Zolmitriptan (nasal spray)
{{DrugProjectFormSinglePage |indicationType=treatment |blackBoxWarningTitle=TITLE |blackBoxWarningBody=Condition Name: (Content) |fdaLIADAdult====Indications=== ZOMIG Nasal Spray is indicated for the acute treatment of migraine with or without aura in adults.
Limitations of Use
Only use ZOMIG if a clear diagnosis of migraine has been established. If a patient has no response to ZOMIG treatment for the first migraine attack, reconsider the diagnosis of migraine before ZOMIG is administered to treat any subsequent attacks. ZOMIG is not indicated for the prevention of migraine attacks. Safety and effectiveness of ZOMIG have not been established for cluster headache Not recommended in patients with moderate or severe hepatic impairment [ see DOSAGE AND ADMINISTRATION (2.2)].
Dosage
2.1 Dosing Information The recommended starting dose for ZOMIG nasal spray is 2.5 mg. As the individual response to ZOMIG Nasal spray may vary, the dose should be adjusted on an individual basis. The maximum recommended single dose of ZOMIG is 5 mg.
In controlled clinical trials, a greater proportion of patients had headache response following a 2.5 mg or 5 mg dose than following a 1 mg dose. There was little added benefit from the 5 mg dose compared to the 2.5 mg dose, but adverse reactions were more frequent with the 5 mg dose.
If the migraine has not resolved by 2 hours after taking ZOMIG, or returns after a transient improvement, another dose may be administered at least 2 hours after the previous dose.
The maximum daily dose should not exceed 10 mg in any 24‑hour period.
The safety of ZOMIG in the treatment of an average of more than four headaches in a 30‑day period has not been established.
2.2 Dosing in Patients with Hepatic Impairment ZOMIG nasal spray is not recommended in patients with moderate to severe hepatic impairment because of increased zolmitriptan blood levels in these patients and elevation of blood pressure in some of these patients. The recommended dosage of ZOMIG nasal spray in patients with mild hepatic impairment is the same as for patients with normal hepatic function [see DOSAGE AND ADMINISTRATION 2.1), WARNINGS AND PRECAUTIONS (5.8), USE IN SPECIFIC POPULATIONS (8.6) and CLINICAL PHARMACOLOGY (12.3)].
2.3 Dosing in Patients taking Cimetidine If ZOMIG is co‑administered with cimetidine, limit the maximum single dose of ZOMIG to 2.5 mg, not to exceed 5 mg in any 24‑hour period [see DRUG INTERACTIONS (7.4) and CLINICAL PHARMACOLOGY (12.3)]. |offLabelAdultGuideSupport=There is limited information regarding Off-Label Guideline-Supported Use of Zolmitriptan (nasal spray) in adult patients. |offLabelAdultNoGuideSupport=There is limited information regarding Off-Label Non–Guideline-Supported Use of Zolmitriptan (nasal spray) in adult patients. |offLabelPedGuideSupport=There is limited information regarding Off-Label Guideline-Supported Use of Zolmitriptan (nasal spray) in pediatric patients. |offLabelPedNoGuideSupport=There is limited information regarding Off-Label Non–Guideline-Supported Use of Zolmitriptan (nasal spray) in pediatric patients. |contraindications=Ischemic coronary artery disease (angina pectoris, history of myocardial infarction, or documented silent ischemia), other significant underlying cardiovascular disease, or coronary artery vasospasm including Prinzmetal’s angina [see Warnings and Precautions (5.1)] Wolff-Parkinson White Syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders [see Warnings and Precautions (5.2)] History of stroke, transient ischemic attack (TIA) or history of hemiplegic or basilar migraine because these patients are at higher risk of stroke [see Warnings and Precautions (5.4)] Peripheral vascular disease (PVD) [see Warnings and Precautions (5.5)] Ischemic bowel disease [see Warnings and Precautions (5.5)] Uncontrolled hypertension [see Warnings and Precautions (5.8)] Recent use (i.e., within 24 hours) of another 5 HT1 agonist, ergotamine-containing medication, or ergot type medication (such as dihydroergotamine or methysergide) [see Drug Interactions (7.1, 7.3)] Concurrent administration of an MAO A inhibitor or recent discontinuation of a MAO A inhibitor (that is within 2 weeks) [see Drug Interactions (7.2) and Clinical Pharmacology (12.3)] Known hypersensitivity to ZOMIG (angioedema and anaphylaxis seen) [see Adverse Reactions (6.2)] |warnings=5.1 Myocardial Ischemia, Myocardial Infarction, and Prinzmetal’s Angina ZOMIG is contraindicated in patients with ischemic or vasospastic coronary artery disease (CAD). There have been rare reports of serious cardiac adverse reactions, including acute myocardial infarction, occurring within a few hours following administration of ZOMIG. Some of these reactions occurred in patients without known CAD. 5 HT1 agonists including ZOMIG may cause coronary artery vasospasm (Prinzmetal’s Angina), even in patients without a history of CAD.
