Xibimer

Xibimer Nasal Spray is indicated for the acute treatment of migraine attacks with or without aura.

Xibimer® Injection is indicated in adults for (1) the acute treatment of migraine, with or without aura, and (2) the acute treatment of cluster headache.

Limitations of Use

• Use only if a clear diagnosis of migraine or cluster headache has been established. If a patient has no response to the first migraine or cluster headache attack treated with Xibimer Injection, reconsider the diagnosis before Xibimer Injection is administered to treat any subsequent attacks.
• Xibimer Injection is not indicated for the prevention of migraine or cluster headache attacks.

Xibimer film-coated tablets are indicated for the acute relief of migraine attacks, with or without aura. Xibimer film-coated tablets should only be used where there is a clear diagnosis of migraine.

IMITREX® Injection is indicated in adults for (1) the acute treatment of migraine, with or without aura, and (2) the acute treatment of cluster headache.

Limitations of Use

• Use only if a clear diagnosis of migraine or cluster headache has been established. If a patient has no response to the first migraine or cluster headache attack treated with IMITREX Injection, reconsider the diagnosis before IMITREX Injection is administered to treat any subsequent attacks.
• IMITREX Injection is not indicated for the prevention of migraine or cluster headache attacks.

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

Limitations Of Use

• Use only if a clear diagnosis of migraine has been established.
• If a patient has no response to the first migraine attack treated with Xibimer reconsider the diagnosis of migraine before Xibimer is administered to treat any subsequent attacks.
• Xibimer is not intended for the prevention of migraine attacks.

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

Limitations Of Use

• Use only if a clear diagnosis of migraine has been established.
• If a patient has no response to the first migraine attack treated with ZECUITY reconsider the diagnosis of migraine before ZECUITY is administered to treat any subsequent attacks.
• ZECUITY is not intended for the prevention of migraine attacks.

Xibimer Nasal Spray should not be used prophylactically.

The recommended dose of Xibimer should not be exceeded.

Xibimer is recommended as monotherapy for the acute treatment of a migraine attack and should not be given concomitantly with ergotamine or derivatives of ergotamine (including methysergide).

It is advisable that Xibimer be given as early as possible after the onset of a migraine headache. It is equally effective at whatever stage of the attack it is administered.

Adults (18 years of age and over)

The optimal dose of Xibimer Nasal Spray is 20 mg for administration into one nostril. However, due to inter/intra patient variability of both the migraine attacks and the absorption of sumatriptan, 10 mg may be effective in some patients.

If a patient does not respond to the first dose of Xibimer, a second dose should not be taken for the same attack. In these cases the attack can be treated with paracetamol, acetylsalicylic acid or non-steroidal anti-inflammatory drugs. Xibimer may be taken for subsequent attacks.

If the patient has responded to the first dose but the symptoms recur, a second dose may be given in the following 24 hours, provided that there is a minimum interval of 2 hours between the two doses.

No more than two doses of Xibimer 20 mg Nasal Spray should be taken in any 24-hour period.

Adolescents (12-17 years of age)

Use of sumatriptan in adolescents should be on the recommendation of a specialist or physician who has significant experience in treating migraine, taking into account local guidance.

The recommended dose of Xibimer Nasal Spray is 10 mg for administration into one nostril.

If a patient does not respond to the first dose of Xibimer, a second dose should not be taken for the same attack. In these cases the attack can be treated with paracetamol, acetylsalicylic acid or non-steroidal anti-inflammatory drugs.

Xibimer may be taken for subsequent attacks.

If the patient has responded to the first dose but the symptoms recur, a second dose may be given in the following 24 hours, provided that there is a minimum interval of 2 hours between the two doses.

No more than two doses of Xibimer 10 mg Nasal Spray should be taken in any 24-hour period.

Children (under 12 years of age)

Xibimer Nasal Spray is not recommended for use in children under 12 years of age due to insufficient data on safety and efficacy.

Elderly (over 65)

There is no experience of the use of Xibimer Nasal Spray in patients over 65. The pharmacokinetics in elderly patients have not been sufficiently studied. Therefore the use of sumatriptan is not recommended until further data are available.

Dosing Information

The maximum single recommended adult dose of Xibimer Injection for the acute treatment of migraine or cluster headache is 6 mg injected subcutaneously. For the treatment of migraine, if side effects are dose limiting, lower doses (1 mg to 5 mg) may be used. For the treatment of cluster headache, the efficacy of lower doses has not been established.

The maximum cumulative dose that may be given in 24 hours is 12 mg, two 6-mg injections separated by at least 1 hour. A second 6-mg dose should only be considered if some response to a first injection was observed.

Administration Using The Xibimer STATdose Pen®

An autoinjector device (Xibimer STATdose Pen) is available for use with 4- mg and 6-mg prefilled syringe cartridges. With this device, the needle penetrates approximately 1/4 inch (5 to 6 mm). The injection is intended to be given subcutaneously, and intramuscular or intravascular delivery must be avoided. Instruct patients on the proper use of Xibimer STATdose Pen and direct them to use injection sites with an adequate skin and subcutaneous thickness to accommodate the length of the needle.

Administration Of Doses Of Xibimer Other Than 4 Or 6 mg

In patients receiving doses other than 4 mg or 6 mg, use the 6-mg single-dose vial; do not use the Xibimer STATdose Pen. Visually inspect the vial for particulate matter and discoloration before administration. Do not use if particulates and discolorations are noted.

Posology

Adults

Xibimer film-coated tablets are indicated for the acute intermittent treatment of migraine. They should not be used prophylactically.

It is advisable that Xibimer film-coated tablets be given as early as possible after the onset of migraine attack but it is equally effective at whatever stage of the attack it is administered.

The recommended dose of oral Xibimer film-coated tablets is a single 50 mg tablet. Some patients may require 100 mg. If the patient has responded to the first dose but the symptoms recur a second dose may be given in the next 24 hours provided that there is a minimum interval of two hours between the two doses. No more than 300 mg should be taken in any 24 hour period.

Patients who do not respond to the prescribed dose of Xibimer film-coated tablets should not take a second dose for the same attack. In these cases the attack can be treated with paracetamol, acetylsalicylic acid, or non-steroidal anti-inflammatory drugs. Xibimer film-coated tablets may be taken for subsequent attacks.

Xibimer film-coated tablets is recommended as monotherapy for the acute treatment of migraine and should not be given concomitantly with ergotamine or derivatives of ergotamine (including methysergide).

Paediatric population

The efficacy and safety of Xibimer film-coated tablets in children aged less than 10 years have not been established. No clinical data are available in this age group.

The efficacy and safety of Xibimer film-coated tablets in children 10 to 17 years of age have not been demonstrated in the clinical trials performed in this age group. Therefore the use of Xibimer film-coated tablets in children 10 to 17 years of age is not recommended.

Elderly (Over 65 years of age)

Experience of the use of Xibimer film-coated tablets in patients aged over 65 years is limited. The pharmacokinetics do not differ significantly from a younger population but until further clinical data are available, the use of Xibimer film-coated tablets in patients aged over 65 years is not recommended.

Method of administration

The tablets should be swallowed whole with water.

Dosing Information

The maximum single recommended adult dose of IMITREX Injection for the acute treatment of migraine or cluster headache is 6 mg injected subcutaneously. For the treatment of migraine, if side effects are dose limiting, lower doses (1 mg to 5 mg) may be used. For the treatment of cluster headache, the efficacy of lower doses has not been established.

The maximum cumulative dose that may be given in 24 hours is 12 mg, two 6-mg injections separated by at least 1 hour. A second 6-mg dose should only be considered if some response to a first injection was observed.

Administration Using The IMITREX STATdose Pen®

An autoinjector device (IMITREX STATdose Pen) is available for use with 4- mg and 6-mg prefilled syringe cartridges. With this device, the needle penetrates approximately 1/4 inch (5 to 6 mm). The injection is intended to be given subcutaneously, and intramuscular or intravascular delivery must be avoided. Instruct patients on the proper use of IMITREX STATdose Pen and direct them to use injection sites with an adequate skin and subcutaneous thickness to accommodate the length of the needle.

Administration Of Doses Of IMITREX Other Than 4 Or 6 mg

In patients receiving doses other than 4 mg or 6 mg, use the 6-mg single-dose vial; do not use the IMITREX STATdose Pen. Visually inspect the vial for particulate matter and discoloration before administration. Do not use if particulates and discolorations are noted.

Xibimer is for transdermal use only and is designed for patient self-administration to the upper arm or thigh (see Figure 1). Xibimer should not be applied to other areas of the body. Xibimer should not be cut.

