant cimetidine: max single dose: 2.5mg, not to exceed 5mg in 24hr period.

    Children

    <12yrs: not established.

    Administration

    Place in nostril and actuate to deliver a single dose. Avoid spraying in eyes.

    Nursing Considerations

    Place in nostril and actuate to deliver a single dose. Avoid spraying in eyes.

    Zomig Nasal Spray Contraindications

    Contraindications

    Ischemic coronary artery disease disease (angina pectoris, history of MI, documented silent ischemia). Other significant underlying cardiovascular disease. Coronary artery vasospasm (eg, Prinzmetal's angina). Wolff-Parkinson-White syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders. History of stroke, TIA, or hemiplegic or basilar migraine. Peripheral vascular disease. Ischemic bowel disease. Uncontrolled hypertension. Within 24 hours of ergot-type drugs or other 5-HT1 agonists. During or within 2 weeks after discontinuing MAOIs (type A).

    Zomig Nasal Spray Boxed Warnings

    Not Applicable

    Zomig Nasal Spray Warnings/Precautions

    Warnings/Precautions

    Confirm diagnosis. Exclude underlying cardiovascular disease, supervise 1st dose, and consider monitoring ECG in patients with likelihood of unrecognized coronary disease (eg, postmenopausal women, men over age 40, hypertension, hypercholesterolemia, obesity, diabetes, smokers, strong family history). Discontinue if disturbances in cardiac rhythm occur. Rule out vasospastic reaction before receiving additional doses. Monitor cardiovascular function in long-term intermittent use. Medication overuse headache: detox may be needed. Hepatic dysfunction. Monitor BP. Elderly. Pregnancy. Nursing mothers.

    Warnings/Precautions

    Myocardial Ischemia, Myocardial Infarction, and Prinzmetal Angina

    • Zomig is contraindicated in patients with ischemic or vasospastic coronary artery disease (CAD). Rare reports of serious cardiac adverse reactions, including acute myocardial infarction, have occurred within a few hours following administration.

    • Prior to treatment, perform a cardiovascular evaluation in triptan-naïve patients who have multiple cardiovascular risk factors (eg, increased age, diabetes, hypertension, smoking, obesity, strong family history of CAD). Do not administer if there is evidence of CAD or coronary artery vasospasm (see Contraindications). For patients with multiple cardiovascular risk factors who have a negative cardiovascular evaluation, consider administering the first Zomig dose in a medically-supervised setting and performing an electrocardiogram (ECG) immediately following administration and consider periodic cardiovascular evaluation in intermittent long-term users of Zomig. 

    Arrhythmias

    • Life-threatening disturbances of cardiac rhythm including ventricular tachycardia and ventricular fibrillation leading to death have been reported within a few hours following the administration of 5-HT1 agonists. Discontinue Zomig if these disturbances occur. 

    • Zomig is contraindicated in patients with Wolff-Parkinson-White Syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders.

    Chest, Throat, Neck and Jaw Pain/Tightness/Pressure

    • Perform a cardiac evaluation if patients who are at high cardiac risk experience sensations of tightness, pain, and pressure in the chest, throat, neck, and jaw after treatment with Zomig. 

    • Zomig is contraindicated in patients with CAD or Prinzmetal’s variant angina.

    Cerebrovascular Events

    • Cerebral hemorrhage, subarachnoid hemorrhage, and stroke have occurred in patients treated with 5-HT1 agonists, and some have resulted in fatalities. 

    • Exclude other potentially serious neurological conditions before treating headaches in patients not previously diagnosed as migraineurs, and in migraineurs who present with symptoms atypical for migraine. Zomig is contraindicated in patients with a history of stroke or transient ischemic attack.

    Other Vasospasm Reactions

    • May cause non-coronary vasospastic reactions, such as peripheral vascular ischemia, gastrointestinal vascular ischemia and infarction (presenting with abdominal pain and bloody diarrhea), splenic infarction, and Raynaud’s syndrome. 

    • Rule out a vasospastic reaction before receiving additional Zomig doses in patients who experience symptoms or signs suggestive of a non-coronary vasospastic reaction following the use of any 5-HT1 agonist.

