RECENT MAJOR CHANGES SECTION

RECENT MAJOR CHANGES

Dosage and Administration (2.1, 2.3, 2.4) 09/2012

Warnings and Precautions (5.6) 09/2012

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INDICATIONS & USAGE SECTION

1 INDICATIONS AND USAGE

Zolmitriptan is indicated for the acute treatment of migraine with or without aura in adults.

Limitations of Use

• Only use zolmitriptan if a clear diagnosis of migraine has been established. If a patient has no response to zolmitriptan treatment for the first migraine attack, reconsider the diagnosis of migraine before zolmitriptan is administered to treat any subsequent attacks.
• Zolmitriptan is not indicated for the prevention of migraine attacks.
• Safety and effectiveness of zolmitriptan have not been established for cluster headache.

DOSAGE FORMS & STRENGTHS SECTION

3 DOSAGE FORMS AND STRENGTHS

2.5 mg Orally Disintegrating Tablets: White to off-white, round, flat faced bevelled edge tablets debossed with '359' on one side and 'L' on other side.

5 mg Orally Disintegrating Tablets: White to off-white, round, flat faced bevelled edge tablets debossed with '360' on one side and 'L' on other side.

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CONTRAINDICATIONS SECTION

Highlight: * History of coronary artery disease (CAD)or coronary vasospasm (4)

• Symptomatic Wolff-Parkinson-White syndrome or other cardiac accessory conduction pathway disorders (4)
• History of stroke, transient ischemic attack, or hemiplegic or basilar migraine (4)
• Peripheral vascular disease (4)
• Ischemic bowel disease (4)
• Uncontrolled hypertension (4)
• Recent (within 24 hours) use of another 5-HT1 agonist (e.g., another triptan), or an ergotamine-containing medication (4)
• Monamine oxidase (MAO)-A inhibitor used in past 2 weeks (4)
• Known hypersensitivity to zolmitriptan (4)

4 CONTRAINDICATIONS

Zolmitriptan is contraindicated in patients with:

• 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 a 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 a monoamine oxidase (MAO)-A inhibitor or recent use of a MAO-A inhibitor (that is within 2 weeks) [see Drug Interactions (7.2) and Clinical Pharmacology (12.3)]
• Known hypersensitivity to zolmitriptan (angioedema and anaphylaxis seen) [see Adverse Reactions (6.2)]

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USE IN SPECIFIC POPULATIONS SECTION

Highlight: Pregnancy: Based on animal data, may cause fetal harm (8.1) (8)

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

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.

8.3 Nursing Mothers

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 zolmitriptan, 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.

8.4 Pediatric Use

The safety and effectiveness in pediatric patients have not been established. Therefore, zolmitriptan is not recommended for use in patients under 18 years of age.

One randomized, placebo-controlled clinical trial of zolmitriptan (2.5, 5 and 10 mg) evaluated 696 pediatric patients (aged 12 to 17 years) with migraines. This study did not demonstrate the efficacy of zolmitriptan compared to placebo in the treatment of migraine in adolescents. Adverse reactions in the adolescent patients treated with zolmitriptan were similar in nature and frequency to those reported in clinical trials in adults treated with zolmitriptan. Zolmitriptan has not been studied in pediatric patients less than 12 years old.

In the postmarketing experience with triptans, including zolmitriptan, there were no additional adverse reactions seen in pediatric patients that were not seen in adults.

8.5 Geriatric Use

Clinical studies of zolmitriptan 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.

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) prior to receiving zolmitriptan [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)].

8.6 Patients with Hepatic Impairment

After oral zolmitriptan 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 [see Warnings and Precautions (5.8)]. Therefore, adjust the zolmitriptan tablet dose and administer with caution in patients with moderate or severe hepatic impairment [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].