The maximum recommended single dose is one Xibimer iontophoretic transdermal system (TDS). No more than two Xibimer TDS should be used in any 24 hour period, and the second Xibimer TDS should be applied no sooner than 2 hours after activation of the first Xibimer TDS. There is no evidence of benefit for the use of a second Xibimer TDS to treat headache recurrence or incomplete headache relief during a migraine attack.

Xibimer should be applied to dry intact, non-irritated skin on the upper arm or thigh on a site that is relatively hair free and is without scars, tattoos, abrasions, or other skin conditions (i.e., generalized skin irritation or disease including eczema, psoriasis, melanoma, contact dermatitis). Xibimer should not be applied to a previous application site until the site remains erythema free for at least 3 days.

Figure 1: Applied Transdermal System

Xibimer delivers 6.5 mg of sumatriptan over 4 hours. Once applied, the activation button must be pushed, and the red light emitting diode (LED) will turn on. Xibimer TDS must be applied and activated within 15 minutes of initiation of assembly. When dosing is completed, the system stops operating and the activation light turns off, signaling that the system can be removed. Once dosing is completed, the system cannot be reactivated. If the light turns off before 4 hours, dosing has stopped and Xibimer can be removed. If headache relief is incomplete, a second Xibimer TDS can be applied to a different site..

The Xibimer TDS should remain in place for 4 hours or until the red LED light goes off. The iontophoretic device can be secured with medical tape if needed.

The safety of using more than 4 Xibimer in one month has not been established.

Xibimer is for single use only. After use, the TDS should be folded so the adhesive side sticks to itself and safely discarded away from children and pets. Xibimer contains lithium-manganese dioxide batteries; it should be disposed in accordance with state and local regulations.

ZECUITY is for transdermal use only and is designed for patient self-administration to the upper arm or thigh (see Figure 1). ZECUITY should not be applied to other areas of the body. ZECUITY should not be cut.

The maximum recommended single dose is one ZECUITY iontophoretic transdermal system (TDS). No more than two ZECUITY TDS should be used in any 24 hour period, and the second ZECUITY TDS should be applied no sooner than 2 hours after activation of the first ZECUITY TDS. There is no evidence of benefit for the use of a second ZECUITY TDS to treat headache recurrence or incomplete headache relief during a migraine attack.

ZECUITY should be applied to dry intact, non-irritated skin on the upper arm or thigh on a site that is relatively hair free and is without scars, tattoos, abrasions, or other skin conditions (i.e., generalized skin irritation or disease including eczema, psoriasis, melanoma, contact dermatitis). ZECUITY should not be applied to a previous application site until the site remains erythema free for at least 3 days.

Figure 1: Applied Transdermal System

ZECUITY delivers 6.5 mg of sumatriptan over 4 hours. Once applied, the activation button must be pushed, and the red light emitting diode (LED) will turn on. ZECUITY TDS must be applied and activated within 15 minutes of initiation of assembly. When dosing is completed, the system stops operating and the activation light turns off, signaling that the system can be removed. Once dosing is completed, the system cannot be reactivated. If the light turns off before 4 hours, dosing has stopped and ZECUITY can be removed. If headache relief is incomplete, a second ZECUITY TDS can be applied to a different site..

The ZECUITY TDS should remain in place for 4 hours or until the red LED light goes off. The iontophoretic device can be secured with medical tape if needed.

The safety of using more than 4 ZECUITY in one month has not been established.

ZECUITY is for single use only. After use, the TDS should be folded so the adhesive side sticks to itself and safely discarded away from children and pets. ZECUITY contains lithium-manganese dioxide batteries; it should be disposed in accordance with state and local regulations.

Sumatriptan should not be given to patients who have had myocardial infarction or have ischaemic heart disease, coronary vasospasm (Prinzmetal's angina), peripheral vascular disease or symptoms or signs consistent with ischaemic heart disease.

Sumatriptan should not be administered to patients with a history of cerebrovascular accident (CVA) or transient ischaemic attack (TIA).

Sumatriptan should not be administered to patients with severe hepatic impairment.

The use of sumatriptan in patients with moderate and severe hypertension and mild uncontrolled hypertension is contraindicated.

The concomitant administration of ergotamine, or derivatives of ergotamine (including methysergide) or any triptan/5-hydroxytryptamine₁ (5-HT₁) receptor agonist is contraindicated.

Concurrent administration of monoamine oxidase inhibitors (MAOIs) and sumatriptan is contraindicated.

Xibimer must not be used within 2 weeks of discontinuation of therapy with monoamine oxidase inhibitors.

Xibimer Injection is contraindicated in patients with:

• Ischemic coronary artery disease (CAD) (angina pectoris, history of myocardial infarction, or documented silent ischemia) or coronary artery vasospasm, including Prinzmetal's angina.
• Wolff-Parkinson-White syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders.
• History of stroke or transient ischemic attack (TIA) or history of hemiplegic or basilar migraine because these patients are at a higher risk of stroke.
• Peripheral vascular disease.
• Ischemic bowel disease.
• Uncontrolled hypertension.
• Recent use (i.e., within 24 hours) of ergotamine-containing medication, ergot-type medication (such as dihydroergotamine or methysergide), or another 5-hydroxytryptamine1 (5-HT1) agonist.
• Concurrent administration of a monoamine oxidase (MAO)-A inhibitor or recent (within 2 weeks) use of an MAO-A inhibitor.
• Hypersensitivity to Xibimer (angioedema and anaphylaxis seen).
• Severe hepatic impairment.

Xibimer should not be given to patients who have had myocardial infarction or have ischaemic heart disease, coronary vasospasm (Prinzmetal's angina), peripheral vascular disease or patients who have symptoms or signs consistent with ischaemic heart disease.

Xibimer should not be administered to patients with a history of cerebrovascular accident (CVA) or transient ischaemic attack (TIA).

Xibimer should not be administered to patients with severe hepatic impairment.

The use of Xibimer in patients with moderate and severe hypertension and mild uncontrolled hypertension is contraindicated.

The concomitant administration of ergotamine or derivatives of ergotamine (including methysergide) or any triptan/5-hydroxytryptamine₁ (5-HT₁) receptor agonist with Xibimer is contraindicated.

Concurrent administration of monoamine oxidase inhibitors and Xibimer is contraindicated.

Xibimer film-coated tablets must not be used within two weeks of discontinuation of therapy with monoamine oxidase inhibitors.

IMITREX Injection is contraindicated in patients with:

• Ischemic coronary artery disease (CAD) (angina pectoris, history of myocardial infarction, or documented silent ischemia) or coronary artery vasospasm, including Prinzmetal's angina.
• Wolff-Parkinson-White syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders.
• History of stroke or transient ischemic attack (TIA) or history of hemiplegic or basilar migraine because these patients are at a higher risk of stroke.
• Peripheral vascular disease.
• Ischemic bowel disease.
• Uncontrolled hypertension.
• Recent use (i.e., within 24 hours) of ergotamine-containing medication, ergot-type medication (such as dihydroergotamine or methysergide), or another 5-hydroxytryptamine1 (5-HT1) agonist.
• Concurrent administration of a monoamine oxidase (MAO)-A inhibitor or recent (within 2 weeks) use of an MAO-A inhibitor.
• Hypersensitivity to IMITREX (angioedema and anaphylaxis seen).
• Severe hepatic impairment.

Xibimer is contraindicated in patients with:

• Ischemic coronary artery disease (CAD) (angina pectoris, history of myocardial infarction, or documented silent ischemia) or coronary artery vasospasm, including Prinzmetal's angina.
• Wolff-Parkinson-White syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders.
• History of stroke, transient ischemic attack (TIA), or history of hemiplegic or basilar migraine because these patients are at a higher risk of stroke.
• Peripheral vascular disease.
• Ischemic bowel disease.
• Uncontrolled hypertension.
• Recent (i.e., within 24 hours) use of ergotamine-containing medication, ergot-type medication (such as dihydroergotamine or methysergide), or another 5-hydroxytryptamine₁ (5-HT₁) agonist.
• Concurrent administration of an MAO-A inhibitor or recent (within 2 weeks) use of a MAO-A inhibitor.
• Known hypersensitivity to sumatriptan or components of Xibimer.
• Severe hepatic impairment.
• Allergic contact dermatitis to Xibimer.

ZECUITY is contraindicated in patients with:

• Ischemic coronary artery disease (CAD) (angina pectoris, history of myocardial infarction, or documented silent ischemia) or coronary artery vasospasm, including Prinzmetal's angina.
• Wolff-Parkinson-White syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders.
• History of stroke, transient ischemic attack (TIA), or history of hemiplegic or basilar migraine because these patients are at a higher risk of stroke.
• Peripheral vascular disease.
• Ischemic bowel disease.
• Uncontrolled hypertension.
• Recent (i.e., within 24 hours) use of ergotamine-containing medication, ergot-type medication (such as dihydroergotamine or methysergide), or another 5-hydroxytryptamine₁ (5-HT₁) agonist.
• Concurrent administration of an MAO-A inhibitor or recent (within 2 weeks) use of a MAO-A inhibitor.
• Known hypersensitivity to sumatriptan or components of ZECUITY.
• Severe hepatic impairment.
• Allergic contact dermatitis to ZECUITY.