Perform a cardiovascular evaluation in triptan naïve patients who have multiple cardiovascular risk factors (e.g., increased age, diabetes, hypertension, smoking, obesity, strong family history of CAD) prior to receiving ZOMIG. Do not administer ZOMIG if there is evidence of CAD or coronary artery vasospasm [see Contraindications (4)]. For patients with multiple cardiovascular risk factors who have a negative cardiovascular evaluation, consider administrating the first ZOMIG dose in a medically-supervised setting and performing an electrocardiogram (ECG) immediately following ZOMIG administration. For such patients, consider periodic cardiovascular evaluation in intermittent long-term users of ZOMIG.
5.2 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. Patients with Wolff-Parkinson‑White Syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders should not receive ZOMIG [SEE CONTRAINDICATIONS (4)].
5.3 Chest, Throat, Neck and/or Jaw Pain/Tightness/Pressure As with other 5‑HT1 agonists, sensations of tightness, pain, pressure, and heaviness in the precordium, throat, neck, and jaw commonly occur after treatment with ZOMIG and is usually non-cardiac in origin. However, if a cardiac origin is suspected, patients should be evaluated. Patients shown to have CAD and those with Prinzmetal’s variant angina should not receive 5 HT1 agonists [SEE CONTRAINDICATIONS (4)].
5.4 Cerebrovascular Events Cerebral hemorrhage, subarachnoid hemorrhage, and stroke have occurred in patients treated with 5‑HT1 agonists, and some have resulted in fatalities. In a number of cases, it appears possible that the cerebrovascular events were primary, the 5‑HT1 agonist having been administered in the incorrect belief that the symptoms experienced were a consequence of migraine, when they were not. Discontinue ZOMIG if a cerebrovascular event occurs.
As with other acute migraine therapies, before treating headaches in patients not previously diagnosed as migraineurs, and in migraineurs who present with symptoms atypical for migraine, other potentially serious neurological conditions should be excluded. ZOMIG should not be administered to patients with a history of stroke or transient ischemic attack [SEE CONTRAINDICATIONS (4)].
5.5 Other Vasospasm Reactions 5‑HT1 agonists, including ZOMIG, 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. In patients who experience symptoms or signs suggestive of vasospasm reaction following the use of any 5‑HT1 agonist, the suspected vasospasm reaction should be ruled out before receiving additional ZOMIG doses [SEE CONTRAINDICATIONS (4)].
Reports of transient and permanent blindness and significant partial vision loss have been reported with the use of 5‑HT1 agonists. Since visual disorders may be part of a migraine attack, a causal relationship between these events and the use of 5‑HT1 agonists have not been clearly established.
5.6 Medication Overuse Headache Overuse of acute migraine drugs (e.g. 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. Detoxification of patients, including withdrawal of the overused drugs, and treatment of withdrawal symptoms (which often includes a transient worsening of headache) may be necessary.
5.7 Serotonin Syndrome Serotonin syndrome may occur with triptans, including ZOMIG, particularly during co-administration with selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and MAO inhibitors [see DRUG INTERACTIONS (7.5)]. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The onset of symptoms usually rapidly occurs within minutes to hours of receiving a new or a greater dose of a serotonergic medication. ZOMIG treatment should be discontinued if serotonin syndrome is suspected [see DRUG INTERACTIONS (7.5) and PATIENT COUNSELING INFORMATION (17)].
5.8 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. Very rarely these increases in blood pressure have been associated with significant clinical events. In healthy subjects treated with 5 mg of ZOMIG oral tablet, an increase of 1 and 5 mm Hg in the systolic and diastolic blood pressure, respectively, was seen. In a study of patients with moderate to severe liver impairment, 7 of 27 patients experienced 20 to 80 mm Hg elevations in systolic and/or diastolic blood pressure after a dose of 10 mg of ZOMIG oral tablet. As with all triptans, blood pressure should be monitored in ZOMIG‑treated patients. ZOMIG is contraindicated in patients with uncontrolled hypertension [SEE CONTRAINDICATIONS (4)]. |clinicalTrials=Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.
