Zomig

— 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 Generic Name & Formulations

    Legal Class

    Rx

    General Description

    Zolmitriptan 2.5mg+, 5mg; tabs; +scored.

    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

    2.5 mg Tablets - Yellow, biconvex, round, film-coated, functionally-scored tablets containing 2.5 mg of zolmitriptan identified with “ZOMIG” and “2.5” debossed on one side are supplied in cartons containing a blister pack of 6 tablets. 

    5 mg Tablets – Pink, biconvex, round, film-coated tablets containing 5 mg of zolmitriptan identified with “ZOMIG” and “5” debossed on one side are supplied in cartons containing a blister pack of 3 tablets.

    Storage

    Store Zomig Tablets and Zomig-ZMT Tablets at controlled room temperature, 20 - 25ºC (68 - 77ºF) [see USP]. Protect from light and moisture. 

    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 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 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

    ≥18yrs: Initially 1.25–2.5mg; max single dose: 5mg. If headache returns, may repeat after 2 hrs; max 10mg/day. Reevaluate if no response after 1st dose. The safety of treating an average of more than 3 headaches in a 30-day period has not been established. Moderate to severe hepatic impairment: 1.25mg; severe hepatic impairment: max 5mg/day. Concomitant cimetidine: max single dose: 2.5mg, not to exceed 5mg in 24hr period. ZMT: do not break tabs; dissolve on tongue and swallow without water (not for use in moderate to severe hepatic impairment).

    Children

    <18yrs: not recommended.

    Administration

    The 1.25mg dose can be achieved by manually breaking the functionally-scored 2.5mg tablet in half.

    Nursing Considerations

    The 1.25mg dose can be achieved by manually breaking the functionally-scored 2.5mg tablet in half.

    Zomig 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 Boxed Warnings

    Not Applicable

    Zomig 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

    • The safety and effectiveness of Zomig Tablets and Zomig-ZMT Orally Disintegrating Tablets in pediatric patients have not been established.
    • Therefore, Zomig Tablets and Zomig-ZMT Orally Disintegrating Tablets are not recommended for use in patients under 18 years of age.

    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

    After oral Zomig Tablets and Zomig-ZMT Orally Disintegrating Tablets 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. Adjust the Zomig Tablets and Zomig-ZMT Orally Disintegrating Tablets dose and administer with caution in patients with moderate or severe hepatic impairment.

    Zomig Pharmacokinetics

    Absorption

    Zolmitriptan is well absorbed after oral administration for both Zomig tablets and the Zomig-ZMT 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 Zomig-ZMT Orally Disintegrating Tablet compared with 1.5 hours for the Zomig 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 Zomig 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. 

    Distribution

    Zolmitriptan Tablets: 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 10-1000 ng/mL.

    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

    Total radioactivity recovered in urine and feces was 65% and 30% of the administered dose, respectively. Mean total plasma clearance is 31.5 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 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 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 Clinical Trials

    Clinical Trials

    Zomig Tablets

    The efficacy of Zomig tablets in the acute treatment of migraine headaches was demonstrated in five randomized, double-blind, placebo-controlled studies (Studies 1, 2, 3, 4, and 5), of which two utilized the 1 mg dose, two utilized the 2.5 mg dose and four utilized the 5 mg dose. 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 post-dose. 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 Zomig was compared to placebo in the treatment of a single migraine attack.

    In all five studies, a significantly greater proportion of patients who received Zomig 1 mg, 2.5 mg, and 5mg doses (except for the 1 mg dose in the smallest study) achieved headache responses 2 hours after treatment compared to those who received placebo. The following percentages of patients achieved headache response 2 hours after treatment in Studies 1 through 5: 

    • Study 1: 

      • Zomig 1 mg: 27% (n=22); Zomig 2 mg: Not applicable (NA); Zomig 5 mg: 60% (n=20; P <.05 in comparison with placebo and 1mg) vs placebo: 16% (n=19)

    • Study 2: 

      • Zomig 1 mg: NA; Zomig 2 mg: NA; Zomig 5 mg: 66% (n=179; P <.05 in comparison with placebo) vs placebo: 19% (n=88)

    • Study 3: 

      • Zomig 1 mg: 50% (n=140; P <.05 in comparison with placebo); Zomig 2mg: 65% (n=260; P <.05 in comparison with placebo and 1mg); Zomig 5 mg: 67% (n=245; P <.05 in comparison with placebo and 1mg) vs placebo: 34% (n=121)

    • Study 4: 

      • Zomig 1 mg: NA; Zomig 2 mg: NA; Zomig 5 mg: 59% (n=491; P <.05 in comparison with placebo) vs placebo: 44% (n=55)

    • Study 5:

      • Zomig 1 mg: NA; Zomig 2 mg: 62% (n=178; P <.05 in comparison with placebo); Zomig 5 mg: NA vs placebo: 36% (n=92)

    For patients with migraine associated photophobia, phonophobia, and nausea at baseline, there was a decreased incidence of these symptoms following administration of Zomig tablets as compared with placebo.

    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; pre-treatment nausea or concomitant use of common migraine prophylactic drugs.

    Zomig Note

    Not Applicable

    Zomig 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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