Xibimer Nasal Spray should only be used where there is a clear diagnosis of migraine.

Sumatriptan is not indicated for use in the management of hemiplegic, basilar or ophthalmoplegic migraine.

Before treating with sumatriptan care should be taken to exclude other potentially serious neurological conditions (e.g. CVA, TIA) if the patient presents with atypical symptoms or if they have not received an appropriate diagnosis for sumatriptan use.

Following administration, sumatriptan can be associated with transient symptoms including chest pain and tightness, which may be intense and involve the throat. Where such symptoms are thought to indicate ischaemic heart disease, no further doses of sumatriptan should be given and an appropriate evaluation should be carried out.

Sumatriptan should not be given to patients with risk factors for ischaemic heart disease, including those patients who are heavy smokers or users of nicotine substitution therapies, without prior cardiovascular evaluation.Special consideration should be give to postmenopausal women and males over 40 with these risk factors. These evaluations however, may not identify every patient who has cardiac disease and, in very rare cases, serious cardiac events have occurred in patients without underlying cardiovascular disease and in adolescents.

Sumatriptan should be given with caution in patients with mild controlled hypertension, since transient increases in blood pressure and peripheral vascular resistance have been observed in a small proportion of patients.

There have been rare post-marketing reports describing patients with serotonin syndrome (including altered mental status, autonomic instability and neuromuscular abnormalities) following the use of a selective serotonin reuptake inhibitor (SSRI) and sumatriptan. Serotonin syndrome has been reported following concomitant treatment with triptans and serotonin noradrenaline reuptake inhibitors (SNRIs).

If concomitant treatment with sumatriptan and an SSRI/SNRI is clinically warranted, appropriate observation of the patient is advised

Sumatriptan should be administered with caution to patients with conditions that may affect significantly the absorption, metabolism, or excretion of the drug, e.g. impaired hepatic (mild to moderate impairment) or renal function.

Sumatriptan should be used with caution in patients with a history of seizures or other risk factors which lower the seizure threshold, as seizures have been reported in association with sumatriptan.

Patients with known hypersensitivity to sulphonamides may exhibit an allergic reaction following administration of sumatriptan. Reactions may range from cutaneous hypersensitivity to anaphylaxis. Evidence of cross sensitivity is limited however, caution should be exercised before using sumatriptan in these patients.

Undesirable effects may be more common during concomitant use of triptans and herbal preparations containing St John's Wort (Hypericum perforatum).

Prolonged use of any type of painkiller for headaches can make them worse. If this situation is experienced or suspected, medical advice should be obtained and treatment should be discontinued. The diagnosis of medication overuse headache (MOH) should be suspected in patients who have frequent or daily headaches despite (or because of) the regular use of headache medications.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Myocardial Ischemia, Myocardial Infarction, And Prinzmetal's Angina

The use of Xibimer Injection is contraindicated in patients with ischemic or vasospastic CAD. There have been rare reports of serious cardiac adverse reactions, including acute myocardial infarction, occurring within a few hours following administration of Xibimer Injection. Some of these reactions occurred in patients without known CAD. Xibimer Injection may cause coronary artery vasospasm (Prinzmetal's angina), even in patients without a history of CAD.

Perform a cardiovascular evaluation in triptan-naive patients who have multiple cardiovascular risk factors (e.g., increased age, diabetes, hypertension, smoking, obesity, strong family history of CAD) prior to receiving Xibimer Injection. If there is evidence of CAD or coronary artery vasospasm, Xibimer Injection is contraindicated. For patients with multiple cardiovascular risk factors who have a negative cardiovascular evaluation, consider administering the first dose of Xibimer Injection in a medically supervised setting and performing an electrocardiogram (ECG) immediately following administration of Xibimer Injection. For such patients, consider periodic cardiovascular evaluation in intermittent long-term users of Xibimer Injection.

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 Xibimer Injection if these disturbances occur. Xibimer Injection is contraindicated in patients with Wolff-Parkinson-White syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders.

Chest, Throat, Neck, And/Or Jaw Pain/Tightness/Pressure

Sensations of tightness, pain, pressure, and heaviness in the precordium, throat, neck, and jaw commonly occur after treatment with Xibimer Injection and are usually non-cardiac in origin. However, perform a cardiac evaluation if these patients are at high cardiac risk. The use of Xibimer Injection is contraindicated in patients with CAD and those with 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. 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. Also, patients with migraine may be at increased risk of certain cerebrovascular events (e.g., stroke, hemorrhage, TIA). Discontinue Xibimer Injection if a cerebrovascular event occurs.

Before treating headaches in patients not previously diagnosed with migraine or cluster headache or in patients who present with atypical symptoms, exclude other potentially serious neurological conditions. Xibimer Injection is contraindicated in patients with a history of stroke or TIA.

Other Vasospasm Reactions

Xibimer Injection 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 non-coronary vasospasm reaction following the use of any 5-HT1 agonist, rule out a vasospastic reaction before receiving additional Xibimer Injections.

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.

Medication Overuse Headache

Overuse of acute migraine drugs (e.g., ergotamine, triptans, opioids, or combination of these 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.

Serotonin Syndrome

Serotonin syndrome may occur with Xibimer Injection, particularly during co-administration with selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and MAO inhibitors. 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 occurs within minutes to hours of receiving a new or a greater dose of a serotonergic medication. Discontinue Xibimer Injection if serotonin syndrome is suspected.

Increase In Blood Pressure

Significant elevation in blood pressure, including hypertensive crisis with acute impairment of organ systems, has been reported on rare occasions in patients treated with 5-HT1 agonists, including patients without a history of hypertension. Monitor blood pressure in patients treated with Xibimer. Xibimer Injection is contraindicated in patients with uncontrolled hypertension.

Anaphylactic/Anaphylactoid Reactions

Anaphylactic/anaphylactoid reactions have occurred in patients receiving Xibimer. Such reactions can be life threatening or fatal. In general, anaphylactic reactions to drugs are more likely to occur in individuals with a history of sensitivity to multiple allergens. Xibimer Injection is contraindicated in patients with a history of hypersensitivity reaction to Xibimer.

Seizures

Seizures have been reported following administration of Xibimer. Some have occurred in patients with either a history of seizures or concurrent conditions predisposing to seizures. There are also reports in patients where no such predisposing factors are apparent. Xibimer Injection should be used with caution in patients with a history of epilepsy or conditions associated with a lowered seizure threshold.

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION and Instructions for Use).

Risk of Myocardial Ischemia and/or Infarction, Prinzmetal's Angina, Other Vasospasm-Related Events, Arrhythmias, and Cerebrovascular Events

Inform patients that Xibimer Injection may cause serious cardiovascular side effects such as myocardial infarction or stroke. Although serious cardiovascular events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, irregular heartbeat, significant rise in blood pressure, weakness, and slurring of speech, and should ask for medical advice if any indicative sign or symptoms are observed. Apprise patients of the importance of this follow-up.

Anaphylactic/Anaphylactoid Reactions

Inform patients that anaphylactic/anaphylactoid reactions have occurred in patients receiving Xibimer Injection. Such reactions can be life threatening or fatal. In general, anaphylactic reactions to drugs are more likely to occur in individuals with a history of sensitivity to multiple allergens.

Concomitant Use with Other Triptans or Ergot Medications

Inform patients that use of Xibimer Injection within 24 hours of another triptan or an ergot-type medication (including dihydroergotamine or methysergide) is contraindicated.

Serotonin Syndrome

Caution patients about the risk of serotonin syndrome with the use of Xibimer Injection or other triptans, particularly during combined use with SSRIs, SNRIs, TCAs, and MAO inhibitors.

Medication Overuse Headache

Inform patients that use of acute migraine drugs 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).

Pregnancy

Inform patients that Xibimer Injection should not be used during pregnancy unless the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

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

Ability to Perform Complex Tasks

Treatment with Xibimer Injection may cause somnolence and dizziness; instruct patients to evaluate their ability to perform complex tasks after administration of Xibimer Injection.

How to Use Xibimer Injection

Provide patients instruction on the proper use of Xibimer Injection if they are able to self-administer Xibimer Injection in medically unsupervised situations.