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ADVERSE REACTIONS SECTION

Highlight: Most common adverse reactions (≥5% and >placebo) were neck/throat/ jaw pain/tightness/pressure, dizziness, paresthesia, asthenia, somnolence, warm/cold sensation, nausea, heaviness sensation, and dry mouth (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6 ADVERSE REACTIONS

The following adverse reactions are described elsewhere in other sections of the prescribing information:

• Myocardial Ischemia, Myocardial Infarction, and Prinzmetal Angina

[seeWarnings and Precautions (5.1)].

• Arrthymias

[see Warnings and Precautions (5.2)].

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

[see Warnings and Precautions (5.3)].

• Cerebrovascular Events

[seeWarnings and Precautions (5.4)].

• Other Vasospasm Reactions

[seeWarnings and Precautions (5.5)].

• Medication Overuse Headache

[seeWarnings and Precautions (5.6)].

• Serotonin Syndrome

[seeWarnings and Precautions (5.7)].

• Increase in Blood Pressure

[seeWarnings and Precautions (5.8)].

• Risks in Patients with Phenylketonuria

[seeWarnings and Precautions (5.9)].

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.

In a long-term, open-label study where patients were allowed to treat multiple migraine attacks for up to 1 year, 8% (167 out of 2,058) withdrew from the trial because of adverse reaction.

The most common adverse reactions (≥5% and >placebo) in these trials were neck/throat/jaw pain, dizziness, paresthesia, asthenia, somnolence, warm/cold sensation, nausea, heaviness sensation, and dry mouth.

Table 1 lists the adverse reactions that occurred in ≥2% of the 2,074 patients in any one of the zolmitriptan 1 mg, 2.5 mg, or 5 mg dose groups in the controlled clinical trials of zolmitriptan in patients with migraines (Studies 1, 2, 3, 4, and 5) [see Clinical Studies (14)]. Only adverse reactions that were at least 2% more frequent in a zolmitriptan group compared to the placebo group are included.

Several of the adverse reactions appear dose related, notably paresthesia, sensation of heaviness or tightness in chest, neck, jaw, and throat, dizziness, somnolence and possibly asthenia and nausea.

Table 1: Adverse Reaction Incidence in Five Pooled Placebo-Controlled MigraineClinical Trials1

1Only adverse reactions that were at least 2% more frequent in a zolmitriptan group compared to the placebo group are included.

There were no differences in the incidence of adverse reactions in controlled clinical trials in the following subgroups: gender, weight, age, use of prophylactic medications, or presence of aura. There were insufficient data to assess the impact of race on the incidence of adverse reactions.

Less Common Adverse Reactions with Zolmitriptan Tablets:

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. Adverse reaction frequencies were calculated as the number of patients who used zolmitriptan tablets and reported a reaction divided by the total number of patients exposed to zolmitriptan tablets (n=4,027). Reactions were further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: infrequent adverse reactions (those occurring in 1/100 to 1/1,000 patients) and rare adverse reactions (those occurring in less than 1/1,000 patients).

General**:**Infrequent were allergic reactions.

Cardiovascular**:**Infrequent were arrhythmias, hypertension, and syncope. Rare was tachycardia.

Neurological**:**Infrequent were agitation, anxiety, depression, emotional lability and insomnia; Rare were amnesia, hallucinations, and cerebral ischemia.

Skin**:**Infrequent were pruritus, rash and urticaria.

Urogenital: Infrequent were polyuria, urinary frequency and urinary urgency.

Adverse Reactions with Zolmitriptan Oral Disintegrating Tablets

The adverse reaction profile seen with zolmitriptan oral disintegrating tablets was similar to that seen with zolmitriptan tablets.

6.2 Postmarketing Experience

The following adverse reactions were identified during post approval use of zolmitriptan. 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 zolmitriptan. Zolmitriptan is contraindicated in patients with a history of hypersensitivity reaction to zolmitriptan.

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HOW SUPPLIED SECTION

16 HOW SUPPLIED/STORAGE AND HANDLING

**2.5 mg Orally Disintegrating Tablets -**White to off-white, round, flat faced bevelled edge tablets debossed with ‘359’ on one side and ‘L’ on other side.

