Zolmitriptan (Page 2 of 7)

5.5 Other Vasospasm Reactions

5-HT₁ agonists, including zolmitriptan, 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 zolmitriptan 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 zolmitriptan, 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. Zolmitriptan 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 zolmitriptan 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 zolmitriptan oral tablet. As with all triptans, blood pressure should be monitored in zolmitriptan-treated patients. Zolmitriptan is contraindicated in patients with uncontrolled hypertension [see Contraindications (4) ].

6 ADVERSE REACTIONS

The following adverse reactions are discussed in more detail in other sections of labeling:

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Myocardial Ischemia, Myocardial Infarction, and Prinzmetal’s Angina [see Warnings and Precautions (5.1) ]

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Arrhythmias [see Warnings and Precautions (5.2) ]

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Chest, Throat, Neck and/or Jaw Pain/Tightness/Pressure [see Warnings and Precautions (5.3) ]

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Cerebrovascular Events [see Warnings and Precautions (5.4) ]

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Other Vasospasm Reactions [see Warnings and Precautions (5.5) ]

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Medication Overuse Headache [see Warnings and Precautions (5.6) ]

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Serotonin Syndrome [see Warnings and Precautions (5.7) ]

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Increase in Blood Pressure [see Warnings and Precautions (5.8) ]

6.1 Clinical Trials Experience

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.

Adults

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 zolmitriptan nasal spray.

The most common adverse reactions (≥ 5% and > placebo) in any dosage strength in clinical trials for zolmitriptan 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.

Table 1: Adverse reactions in a Placebo-Controlled Study in Adult Patients with Migraine (Study 1)

Body System Adverse Reaction	Placebo (N=228)	Zolmitriptan 2.5 mg (N=224)	Zolmitriptan 5 mg (N=236)
Atypical Sensations
Hyperesthesia	0%	1%	5%
Paraesthesia	6%	5%	10%
Warm Sensation	2%	4%	0%
Ear/Nose/ Throat
Disorder/Discomfort of nasal cavity	2%	1%	3%
Pain and Pressure Sensations
Pain Location Specified	1%	2%	4%
Throat Pain	1%	4%	4%
Throat Tightness	1%	<1%	2%
Digestive
Dry Mouth	<1%	3%	2%
Nausea	1%	1%	4%
Neurological
Dizziness	4%	6%	3%
Somnolence	2%	1%	4%
Other
Unusual Taste	3%	17%	21%
Asthenia	1%	3%	3%

In Study 1, adverse 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: abdominal pain, chills, throat pressure, facial edema, chest pressure, 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 zolmitriptan 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 zolmitriptan nasal spray.

All nasopharyngeal adverse reactions with an incidence of ≥ 2% of patients in any zolmitriptan nasal spray dose groups are included in 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 zolmitriptan 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 zolmitriptan nasal spray and reported a reaction divided by the total number of patients exposed to zolmitriptan 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 reaction profile seen with zolmitriptan nasal spray is similar to that seen with zolmitriptan tablets and zolmitriptan oral disintegrating tablets except for the occurrence of local adverse reactions from the nasal spray.

Pediatric Patients 12 to 17 Years of Age

The safety of zolmitriptan nasal spray in the acute treatment of migraine in pediatric patients 12 to 17 years of age was established in two studies [see Pediatric Use (8.4) and Clinical Studies (14.2)].

The most common adverse reactions (incidence of ≥ 2% of pediatric patients receiving 2.5 mg and 5 mg zolmitriptan nasal spray and numerically greater than placebo) after a single dose are summarized in Table 2. Dysgeusia (unusual taste) was the most common adverse reaction, with a numerically greater incidence for patients receiving zolmitriptan compared to placebo (10% vs. 2%). Other common adverse reactions were nasal discomfort, dizziness, oropharyngeal pain, and nausea.

Table 2 lists the adverse reactions from the pooled placebo-controlled studies that occurred in ≥ 2% of pediatric patients 12 to 17 years of age in either the 2.5 mg or 5 mg zolmitriptan dose groups and with an incidence greater than placebo.

Table 2: Adverse reactions in Pooled Placebo-Controlled Studies in Pediatric Patients 12 to 17 years of Age with Migraine

Adverse Reaction	Placebo (N=437)	Zolmitriptan 2.5 mg (N=81)	Zolmitriptan 5 mg (N=431)
Unusual taste	2%	6%	10%
Nasal discomfort	1%	3%	3%
Dizziness	1%	0%	2%
Oropharyngeal pain	2%	0%	2%
Nausea	1%	1%	2%

The adverse reaction profile was similar across gender. There were insufficient data to assess the impact of race on the incidence of adverse reactions.