Inform patients that the needle in the Xibimer STATdose Pen penetrates approximately 1/4 of an inch (5 to 6 mm). Inform patients that the injection is intended to be given subcutaneously and intramuscular or intravascular delivery should be avoided. Instruct patients to use injection sites with an adequate skin and subcutaneous thickness to accommodate the length of the needle.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

In carcinogenicity studies in mouse and rat in which sumatriptan was administered orally for 78 weeks and 104 weeks, respectively, at doses up to 160 mg/kg/day (the highest dose in rat was reduced from 360 mg/kg/day during Week 21). The highest dose to mice and rats was approximately 130 and 260 times the single MRHD of 6 mg administered subcutaneously on a mg/m² basis. There was no evidence in either species of an increase in tumors related to sumatriptan administration.

Mutagenesis

Sumatriptan was negative in in vitro (bacterial reverse mutation [Ames], gene cell mutation in Chinese hamster V79/HGPRT, chromosomal aberration in human lymphocytes) and in vivo (rat micronucleus) assays.

Impairment of Fertility

When sumatriptan was administered by subcutaneous injection to male and female rats prior to and throughout the mating period, there was no evidence of impaired fertility at doses up to 60 mg/kg/day or approximately 100 times the single human dose of 6 mg on a mg/m² basis. When sumatriptan (5, 50, 500 mg/kg/day) was administered orally to male and female rats prior to and throughout the mating period, there was a treatment-related decrease in fertility secondary to a decrease in mating in animals treated with doses greater than 5 mg/kg/day. It is not clear whether this finding was due to an effect on males or females or both.

Use In Specific Populations

Pregnancy

Pregnancy Category C

There are no adequate and well-controlled trials of Xibimer Injection in pregnant women. In developmental toxicity studies in rats and rabbits, oral administration of sumatriptan to pregnant animals was associated with embryolethality, fetal abnormalities, and pup mortality. When administered by the intravenous route to pregnant rabbits, sumatriptan was embryolethal. Xibimer Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Oral administration of sumatriptan to pregnant rats during the period of organogenesis resulted in an increased incidence of fetal blood vessel (cervicothoracic and umbilical) abnormalities. The highest no-effect dose for embryofetal developmental toxicity in rates was 60 mg/kg/day, or approximately 100 times the single maximum recommended human dose (MRHD) of 6 mg administered subcutaneously on a mg/m² basis. Oral administration of sumatriptan to pregnant rabbits during the period of organogenesis resulted in increased incidences of embryolethality and fetal cervicothoracic vascular and skeletal abnormalities. Intravenous administration of sumatriptan to pregnant rabbits during the period of organogenesis resulted in an increased incidence of embryolethality. The highest oral and intravenous no-effect doses for developmental toxicity in rabbits were 15 and 0.75 mg/kg/day, or approximately 50 and 2 times, respectively, the single MRHD of 6 mg administered subcutaneously on a mg/m² basis.

Oral administration of sumatriptan to rats prior to and throughout gestation resulted in embryofetal toxicity (decreased body weight, decreased ossification, increased incidence of skeletal abnormalities). The highest no-effect dose was 50 mg/kg/day, or approximately 80 times the single MRHD of 6 mg administered subcutaneously on a mg/m² basis. In offspring of pregnant rats treated orally with sumatriptan during organogenesis, there was a decrease in pup survival. The highest no-effect dose for this effect was 60 mg/kg/day, or approximately 100 times the single MRHD of 6 mg administered subcutaneously on a mg/m² basis. Oral treatment of pregnant rats with sumatriptan during the latter part of gestation and throughout lactation resulted in a decrease in pup survival. The highest no-effect dose for this finding was 100 mg/kg/day, or approximately 160 times the single MRHD of 6 mg administered subcutaneously on a mg/m² basis.

Nursing Mothers

Sumatriptan is excreted in human milk following subcutaneous administration. Infant exposure to sumatriptan can be minimized by avoiding breastfeeding for 12 hours after treatment with Xibimer Injection.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established. Xibimer Injection is not recommended for use in patients younger than 18 years of age.

Two controlled clinical trials evaluated Xibimer Nasal Spray (5 to 20 mg) in 1,248 pediatric migraineurs 12 to 17 years of age who treated a single attack. The trials did not establish the efficacy of Xibimer Nasal Spray compared with placebo in the treatment of migraine in pediatric patients. Adverse reactions observed in these clinical trials were similar in nature to those reported in clinical trials in adults.

Five controlled clinical trials (2 single-attack trials, 3 multiple-attack trials) evaluating oral Xibimer (25 to 100 mg) in pediatric patients 12 to 17 years of age enrolled a total of 701 pediatric migraineurs. These trials did not establish the efficacy of oral Xibimer compared with placebo in the treatment of migraine in pediatric patients. Adverse reactions observed in these clinical trials were similar in nature to those reported in clinical trials in adults. The frequency of all adverse reactions in these patients appeared to be both dose- and age-dependent, with younger patients reporting reactions more commonly than older pediatric patients.

Postmarketing experience documents that serious adverse reactions have occurred in the pediatric population after use of subcutaneous, oral, and/or intranasal Xibimer. These reports include reactions similar in nature to those reported rarely in adults, including stroke, visual loss, and death. A myocardial infarction has been reported in a 14-year-old male following the use of oral Xibimer; clinical signs occurred within 1 day of drug administration. Clinical data to determine the frequency of serious adverse reactions in pediatric patients who might receive subcutaneous, oral, or intranasal Xibimer are not presently available.

Geriatric Use

Clinical trials of Xibimer Injection did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger patients. 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 CAD) prior to receiving Xibimer Injection.

Xibimer film-coated tablets should only be used where there is a clear diagnosis of migraine.

Xibimer is not indicated for use in the management of hemiplegic, basilar or ophthalmoplegic migraine.

The recommended doses of Xibimer should not be exceeded. As with other migraine therapies, before treating headaches in patients not previously diagnosed as migraineurs, and in migraineurs who present atypical symptoms, care should be taken to exclude other potentially serious neurological conditions.

It should be noted that migraineurs may be at risk of certain cerebrovascular events (e.g. cerebrovascular accident, transient ischaemic attack).

Following administration, Xibimer can be associated with transient symptoms including chest pain and tightness which may be intense and involve the throat. Where such symptoms are thought to indicate ischaemic heart disease, no further doses of Xibimer should be given and appropriate evaluation should be carried out.

Xibimer should not be given to patients with risk factors for ischaemic heart disease, including those patients who are heavy smokers or users of nicotine substitution therapies, without prior cardiovascular evaluation. Special consideration should be given to postmenopausal women and males over 40 with these risk factors. These evaluations however, may not identify every patient who has cardiac disease and, in very rare cases, serious cardiac events have occurred in patients without underlying cardiovascular disease.

Xibimer should be administered with caution to patients with mild controlled hypertension, since transient increases in blood pressure and peripheral vascular resistance have been observed in a small proportion of patients.

There have been rare post-marketing reports describing patients with serotonin syndrome (including altered mental status, autonomic instability and neuromuscular abnormalities) following the use of a selective serotonin reuptake inhibitor (SSRI) and Xibimer. Serotonin syndrome has been reported following concomitant treatment with triptans and serotonin noradrenaline reuptake inhibitors (SNRIs).

If concomitant treatment with Xibimer and an SSRI/SNRI is clinically warranted, appropriate observation of the patient is advised.

Xibimer should be administered with caution to patients with conditions which may affect significantly the absorption, metabolism or excretion of drugs, e.g. impaired hepatic or renal function. A 50mg dose should be considered in patients with hepatic impairment.

Xibimer should be used with caution in patients with a history of seizures or other risk factors which lower the seizure threshold, as seizures have been reported in association with Xibimer.

Patients with known hypersensitivity to sulphonamides may exhibit an allergic reaction following administration of Xibimer. Reactions may range from cutaneous hypersensitivity to anaphylaxis. Evidence of cross-sensitivity is limited, however, caution should be exercised before using Xibimer in these patients

Undesirable effects may be more common during concomitant use of triptans and herbal preparations containing St John's Wort (Hypericum perforatum).

Prolonged use of any type of painkiller for headaches can make them worse. If this situation is experienced or suspected, medical advice should be obtained and treatment should be discontinued. The diagnosis of medication overuse headache (MOH) should be suspected in patients who have frequent or daily headaches despite (or because of) the regular use of headache medications.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine as it contains lactose.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Myocardial Ischemia, Myocardial Infarction, And Prinzmetal's Angina

The use of IMITREX Injection is contraindicated in patients with ischemic or vasospastic CAD. There have been rare reports of serious cardiac adverse reactions, including acute myocardial infarction, occurring within a few hours following administration of IMITREX Injection. Some of these reactions occurred in patients without known CAD. IMITREX Injection may cause coronary artery vasospasm (Prinzmetal's angina), even in patients without a history of CAD.