NDC 46708-181-06 Carton of 1 blister of 6 tablets
**5 mg Orally Disintegrating Tablets -**White to off-white, round, flat faced bevelled edge tablets debossed with ‘360’ on one side and ‘L’ on other side.

NDC 46708-182-03 Carton of 1 blister of 3 tablets

Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Protect from light and moisture.

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SPL UNCLASSIFIED SECTION

Patient Information

Zolmitriptan (ZOLE-mi-TRIP-tan) Orally Disintegrating Tablets

Please read this information before you start taking zolmitriptan and each time you renew your prescription just in case anything has changed. Remember, this summary does not take the place of discussions with your doctor. You and your doctor should discuss zolmitriptan when you start taking your medication and at regular checkups.

What is zolmitriptan?
****Zolmitriptan is a prescription medication used to treat migraine headaches in adults. Zolmitriptan is not for other types of headaches. The safety and efficacy of zolmitriptan in patients under 18 have not been established.

What is a Migraine Headache?
****Migraine is an intense, throbbing headache. You may have pain on one or both sides of your head. You may have nausea and vomiting, and be sensitive to light and noise. The pain and symptoms of a migraine headache can be worse than a common headache. Some women get migraines around the time of their menstrual period. Some people have visual symptoms before the headache, such as flashing lights or wavy lines, called an aura.

How does zolmitriptan work?
****Treatment with zolmitriptan reduces swelling of blood vessels surrounding the brain. This swelling is associated with the headache pain of a migraine attack. Zolmitriptan blocks the release of substances from nerve endings that cause more pain and other symptoms like nausea, and sensitivity to light and sound. It is thought that these actions contribute to relief of your symptoms by zolmitriptan.

Who should not take zolmitriptan?
** Do not take zolmitriptan if you:**
****•Have heart disease or a history of heart disease
•Have uncontrolled high blood pressure
•Have hemiplegic or basilar migraine (if you are not sure about this, ask your doctor)
•Have or had a stroke or problems with your blood circulation
•Have serious liver problems
•Have taken any of the following medicines in the last 24 hours: other “triptans” like almotriptan (AXERT®), eletriptan (RELPAX®), frovatriptan (FROVA®), naratriptan (AMERGE®), rizatriptan (MAXALT®), sumatriptan (IMITREX®), sumatriptan/naproxen (TREXIMET); ergotamines like BELLERGAL-S®, CAFERGOT®, ERGOMAR®, WIGRAINE®; dihydroergotamine like D.H.E. 45® or MIGRANAL®; or methysergide (SANSERT®). These medications have side effects similar to zolmitriptan.
•Have taken monoamine oxidase (MAO) inhibitors such as phenelzine sulfate (NARDIL®) or tranylcypromine sulfate (PARNATE®) for depression or other conditions within the last 2 weeks.
•Are allergic to zolmitriptan or any of its ingredients. The active ingredient is zolmitriptan. The inactive ingredients are listed at the end of this leaflet.

Tell your doctor about all the medicines you take or plan to take, including prescription and non-prescription medicines, supplements, and herbal remedies.

Tell your doctor if you are sensitive to phenylalanine, which can be found in the artificial sweetener aspartame. Zolmitriptan orally disintegrating tablet contains phenylalanine.

Tell your doctor if you are taking selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs), two types of drugs for depression or other disorders. Common SSRIs are CELEXA® (citalopram HBr), LEXAPRO® (escitalopram oxalate), PAXIL® (paroxetine), PROZAC® (fluoxetine), SYMBYAX® (olanzapine/fluoxetine), ZOLOFT® (sertraline), SARAFEM® (fluoxetine) and LUVOX® (fluvoxamine). Common SNRIs are CYMBALTA® (duloxetine) and EFFEXOR® (venlafaxine). Your doctor will decide if you can take zolmitriptan with your other medicines.

Tell your doctor if you know that you have any of the following: risk factors for heart disease like high cholesterol, diabetes, smoking, obesity (overweight), menopause, or a family history of heart disease or stroke.

Tell your doctor if you are pregnant, planning to become pregnant, breast feeding, planning to breast feed, or not using effective birth control.