    • Reports of transient and permanent blindness and significant partial vision loss have been reported with the use of 5-HT1 agonists. A causal relationship between visual  disorders and the use of 5-HT1 agonists has not been clearly established. 

    Medication Overuse Headache

    • Overuse of acute migraine drugs (eg, ergotamine, triptans, opioids, or a combination of drugs for 10 or more days per month) may lead to exacerbation of headache (medication overuse headache).

    • Medication overuse headache may present as migraine-like daily headaches or as a marked increase in frequency of migraine attacks. 

    • May be necessary to detoxify patients, including withdrawal of the overused drugs, and treatment of withdrawal symptoms (which often includes a transient worsening of headache). 

    Serotonin Syndrome

    • The onset of symptoms usually rapidly occurs within minutes to hours of receiving a new or a greater dose of a serotonergic medication. 

    • Discontinue if serotonin syndrome is suspected.

    Increase in Blood Pressure

    • Significant elevations in systemic blood pressure have been reported in patients treated with 5-HT1 agonists including patients without a history of hypertension. 

    • Monitor blood pressure. Zomig is contraindicated in patients with uncontrolled hypertension.

    Risks in Patients with Phenylketonuria

    • Phenylalanine can be harmful to patients with phenylketonuria (PKU). Zomig-ZMT Orally Disintegrating Tablets contain phenylalanine (a component of aspartame). Each 2.5 mg and 5 mg orally disintegrating tablet contains 2.81 and 5.62 mg of phenylalanine, respectively.

    • Zomig tablets do not contain phenylalanine.

    Pregnancy Considerations

    Risk Summary

    • There are no adequate data on the developmental risk associated with the use of Zomig in pregnant women. 

    Clinical Considerations

    • Women with migraine may be at increased risk of preeclampsia during pregnancy.

    Nursing Mother Considerations

    Risk Summary

    • There are no data on the presence of zolmitriptan or its metabolites in human milk, the effects on the breastfed infant, or the effects of zolmitriptan and its metabolites on milk production. 

    • The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Zomig and any potential adverse effects on the breastfed infant from Zomig or from the underlying maternal condition.

    Pediatric Considerations

    Safety and effectiveness of Zomig Nasal Spray in pediatric patients under 12 years of age have not been established.

    Geriatric Considerations

    Clinical studies of Zomig did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. 

    Use caution for dose selection in an elderly patient, 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.

    Prior to receiving Zomig, 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).

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

    Hepatic Impairment Considerations

    The effect of hepatic disease on the pharmacokinetics of zolmitriptan nasal spray has not been evaluated. Zomig nasal spray is not recommended in patients with moderate to severe hepatic impairment.

    Zomig Nasal Spray Pharmacokinetics

    Absorption

    • 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. 

    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; 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.

    Elimination

    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.

    Zomig Nasal Spray Interactions

    Interactions

    MAOIs (type A), methysergide, other ergotamines, other 5-HT1 agonists: see Contraindications. Serotonin syndrome with SSRIs, SNRIs, TCAs, MAOIs; discontinue if suspected. Absorption and half-life increased by cimetidine.

    Zomig Nasal Spray Adverse Reactions

    Adverse Reactions

    Neck/throat/jaw pain/tightness/pressure, dizziness, paresthesia, asthenia, somnolence, warm/cold sensation, nausea, heaviness sensation, dry mouth; rare: serious cardiac events. Nasal spray: also taste disturbances, local reactions.

    Zomig Nasal Spray Clinical Trials

    Clinical Trials

    Zomig Nasal Spray (Adults)

    The efficacy of Zomig nasal spray 2.5 mg and 5 mg in the acute treatment of migraine headache with or without aura in adults 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 was defined as a reduction in headache severity from moderate or severe pain to mild or no pain, and was assessed 15, 30, 45 minutes and 1, 2, and 4 hours after dosing. Patients were allowed to take a dose of escape medication at 4 to 24 hours after the initial treatment for persistent and recurrent headache. 