Perform a cardiovascular evaluation in triptan-naive patients who have multiple cardiovascular risk factors (e.g., increased age, diabetes, hypertension, smoking, obesity, strong family history of CAD) prior to receiving IMITREX Injection. If there is evidence of CAD or coronary artery vasospasm, IMITREX Injection is contraindicated. For patients with multiple cardiovascular risk factors who have a negative cardiovascular evaluation, consider administering the first dose of IMITREX Injection in a medically supervised setting and performing an electrocardiogram (ECG) immediately following administration of IMITREX Injection. For such patients, consider periodic cardiovascular evaluation in intermittent long-term users of IMITREX Injection.

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 IMITREX Injection if these disturbances occur. IMITREX Injection is contraindicated in patients with Wolff-Parkinson-White syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders.

Chest, Throat, Neck, And/Or Jaw Pain/Tightness/Pressure

Sensations of tightness, pain, pressure, and heaviness in the precordium, throat, neck, and jaw commonly occur after treatment with IMITREX Injection and are usually non-cardiac in origin. However, perform a cardiac evaluation if these patients are at high cardiac risk. The use of IMITREX Injection is contraindicated in patients with CAD and those with 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. 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. Also, patients with migraine may be at increased risk of certain cerebrovascular events (e.g., stroke, hemorrhage, TIA). Discontinue IMITREX Injection if a cerebrovascular event occurs.

Before treating headaches in patients not previously diagnosed with migraine or cluster headache or in patients who present with atypical symptoms, exclude other potentially serious neurological conditions. IMITREX Injection is contraindicated in patients with a history of stroke or TIA.

Other Vasospasm Reactions

IMITREX Injection 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 non-coronary vasospasm reaction following the use of any 5-HT1 agonist, rule out a vasospastic reaction before receiving additional IMITREX Injections.

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.

Medication Overuse Headache

Overuse of acute migraine drugs (e.g., ergotamine, triptans, opioids, or combination of these 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.

Serotonin Syndrome

Serotonin syndrome may occur with IMITREX Injection, particularly during co-administration with selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and MAO inhibitors. 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 occurs within minutes to hours of receiving a new or a greater dose of a serotonergic medication. Discontinue IMITREX Injection if serotonin syndrome is suspected.

Increase In Blood Pressure

Significant elevation in blood pressure, including hypertensive crisis with acute impairment of organ systems, has been reported on rare occasions in patients treated with 5-HT1 agonists, including patients without a history of hypertension. Monitor blood pressure in patients treated with IMITREX. IMITREX Injection is contraindicated in patients with uncontrolled hypertension.

Anaphylactic/Anaphylactoid Reactions

Anaphylactic/anaphylactoid reactions have occurred in patients receiving IMITREX. Such reactions can be life threatening or fatal. In general, anaphylactic reactions to drugs are more likely to occur in individuals with a history of sensitivity to multiple allergens. IMITREX Injection is contraindicated in patients with a history of hypersensitivity reaction to IMITREX.

Seizures

Seizures have been reported following administration of IMITREX. Some have occurred in patients with either a history of seizures or concurrent conditions predisposing to seizures. There are also reports in patients where no such predisposing factors are apparent. IMITREX Injection should be used with caution in patients with a history of epilepsy or conditions associated with a lowered seizure threshold.

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION and Instructions for Use).

Risk of Myocardial Ischemia and/or Infarction, Prinzmetal's Angina, Other Vasospasm-Related Events, Arrhythmias, and Cerebrovascular Events

Inform patients that IMITREX Injection may cause serious cardiovascular side effects such as myocardial infarction or stroke. Although serious cardiovascular events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, irregular heartbeat, significant rise in blood pressure, weakness, and slurring of speech, and should ask for medical advice if any indicative sign or symptoms are observed. Apprise patients of the importance of this follow-up.

Anaphylactic/Anaphylactoid Reactions

Inform patients that anaphylactic/anaphylactoid reactions have occurred in patients receiving IMITREX Injection. Such reactions can be life threatening or fatal. In general, anaphylactic reactions to drugs are more likely to occur in individuals with a history of sensitivity to multiple allergens.

Concomitant Use with Other Triptans or Ergot Medications

Inform patients that use of IMITREX Injection within 24 hours of another triptan or an ergot-type medication (including dihydroergotamine or methysergide) is contraindicated.

Serotonin Syndrome

Caution patients about the risk of serotonin syndrome with the use of IMITREX Injection or other triptans, particularly during combined use with SSRIs, SNRIs, TCAs, and MAO inhibitors.

Medication Overuse Headache

Inform patients that use of acute migraine drugs 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).

Pregnancy

Inform patients that IMITREX Injection should not be used during pregnancy unless the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

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

Ability to Perform Complex Tasks

Treatment with IMITREX Injection may cause somnolence and dizziness; instruct patients to evaluate their ability to perform complex tasks after administration of IMITREX Injection.

How to Use IMITREX Injection

Provide patients instruction on the proper use of IMITREX Injection if they are able to self-administer IMITREX Injection in medically unsupervised situations.

Inform patients that the needle in the IMITREX STATdose Pen penetrates approximately 1/4 of an inch (5 to 6 mm). Inform patients that the injection is intended to be given subcutaneously and intramuscular or intravascular delivery should be avoided. Instruct patients to use injection sites with an adequate skin and subcutaneous thickness to accommodate the length of the needle.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

In carcinogenicity studies in mouse and rat in which sumatriptan was administered orally for 78 weeks and 104 weeks, respectively, at doses up to 160 mg/kg/day (the highest dose in rat was reduced from 360 mg/kg/day during Week 21). The highest dose to mice and rats was approximately 130 and 260 times the single MRHD of 6 mg administered subcutaneously on a mg/m² basis. There was no evidence in either species of an increase in tumors related to sumatriptan administration.

Mutagenesis

Sumatriptan was negative in in vitro (bacterial reverse mutation [Ames], gene cell mutation in Chinese hamster V79/HGPRT, chromosomal aberration in human lymphocytes) and in vivo (rat micronucleus) assays.

Impairment of Fertility

When sumatriptan was administered by subcutaneous injection to male and female rats prior to and throughout the mating period, there was no evidence of impaired fertility at doses up to 60 mg/kg/day or approximately 100 times the single human dose of 6 mg on a mg/m² basis. When sumatriptan (5, 50, 500 mg/kg/day) was administered orally to male and female rats prior to and throughout the mating period, there was a treatment-related decrease in fertility secondary to a decrease in mating in animals treated with doses greater than 5 mg/kg/day. It is not clear whether this finding was due to an effect on males or females or both.

Use In Specific Populations

Pregnancy

Pregnancy Category C

There are no adequate and well-controlled trials of IMITREX Injection in pregnant women. In developmental toxicity studies in rats and rabbits, oral administration of sumatriptan to pregnant animals was associated with embryolethality, fetal abnormalities, and pup mortality. When administered by the intravenous route to pregnant rabbits, sumatriptan was embryolethal. IMITREX Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Oral administration of sumatriptan to pregnant rats during the period of organogenesis resulted in an increased incidence of fetal blood vessel (cervicothoracic and umbilical) abnormalities. The highest no-effect dose for embryofetal developmental toxicity in rates was 60 mg/kg/day, or approximately 100 times the single maximum recommended human dose (MRHD) of 6 mg administered subcutaneously on a mg/m² basis. Oral administration of sumatriptan to pregnant rabbits during the period of organogenesis resulted in increased incidences of embryolethality and fetal cervicothoracic vascular and skeletal abnormalities. Intravenous administration of sumatriptan to pregnant rabbits during the period of organogenesis resulted in an increased incidence of embryolethality. The highest oral and intravenous no-effect doses for developmental toxicity in rabbits were 15 and 0.75 mg/kg/day, or approximately 50 and 2 times, respectively, the single MRHD of 6 mg administered subcutaneously on a mg/m² basis.

Oral administration of sumatriptan to rats prior to and throughout gestation resulted in embryofetal toxicity (decreased body weight, decreased ossification, increased incidence of skeletal abnormalities). The highest no-effect dose was 50 mg/kg/day, or approximately 80 times the single MRHD of 6 mg administered subcutaneously on a mg/m² basis. In offspring of pregnant rats treated orally with sumatriptan during organogenesis, there was a decrease in pup survival. The highest no-effect dose for this effect was 60 mg/kg/day, or approximately 100 times the single MRHD of 6 mg administered subcutaneously on a mg/m² basis. Oral treatment of pregnant rats with sumatriptan during the latter part of gestation and throughout lactation resulted in a decrease in pup survival. The highest no-effect dose for this finding was 100 mg/kg/day, or approximately 160 times the single MRHD of 6 mg administered subcutaneously on a mg/m² basis.