Among 460 patients treating 1180 single attacks with zolmitriptan nasal spray in a blinded placebo controlled trial (Study 1), there was a low withdrawal rate related to adverse reactions: 5 mg (1.3%), 2.5 mg (0%) and placebo (0.4%). None of the withdrawals were due to a serious event. One patient was withdrawn due to abnormal ECG changes from baseline that were incidentally found 23 days after the last dose of ZOMIG Nasal Spray.
The most common adverse reactions (≥5% and > placebo) in any dosage strength in clinical trials for ZOMIG Nasal Spray were: unusual taste, paresthesia, hyperesthesia, and dizziness. The incidence of adverse reactions was generally dose‑related.
Table 1 lists the adverse reactions from the controlled clinical trial (Study 1) that occurred in ≥2% of patients in either the 2.5 or 5 mg zolmitriptan nasal spray dose groups and with an incidence greater than placebo.
In Study 1, adverse clinical reactions occurring in ≥1% and < 2% of patients in all attacks in either zolmitriptan nasal spray dose group and with incidence greater than that of placebo were pain abdominal, chills, pressure throat, edema face, pressure chest, palpitation, dysphagia, arthralgia, myalgia, and depersonalization.
The incidence of adverse reactions in controlled clinical trials was not affected by gender, weight, or age of the patients (18 39 vs. 40 65 years of age), or presence of aura. There were insufficient data to assess the impact of race on the incidence of adverse reactions.
Local Adverse Reactions:
Among 460 patients using ZOMIG 2.5 mg or 5 mg in the controlled clinical trial, approximately 3% noted local irritation or soreness at the site of administration. Adverse reactions of any kind, perceived in the nasopharynx (which may include systemic effects of triptans) were severe in about 1% of patients and approximately 57% resolved in 1 hour. Nasopharyngeal examinations, in a subset of patients participating in two long term trials of up to one year duration, failed to demonstrate any clinically significant changes with repeated use of ZOMIG Nasal Spray.
All nasopharyngeal adverse reactions with an incidence of ≥ 2% of patients in any zolmitriptan nasal spray dose groups are included in ADVERSE REACTIONS Table 1.
Other Adverse Reactions:
In the paragraphs that follow, the frequencies of less commonly reported adverse clinical reactions are presented. Because the reports include reactions observed in open and uncontrolled studies, the role of ZOMIG in their causation cannot be reliably determined. Furthermore, variability associated with adverse reaction reporting, the terminology used to describe adverse reactions, etc., limit the value of the quantitative frequency estimates provided. Reaction frequencies are calculated as the number of patients who used ZOMIG Nasal Spray and reported a reaction divided by the total number of patients exposed to ZOMIG Nasal Spray (n=3059). All reported reactions are included except those already listed in the previous table, those too general to be informative, and those not reasonably associated with the use of the drug. Reactions are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: infrequent adverse reactions are those occurring in 1/100 to 1/1,000 patients and rare adverse reactions are those occurring in fewer than 1/1,000 patients.
General: Infrequent: allergic reactions.
Cardiovascular: Infrequent: arrhythmias, hypertension, syncope and tachycardia. Rare: angina pectoris and myocardial infarct.
Digestive: Rare: stomatitis.
Neurological: Infrequent: agitation, amnesia, anxiety, depression, insomnia, and nervousness. Rare: convulsions.
Respiratory: Infrequent: bronchitis, increased cough, dyspnea, epistaxis, laryngeal edema, pharyngitis, rhinitis, and sinusitis.
Skin: Infrequent: pruritus, rash, and urticaria.
Urogenital: Infrequent: polyuria and urinary urgency. Rare: urinary frequency.
Special senses: Infrequent: tinnitus. Rare: conjunctivitis, dry eye, and visual field defect.
The adverse experience profile seen with ZOMIG Nasal Spray is similar to that seen with ZOMIG tablets and ZOMIG/ZMT tablets except for the occurrence of local adverse reactions from the nasal spray (see ZOMIG tablet/ZOMIG‑ZMT oral disintegrating tablet Prescribing Information). |postmarketing=The following adverse reactions were identified during post approval use of ZOMIG. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
The reactions enumerated include all except those already listed in the Clinical Trials Experience section above or the Warnings and Precautions section.
Hypersensitivity Reactions:
As with other 5 HT1B/1D agonists, there have been reports of anaphylaxis, anaphylactoid, and hypersensitivity reactions including angioedema in patients receiving ZOMIG. ZOMIG is contraindicated in patients with a history of hypersensitivity reaction to ZOMIG. |drugInteractions=7.1 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 ZOMIG within 24 hours of each other is contraindicated [see CONTRAINDICATIONS (4)].
7.2 MAO-A Inhibitors MAO-A inhibitors increase the systemic exposure of zolmitriptan. Therefore, the use of ZOMIG in patients receiving MAO-A inhibitors is contraindicated [see Contraindications (4) and CLINICAL PHARMACOLOGY (12.3)].