How should I take zolmitriptan?
****•Take zolmitriptan exactly as your doctor tells you to take it. Your doctor will tell you how much zolmitriptan to take and when to take it.
•If you take zolmitriptan oral disintegrating tablets, do not remove the tablet from the blister pack until you are ready to take your medicine.
•You do not need to take any liquids with your zolmitriptan oral disintegrating tablets.
•Take zolmitriptan oral disintegrating tablets whole.
•Place zolmitriptan oral disintegrating tablets on your tongue, where it will dissolve.
•Safely throw away any unused tablets or pieces of tablets that have been removed from the blister packaging.
•If your headache comes back after your first dose, you may take a second dose anytime after 2 hours of taking the first dose. For any attack where the first dose did not work, do not take a second dose without talking with your doctor. Do not take more than a total of 10 mg of zolmitriptan (tablets or spray combined in any 24 hour period). If you take too much medicine, contact your doctor, hospital emergency department, or poison control center right away.

What are the possible side effects of zolmitriptan?
****Zolmitriptan is generally well tolerated. As with any medicine, people taking zolmitriptan may have side effects. The side effects are usually mild and do not last long.

The most common side effects of zolmitriptan are:
•Pain, pressure or tightness in the neck, throat or jaw
•dizziness
•tingling or other abnormal sensations
•tiredness
•drowsiness
•feeling warm or cold
•nausea
•feeling of tightness or heaviness in other areas of the body
•dry mouth

In very rare cases, patients taking triptans may experience serious side effects, such as heart attacks, high blood pressure, stroke, or serious allergic reactions. Extremely rarely, patients have died.Call your doctor right away if you have any of the following problems after taking zolmitriptan:

•severe tightness, pain, pressure or heaviness in your chest, throat, neck, or jaw
** •shortness of breath or wheezing**
** •sudden or severe stomach pain**
** •hives; tongue, mouth, or throat swelling**
** •problems seeing**
** •unusual weakness or numbness**

Some people may have a reaction called serotonin syndrome, which can be life- threatening, when they use zolmitriptan. In particular, this reaction may occur when they use zolmitriptan together with certain types of antidepressants known as SSRIs or SNRIs. Symptoms may include mental changes (hallucinations, agitation, coma), fast heartbeat, changes in blood pressure, high body temperature or sweating, tight muscles, trouble walking, nausea, vomiting, and diarrhea. Call your doctor immediately if you have any of these symptoms after taking zolmitriptan.

Call your doctor for medical advice about side effects. You may report side effects at 1-866-562-4597 or FDA at 1-800-FDA-1088.

This is not a complete list of side effects. Talk to your doctor if you develop any symptoms that concern you.

What to do in case of an overdose?
****Call your doctor or poison control center or go to the nearest hospital emergency room.

General advice about zolmitriptan
****Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use zolmitriptan for a condition for which it was not prescribed. Do not give zolmitriptan to other people, even if they have the same symptoms as you. People may be harmed if they take medicines that have not been prescribed for them.

This leaflet summarizes the most important information about zolmitriptan. If you would like more information about zolmitriptan, talk to your doctor. You can ask your doctor or pharmacist for information on zolmitriptan that is written for healthcare professionals.

What are the Ingredients in zolmitriptan?
****Zolmitriptan Orally Disintegrating Tablets
Active ingredient: zolmitriptan
Inactive ingredients: mannitol, microcrystalline cellulose, crospovidone, aspartame, sodium stearyl fumarate, colloidal silicon dioxide, magnesium stearate, orange flavor, modified food starch and triacetin.

Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature] and away from children. Protect from light and moisture. Discard when expired.

Other brands mentioned are trademarks of their respective owners. The makers of these brands are not affiliated with Alembic Pharmaceuticals Limited or its products.

Manufactured by:
Alembic Pharmaceuticals Limited
(Formulation Division),
Village Panelav, P. O. Tajpura, Near Baska,
Taluka-Halol, Panchmahal, Gujarat, India.

Revised: 03/2016

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