Nursing Mothers

Sumatriptan is excreted in human milk following subcutaneous administration. Infant exposure to sumatriptan can be minimized by avoiding breastfeeding for 12 hours after treatment with IMITREX Injection.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established. IMITREX Injection is not recommended for use in patients younger than 18 years of age.

Two controlled clinical trials evaluated IMITREX Nasal Spray (5 to 20 mg) in 1,248 pediatric migraineurs 12 to 17 years of age who treated a single attack. The trials did not establish the efficacy of IMITREX Nasal Spray compared with placebo in the treatment of migraine in pediatric patients. Adverse reactions observed in these clinical trials were similar in nature to those reported in clinical trials in adults.

Five controlled clinical trials (2 single-attack trials, 3 multiple-attack trials) evaluating oral IMITREX (25 to 100 mg) in pediatric patients 12 to 17 years of age enrolled a total of 701 pediatric migraineurs. These trials did not establish the efficacy of oral IMITREX compared with placebo in the treatment of migraine in pediatric patients. Adverse reactions observed in these clinical trials were similar in nature to those reported in clinical trials in adults. The frequency of all adverse reactions in these patients appeared to be both dose- and age-dependent, with younger patients reporting reactions more commonly than older pediatric patients.

Postmarketing experience documents that serious adverse reactions have occurred in the pediatric population after use of subcutaneous, oral, and/or intranasal IMITREX. These reports include reactions similar in nature to those reported rarely in adults, including stroke, visual loss, and death. A myocardial infarction has been reported in a 14-year-old male following the use of oral IMITREX; clinical signs occurred within 1 day of drug administration. Clinical data to determine the frequency of serious adverse reactions in pediatric patients who might receive subcutaneous, oral, or intranasal IMITREX are not presently available.

Geriatric Use

Clinical trials of IMITREX Injection did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger patients. 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 CAD) prior to receiving IMITREX Injection.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Risk Of Injury During Magnetic Resonance Imaging (MRI) Procedure

Xibimer contains metal parts and must be removed before an MRI procedure.

Allergic Contact Dermatitis

Use of Xibimer may lead to allergic contact dermatitis (ACD). In two long-term open-label studies where patients were allowed to treat multiple migraine attacks for up to 1 year, the overall adverse event rate of ACD was 4%. Xibimer should be discontinued if ACD is suspected. Erythema is commonly seen with use of Xibimer and is not by itself an indication of sensitization. Following sensitization with Xibimer, erythematous plaque and/or erythemato-vesicular or erythemato-bullous eruptions may develop. Clinical course is characterized by crescendo phenomenon of worsening pruritus and appearance over time with slower resolution to normal of affected skin areas.

Patients sensitized from use of Xibimer, as evidenced by development of ACD, may develop systemic sensitization or other systemic reactions if sumatriptan-containing products are taken via other routes, e.g., orally or subcutaneously. It is possible that some patients who developed ACD with sumatriptan by exposure to Xibimer, and who have developed systemic sensitization, may not be able to take sumatriptan in any form.

Patients who develop ACD with Xibimer and require treatment with sumatriptan via other routes should receive their first subsequent dose under close medical supervision.

Myocardial Ischemia, Myocardial Infarction, And Prinzmetal’s Angina

The use of Xibimer is contraindicated in patients with ischemic or vasospastic CAD. There have been rare reports of serious cardiac adverse reactions, including acute myocardial infarction, occurring within a few hours following administration of sumatriptan. Some of these reactions occurred in patients without known CAD. 5-HT₁ agonists, including Xibimer, may cause coronary artery vasospasm (Prinzmetal's angina), even in patients without a history of CAD.

Perform a cardiovascular evaluation in triptan-naive patients who have multiple cardiovascular risk factors (e.g., increased age, diabetes, hypertension, smoking, obesity, strong family history of CAD) prior to using Xibimer. Do not use Xibimer if there is evidence of CAD or coronary artery vasospasm. For patients with multiple cardiovascular risk factors who have a negative cardiovascular evaluation, consider using the first Xibimer TDS in a medically supervised setting and performing an electrocardiogram (ECG) upon activation of Xibimer. For such patients, consider periodic cardiovascular evaluation in intermittent long-term users of Xibimer.

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 5HT₁ agonists. Discontinue Xibimer if these disturbances occur. Xibimer is contraindicated in patients with Wolff-Parkinson-White syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders.

Chest, Throat, Neck And/Or Jaw Pain/Tightness /Pressure

Sensations of tightness, pain, pressure, and heaviness in the chest, throat, neck, and jaw commonly occur after treatment with sumatriptan and are usually non-cardiac in origin. However, perform a cardiac evaluation if these patients are at high cardiac risk. The use of Xibimer is contraindicated in patients shown with CAD and those with Prinzmetal's variant angina.

Cerebrovascular Events

Cerebral hemorrhage, subarachnoid hemorrhage, and stroke have occurred in patients treated with 5HT₁ 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.

As with other acute migraine therapies, before treating headaches in patients not previously diagnosed as migraineurs, and in migraineurs who present with atypical symptoms, exclude other potentially serious neurological conditions. Xibimer is contraindicated in patients with a history of stroke or TIA.

Other Vasospasm Reactions

5-HT₁ agonists, including Xibimer, 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 a vasospastic reaction following the use of any 5-HT₁ agonist, rule out a vasospastic reaction before using Xibimer.

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.

Medication Overuse Headache

Overuse of acute migraine drugs (e.g., ergotamine, triptans, opioids, 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.

Serotonin Syndrome

Serotonin syndrome may occur with triptans, including Xibimer, particularly during coadministration with selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and MAO inhibitors. 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 occurs within minutes to hours of receiving a new or a greater dose of a serotonergic medication. Discontinue Xibimer if serotonin syndrome is suspected.

Increase In Blood Pressure

Significant elevation in blood pressure, including hypertensive crisis with acute impairment of organ systems, has been reported on rare occasions in patients treated with 5-HT₁ agonists, including patients without a history of hypertension. Monitor blood pressure in patients treated with Xibimer. Xibimer is contraindicated in patients with uncontrolled hypertension.

Anaphylactic/Anaphylactoid Reactions

Anaphylactic/anaphylactoid reactions have occurred in patients receiving sumatriptan. Such reactions can be life threatening or fatal. In general, anaphylactic reactions to drugs are more likely to occur in individuals with a history of sensitivity to multiple allergens. Xibimer is contraindicated in patients with prior serious anaphylactic reaction.

Seizures

Seizures have been reported following administration of sumatriptan. Some have occurred in patients with either a history of seizures or concurrent conditions predisposing to seizures. There are also reports in patients where no such predisposing factors are apparent. Xibimer should be used with caution in patients with a history of epilepsy or conditions associated with a lowered seizure threshold.

Electrically-Active Implantable Or Body-Worn Medical Devices

Xibimer should not be applied in areas near or over electrically-active implantable or body-worn medical devices (e.g., implantable cardiac pacemaker, body-worn insulin pump, implantable deep brain stimulator).

Patient Counseling Information

See FDA-approved patient labeling (PATIENT INFORMATION and Instructions for Use).

How To Use Xibimer

Advise patients to carefully read the Patient Instructions for Use. Only patients who are able to understand and follow the instructions should use Xibimer.

Advise patients that the Xibimer iontophoretic transdermal system (TDS) must be properly applied and activated within 15 minutes of initiating Step 1 (Pull Tabs) of the Patient Instructions for Use, or the TDS will not operate.

Advise patients not to bathe, shower or swim while wearing Xibimer.

Advise patients that upon removal of the Xibimer TDS, most patients experience some skin redness under the transdermal system, which usually disappears within 24 hours.

Advise patients that Xibimer is single-use and should not be cut. Advise patients that no more than two Xibimer TDS should be used in a 24 hour period, and that a second Xibimer TDS should not be applied until at least 2 hours after activation of the first Xibimer TDS.

Instruct patients to apply the Xibimer TDS to the upper arm or thigh and not to other areas of the body. Instruct patients to apply the Xibimer TDS to dry intact, non-irritated skin on a site that is relatively hair free and without scars, tattoos, abrasions, or other skin conditions (i.e., generalized skin irritation or disease including eczema, psoriasis, melanoma, contact dermatitis).

Advise patients that the Xibimer TDS should not be applied to a previous application site until the site remains erythema free for 3 days.

Inform patients that the safety of using more than 4 Xibimer in one month has not been established.

Risk Of Injury During Magnetic Resonance Imaging (MRI) Procedure

Inform patients that Xibimer contains metal parts and must be removed before an MRI procedure.

Potential For Allergic Contact Dermatitis

Caution patients about the potential for developing allergic contact dermatitis (ACD) after use of Xibimer. Inform patients of the signs and symptoms of ACD, and instruct patients to seek medical advice if they develop skin lesions suggestive of ACD. Inform patients that it is possible that some patients who develop ACD with sumatriptan by exposure to Xibimer may not be able to take sumatriptan in any form.