7.3 5-HT1B/1D agonists (e.g. triptans) Concomitant use of other 5-HT1B/1D agonists (including triptans) within 24 hours of ZOMIG treatment is contraindicated because the risk of vasospastic reactions may be additive [see CONTRAINDICATIONS (4)].
7.4 Cimetidine Following administration of cimetidine, the half‑life and AUC of ZOMIG and its active metabolites were approximately doubled [see CLINICAL PHARMACOLOGY (12.3)]. If cimetidine and ZOMIG are used concomitantly, limit the maximum single dose of ZOMIG to 2.5 mg, not to exceed 5 mg in any 24 hour period [see DOSAGE AND ADMINISTRATION (2.3) and CLINICAL PHARMACOLOGY (12.3)].
7.5 Selective Serotonin Reuptake Inhibitors/Serotonin Norepinephrine Reuptake Inhibitors and Serotonin Syndrome Cases of life-threatening serotonin syndrome have been reported during combined use of selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs) and triptans [see WARNINGS AND PRECAUTIONS (5.7)]. |FDAPregCat=C |useInPregnancyFDA=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. |useInNursing=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 ZOMIG, 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. |useInPed=Safety and effectiveness in pediatric patients have not been established.
A single, multicenter, double-blind, randomized placebo-controlled, study was conducted to evaluate the efficacy of ZOMIG 5 mg nasal spray in the acute treatment of migraine headache in 171 evaluable adolescent subjects 12 to 17 years of age. Efficacy was not established in that study.
Adverse reactions observed in this study were similar in nature and frequency to those reported in clinical trials of ZOMIG Nasal Spray in adults. The most commonly reported adverse reactions (≥ 2% and > placebo) were dysgeusia (7%), nasal discomfort (3%), dizziness (2%), nasal congestion (2%), nausea (2%), and throat irritation (2%).
ZOMIG Nasal Spray has not been studied in pediatric patients age 11 years and under.
In the postmarketing experience with triptans, including ZOMIG, there is a limited number of reports that describe pediatric patients who have experienced clinically serious adverse events; those that were reported are similar in nature to those reported rarely in adults. |useInGeri=Clinical studies of ZOMIG 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. Geriatric patients who have other cardiovascular risk factors (e.g., diabetes, hypertension, smoking, obesity, strong family history of coronary artery disease) should have a cardiovascular evaluation prior to receiving ZOMIG [see WARNINGS AND PRECAUTIONS (5.1)]. The pharmacokinetics of zolmitriptan were similar in geriatric patients (aged > 65 years) compared to younger patients [see CLINICAL PHARMACOLOGY (12.3)]. |useInHepaticImpair=The effect of hepatic disease on the pharmacokinetics of zolmitriptan nasal spray has not been evaluated. After oral 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 [seeWARNINGS AND PRECAUTIONS (5.8)]. ZOMIG nasal spray is not recommended in patients with moderate to severe hepatic impairment [see DOSAGE AND ADMINISTRATION (2.2) and CLINICAL PHARMACOLOGY (12.3)]. |overdose=There is no experience with acute overdose. Clinical study subjects receiving single 50 mg oral doses of zolmitriptan commonly experienced sedation.
The elimination half-life of ZOMIG is 3 hours[see CLINICAL PHARMACOLOGY (12.1)] and therefore monitoring of patients after overdose with ZOMIG should continue for at least 15 hours or while symptoms or signs persist.
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.
It is unknown what effect hemodialysis or peritoneal dialysis has on the plasma concentrations of zolmitriptan. |structure=zolmitriptan nasal spray contains zolmitriptan, which is a selective 5-hydroxytryptamine 1B/1D (5-HT1B/1D) receptor agonist. Zolmitriptan is chemically designated as (S)-4-[[3-[2-(dimethylamino)ethyl]-1H-indol-5-yl]methyl]-2-oxazolidinone and has the following chemical structure:
The empirical formula is C16H21N3O2, representing a molecular weight of 287.36. Zolmitriptan is a white to almost white powder that is readily soluble in water. ZOMIG Nasal Spray is supplied as a clear to pale yellow solution of zolmitriptan, buffered to a pH 5.0. Each ZOMIG Nasal Spray 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.
ZOMIG Nasal Spray is hypertonic. The osmolarity of ZOMIG Nasal Spray for 2.5 mg is 360 to 420 mOsmol, and for 5 mg is 420 to 470 mOsmol.
|alcohol=Alcohol-Zolmitriptan (nasal spray) interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. }}