    Results showed that the 2-hour headache response rates in patients treated with Zomig  nasal spray 2.5 mg and 5 mg were significantly higher compared with placebo, 55% and 69% vs 31%, respectively (P <.001).

    Among patients with migraine associated photophobia, phonophobia, and nausea at baseline, treatment with Zomig nasal spray achieved a decreased incidence of these symptoms compared with placebo.

    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 pretreatment 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 =.0006).

     

    Zomig Nasal Spray (Pediatric Patients 12 to 17 Years of Age)

    The efficacy of Zomig nasal spray 2.5 mg or 5 mg in the acute treatment of migraine headache with or without aura in pediatrics patients 12 to 17 years of age was demonstrated in Study 2, a randomized, double-blind, placebo-controlled trial with a single-blind run-in period.

    Patients had to have an established diagnosis of migraine (history indicating the presence of migraine for at least 1 year) with or without aura with a typical untreated migraine headache attack lasting 3 hours or more. The study included treatment of a single migraine headache attack with 1 dose of single-blind placebo during the 30-day run-in period. If the patient met all conditions for randomization, including a lack of response to the placebo run-in, a subsequent single migraine headache attack was treated with 1 blinded dose of either Zomig nasal spray 5 mg, 2.5 mg, or matching placebo.

    Headache response was defined as a reduction in migraine-related headache pain severity from moderate or severe pain to mild or no pain, and the absence of nausea, photophobia, and phonophobia at 2 hours post treatment were also assessed. 

    The following results showed the proportion of pediatric patients who received Zomig 2.5 mg and 5 mg achieved no headache pain at 2 hours after treatment compared with placebo, respectively:

    • No headache pain: 25% and 30% (P <.05) vs 17%

    • With headache response: 53% (P <.05) and 51% (P <.05) vs 30%

    • No photophobia: 66% (P <.05) and 56% (P <.05) vs 44%

    • No phonophobia: 61% (P <.05) and 58% (P <.05) vs 48% 

    • No nausea: 70% and 72% vs 66%

    Zomig Nasal Spray Note

    Not Applicable

    Zomig Nasal Spray Patient Counseling

    Patient Counseling

    Myocardial Ischemia and/or Infarction, Prinzmetal’s Angina, Other Vasospastic Reactions, and Cerebrovascular Events 

    • Inform patients that Zomig may cause serious cardiovascular adverse reactions such as myocardial infarction or stroke, which may result in hospitalization and even death. Instruct patients to be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and instruct them to ask for medical advice when observing any indicative sign or symptoms; serious cardiovascular reactions may occur without warning symptoms. Instruct patients to seek medical advice if they have symptoms of other vasospastic reactions.

    Medication Overuse Headache

    • Inform patients that use of drugs to treat acute migraines for 10 or more days per month may lead to an exacerbation of headache, and encourage patients to record headache frequency and drug use (e.g., by keeping a headache diary). 

    Serotonin Syndrome

    • Inform patients about the risk of serotonin syndrome with the use of Zomig or other triptans, particularly during combined use with selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs).

    Pregnancy 

    • Advise patients to notify their healthcare provider if they are pregnant or plan to become pregnant.

    Lactation 

    • Advise patients to notify their healthcare provider if they are breastfeeding or plan to breastfeed.

    Handling of Zomig-ZMT Orally Disintegrating Tablets 

    • Inform patients that the Zomig-ZMT Orally Disintegrating Tablets are packaged in a blister and not to remove the orally disintegrating tablet from the blister until just prior to dosing. Instruct patients that prior to dosing, peel open the blister pack and place the orally disintegrating tablet on the tongue, where it will dissolve and be swallowed with the saliva.

    Patients with Phenylketonuria 

    • Inform patients with phenylketonuria (PKU) that Zomig-ZMT contains phenylalanine (a component of aspartame).

    Handling of Zomig nasal spray device 

    • The Zomig Nasal Spray device is packaged in a carton and is a blue-colored plastic device with a gray protection cap, labeled to indicate the nominal dose. Caution patients to not remove the gray protection cap until prior to dosing. Caution patients to avoid spraying the contents of the device in their eyes.

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