Risk Of Myocardial Ischemia And/Or Infarction, Prinzmetal’s Angina, Other Vasospasm-related Events, Arrhythmias, And Cerebrovascular Events

Inform patients that the medication in Xibimer or other triptans may cause serious cardiovascular side effects such as myocardial infarction or stroke, which may result in hospitalization and even death. Although serious cardiovascular events can occur without warning symptoms, advise patients that they should be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and should seek medical advice when observing any indicative sign or symptoms. Apprise patients of the importance of this follow-up.

Anaphylactic/Anaphylactoid Reactions

Inform patients that anaphylactic/anaphylactoid reactions have occurred in patients receiving sumatriptan. Such reactions can be life threatening or fatal. In general, anaphylactic reactions to drugs are more likely to occur in individuals with a history of sensitivity to multiple allergens.

Medication Overuse Headache

Inform patients that use of acute migraine drugs 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).

Pregnancy

Inform patients that Xibimer should not be used during pregnancy unless the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

Advise patients to notify their physician if they are breast-feeding or plan to breast-feed.

Ability To Perform Complex Tasks

Since migraines or treatment with sumatriptan may cause somnolence and dizziness, instruct patients to evaluate their ability to perform complex tasks during migraine attacks and after using Xibimer.

Serotonin Syndrome

Caution patients about the risk of serotonin syndrome with the use of Xibimer or other triptans, particularly during combined use with SSRIs, SNRIs, TCAs, and MAO inhibitors.

Xibimer® is a registered trademark of Teva Pharmaceuticals International GmbH. The other brands listed are trademarks of their respective owners and are not trademarks of Teva Pharmaceuticals International GmbH. The makers of these brands are not affiliated with and do not endorse Teva Pharmaceuticals International GmbH or its affiliates or products.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

In carcinogenicity studies, rats and mice were given sumatriptan by oral gavage. Mice were dosed for 78 weeks and rats were dosed for 104 weeks. There was no evidence of an increase in tumors in either species related to sumatriptan administration.

Mutagenesis

Sumatriptan was not mutagenic in the presence or absence of metabolic activation when tested in two gene mutation assays (the Ames test and the in vitro mammalian Chinese hamster V79/HGPRT assay). It was not clastogenic in two cytogenetics assays (in vitro human lymphocyte assay and in vivo rat micronucleus assay).

Impairment Of Fertility

A fertility study by the subcutaneous route, during which male and female rats were dosed daily with sumatriptan prior to and throughout the mating period, demonstrated no evidence of impaired fertility. However, following oral administration, a treatment-related decrease in fertility, secondary to a decrease in mating, was seen for rats treated with 50 and 500 mg/kg/day. It is not clear whether the problem is associated with the treatment of males or females or both.

Use In Specific Populations

Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies in pregnant women. Xibimer should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

When sumatriptan was administered intravenously to pregnant rabbits daily throughout the period of organogenesis, embryolethality was observed at doses at or close to those producing maternal toxicity. Oral administration of sumatriptan to rabbits during organogenesis was associated with increased incidences of fetal vascular and skeletal abnormalities; the highest no-effect dose for these effects was 15 mg/kg/day. The intravenous administration of sumatriptan to pregnant rats throughout organogenesis did not produce evidence of embryolethality. The subcutaneous administration of sumatriptan to pregnant rats prior to and throughout pregnancy did not produce evidence of embryolethality or teratogenicity.

Nursing Mothers

It is not known whether sumatriptan is excreted in human milk following transdermal administration. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from Xibimer, 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.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Two controlled clinical trials evaluated sumatriptan nasal spray (5 to 20 mg) in 1,248 adolescent migraineurs aged 12 to 17 years who treated a single attack. The trials did not establish the efficacy of sumatriptan nasal spray compared with placebo in the treatment of migraine in adolescents. Adverse reactions observed in these clinical trials were similar in nature to those reported in clinical trials in adults.

Five controlled clinical trials (2 single-attack studies, 3 multiple-attack studies) evaluating oral sumatriptan (25 to 100 mg) in pediatric patients aged 12 to 17 years enrolled a total of 701 adolescent migraineurs. These studies did not establish the efficacy of oral sumatriptan compared to placebo in the treatment of migraine in adolescents. Adverse events observed in these clinical trials were similar in nature to those reported in clinical trials in adults. The frequency of all adverse events in these patients appeared to be both dose- and age dependent, with younger patients reporting events more commonly than older adolescents.

Post-marketing experience documents that serious adverse events have occurred in the pediatric population after use of subcutaneous, oral, and/or intranasal sumatriptan. These reports include events similar in nature to those reported rarely in adults, including stroke, visual loss, and death. A myocardial infarction has been reported in a 14-year-old male following the use of oral sumatriptan; clinical signs occurred within 1 day of drug administration. Since clinical data to determine the frequency of serious adverse reactions in pediatric patients who might receive subcutaneous, oral, or intranasal sumatriptan are not presently available, the use of Xibimer in patients under 18 years of age is not recommended.

Geriatric Use

Clinical trials of Xibimer 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 subjects. 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 CAD) prior to using Xibimer.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Risk Of Injury During Magnetic Resonance Imaging (MRI) Procedure

ZECUITY contains metal parts and must be removed before an MRI procedure.

Allergic Contact Dermatitis

Use of ZECUITY may lead to allergic contact dermatitis (ACD). In two long-term open-label studies where patients were allowed to treat multiple migraine attacks for up to 1 year, the overall adverse event rate of ACD was 4%. ZECUITY should be discontinued if ACD is suspected. Erythema is commonly seen with use of ZECUITY and is not by itself an indication of sensitization. Following sensitization with ZECUITY, erythematous plaque and/or erythemato-vesicular or erythemato-bullous eruptions may develop. Clinical course is characterized by crescendo phenomenon of worsening pruritus and appearance over time with slower resolution to normal of affected skin areas.

Patients sensitized from use of ZECUITY, as evidenced by development of ACD, may develop systemic sensitization or other systemic reactions if sumatriptan-containing products are taken via other routes, e.g., orally or subcutaneously. It is possible that some patients who developed ACD with sumatriptan by exposure to ZECUITY, and who have developed systemic sensitization, may not be able to take sumatriptan in any form.

Patients who develop ACD with ZECUITY and require treatment with sumatriptan via other routes should receive their first subsequent dose under close medical supervision.

Myocardial Ischemia, Myocardial Infarction, And Prinzmetal’s Angina

The use of ZECUITY is contraindicated in patients with ischemic or vasospastic CAD. There have been rare reports of serious cardiac adverse reactions, including acute myocardial infarction, occurring within a few hours following administration of sumatriptan. Some of these reactions occurred in patients without known CAD. 5-HT₁ agonists, including ZECUITY, may cause coronary artery vasospasm (Prinzmetal's angina), even in patients without a history of CAD.

Perform a cardiovascular evaluation in triptan-naive patients who have multiple cardiovascular risk factors (e.g., increased age, diabetes, hypertension, smoking, obesity, strong family history of CAD) prior to using ZECUITY. Do not use ZECUITY if there is evidence of CAD or coronary artery vasospasm. For patients with multiple cardiovascular risk factors who have a negative cardiovascular evaluation, consider using the first ZECUITY TDS in a medically supervised setting and performing an electrocardiogram (ECG) upon activation of ZECUITY. For such patients, consider periodic cardiovascular evaluation in intermittent long-term users of ZECUITY.

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 5HT₁ agonists. Discontinue ZECUITY if these disturbances occur. ZECUITY is contraindicated in patients with Wolff-Parkinson-White syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders.

Chest, Throat, Neck And/Or Jaw Pain/Tightness /Pressure

Sensations of tightness, pain, pressure, and heaviness in the chest, throat, neck, and jaw commonly occur after treatment with sumatriptan and are usually non-cardiac in origin. However, perform a cardiac evaluation if these patients are at high cardiac risk. The use of ZECUITY is contraindicated in patients shown with CAD and those with Prinzmetal's variant angina.

Cerebrovascular Events

Cerebral hemorrhage, subarachnoid hemorrhage, and stroke have occurred in patients treated with 5HT₁ 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.

As with other acute migraine therapies, before treating headaches in patients not previously diagnosed as migraineurs, and in migraineurs who present with atypical symptoms, exclude other potentially serious neurological conditions. ZECUITY is contraindicated in patients with a history of stroke or TIA.

Other Vasospasm Reactions

5-HT₁ agonists, including ZECUITY, 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 a vasospastic reaction following the use of any 5-HT₁ agonist, rule out a vasospastic reaction before using ZECUITY.

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.

Medication Overuse Headache

Overuse of acute migraine drugs (e.g., ergotamine, triptans, opioids, 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.

Serotonin Syndrome

Serotonin syndrome may occur with triptans, including ZECUITY, particularly during coadministration with selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and MAO inhibitors. 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 occurs within minutes to hours of receiving a new or a greater dose of a serotonergic medication. Discontinue ZECUITY if serotonin syndrome is suspected.

Increase In Blood Pressure

Significant elevation in blood pressure, including hypertensive crisis with acute impairment of organ systems, has been reported on rare occasions in patients treated with 5-HT₁ agonists, including patients without a history of hypertension. Monitor blood pressure in patients treated with ZECUITY. ZECUITY is contraindicated in patients with uncontrolled hypertension.

Anaphylactic/Anaphylactoid Reactions

Anaphylactic/anaphylactoid reactions have occurred in patients receiving sumatriptan. Such reactions can be life threatening or fatal. In general, anaphylactic reactions to drugs are more likely to occur in individuals with a history of sensitivity to multiple allergens. ZECUITY is contraindicated in patients with prior serious anaphylactic reaction.

Seizures

Seizures have been reported following administration of sumatriptan. Some have occurred in patients with either a history of seizures or concurrent conditions predisposing to seizures. There are also reports in patients where no such predisposing factors are apparent. ZECUITY should be used with caution in patients with a history of epilepsy or conditions associated with a lowered seizure threshold.

Electrically-Active Implantable Or Body-Worn Medical Devices

ZECUITY should not be applied in areas near or over electrically-active implantable or body-worn medical devices (e.g., implantable cardiac pacemaker, body-worn insulin pump, implantable deep brain stimulator).

Patient Counseling Information

See FDA-approved patient labeling (PATIENT INFORMATION and Instructions for Use).

How To Use ZECUITY

Advise patients to carefully read the Patient Instructions for Use. Only patients who are able to understand and follow the instructions should use ZECUITY.

Advise patients that the ZECUITY iontophoretic transdermal system (TDS) must be properly applied and activated within 15 minutes of initiating Step 1 (Pull Tabs) of the Patient Instructions for Use, or the TDS will not operate.

Advise patients not to bathe, shower or swim while wearing ZECUITY.

Advise patients that upon removal of the ZECUITY TDS, most patients experience some skin redness under the transdermal system, which usually disappears within 24 hours.

Advise patients that ZECUITY is single-use and should not be cut. Advise patients that no more than two ZECUITY TDS should be used in a 24 hour period, and that a second ZECUITY TDS should not be applied until at least 2 hours after activation of the first ZECUITY TDS.

Instruct patients to apply the ZECUITY TDS to the upper arm or thigh and not to other areas of the body. Instruct patients to apply the ZECUITY TDS to dry intact, non-irritated skin on a site that is relatively hair free and without scars, tattoos, abrasions, or other skin conditions (i.e., generalized skin irritation or disease including eczema, psoriasis, melanoma, contact dermatitis).

Advise patients that the ZECUITY TDS should not be applied to a previous application site until the site remains erythema free for 3 days.

Inform patients that the safety of using more than 4 ZECUITY in one month has not been established.

Risk Of Injury During Magnetic Resonance Imaging (MRI) Procedure

Inform patients that ZECUITY contains metal parts and must be removed before an MRI procedure.

Potential For Allergic Contact Dermatitis

Caution patients about the potential for developing allergic contact dermatitis (ACD) after use of ZECUITY. Inform patients of the signs and symptoms of ACD, and instruct patients to seek medical advice if they develop skin lesions suggestive of ACD. Inform patients that it is possible that some patients who develop ACD with sumatriptan by exposure to ZECUITY may not be able to take sumatriptan in any form.

Risk Of Myocardial Ischemia And/Or Infarction, Prinzmetal’s Angina, Other Vasospasm-related Events, Arrhythmias, And Cerebrovascular Events

Inform patients that the medication in ZECUITY or other triptans may cause serious cardiovascular side effects such as myocardial infarction or stroke, which may result in hospitalization and even death. Although serious cardiovascular events can occur without warning symptoms, advise patients that they should be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and should seek medical advice when observing any indicative sign or symptoms. Apprise patients of the importance of this follow-up.

Anaphylactic/Anaphylactoid Reactions

Inform patients that anaphylactic/anaphylactoid reactions have occurred in patients receiving sumatriptan. Such reactions can be life threatening or fatal. In general, anaphylactic reactions to drugs are more likely to occur in individuals with a history of sensitivity to multiple allergens.

Medication Overuse Headache

Inform patients that use of acute migraine drugs 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).

Pregnancy

Inform patients that ZECUITY should not be used during pregnancy unless the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

Advise patients to notify their physician if they are breast-feeding or plan to breast-feed.

Ability To Perform Complex Tasks

Since migraines or treatment with sumatriptan may cause somnolence and dizziness, instruct patients to evaluate their ability to perform complex tasks during migraine attacks and after using ZECUITY.

Serotonin Syndrome

Caution patients about the risk of serotonin syndrome with the use of ZECUITY or other triptans, particularly during combined use with SSRIs, SNRIs, TCAs, and MAO inhibitors.

ZECUITY® is a registered trademark of Teva Pharmaceuticals International GmbH. The other brands listed are trademarks of their respective owners and are not trademarks of Teva Pharmaceuticals International GmbH. The makers of these brands are not affiliated with and do not endorse Teva Pharmaceuticals International GmbH or its affiliates or products.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

In carcinogenicity studies, rats and mice were given sumatriptan by oral gavage. Mice were dosed for 78 weeks and rats were dosed for 104 weeks. There was no evidence of an increase in tumors in either species related to sumatriptan administration.

Mutagenesis

Sumatriptan was not mutagenic in the presence or absence of metabolic activation when tested in two gene mutation assays (the Ames test and the in vitro mammalian Chinese hamster V79/HGPRT assay). It was not clastogenic in two cytogenetics assays (in vitro human lymphocyte assay and in vivo rat micronucleus assay).

Impairment Of Fertility

A fertility study by the subcutaneous route, during which male and female rats were dosed daily with sumatriptan prior to and throughout the mating period, demonstrated no evidence of impaired fertility. However, following oral administration, a treatment-related decrease in fertility, secondary to a decrease in mating, was seen for rats treated with 50 and 500 mg/kg/day. It is not clear whether the problem is associated with the treatment of males or females or both.

Use In Specific Populations

Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies in pregnant women. ZECUITY should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

When sumatriptan was administered intravenously to pregnant rabbits daily throughout the period of organogenesis, embryolethality was observed at doses at or close to those producing maternal toxicity. Oral administration of sumatriptan to rabbits during organogenesis was associated with increased incidences of fetal vascular and skeletal abnormalities; the highest no-effect dose for these effects was 15 mg/kg/day. The intravenous administration of sumatriptan to pregnant rats throughout organogenesis did not produce evidence of embryolethality. The subcutaneous administration of sumatriptan to pregnant rats prior to and throughout pregnancy did not produce evidence of embryolethality or teratogenicity.

Nursing Mothers

It is not known whether sumatriptan is excreted in human milk following transdermal administration. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from ZECUITY, 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.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Two controlled clinical trials evaluated sumatriptan nasal spray (5 to 20 mg) in 1,248 adolescent migraineurs aged 12 to 17 years who treated a single attack. The trials did not establish the efficacy of sumatriptan nasal spray compared with placebo in the treatment of migraine in adolescents. Adverse reactions observed in these clinical trials were similar in nature to those reported in clinical trials in adults.

Five controlled clinical trials (2 single-attack studies, 3 multiple-attack studies) evaluating oral sumatriptan (25 to 100 mg) in pediatric patients aged 12 to 17 years enrolled a total of 701 adolescent migraineurs. These studies did not establish the efficacy of oral sumatriptan compared to placebo in the treatment of migraine in adolescents. Adverse events observed in these clinical trials were similar in nature to those reported in clinical trials in adults. The frequency of all adverse events in these patients appeared to be both dose- and age dependent, with younger patients reporting events more commonly than older adolescents.

Post-marketing experience documents that serious adverse events have occurred in the pediatric population after use of subcutaneous, oral, and/or intranasal sumatriptan. These reports include events similar in nature to those reported rarely in adults, including stroke, visual loss, and death. A myocardial infarction has been reported in a 14-year-old male following the use of oral sumatriptan; clinical signs occurred within 1 day of drug administration. Since clinical data to determine the frequency of serious adverse reactions in pediatric patients who might receive subcutaneous, oral, or intranasal sumatriptan are not presently available, the use of ZECUITY in patients under 18 years of age is not recommended.

Geriatric Use

Clinical trials of ZECUITY 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 subjects. 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 CAD) prior to using ZECUITY.

No studies on the effects on the ability to drive and use machines have been performed. Drowsiness may occur as a result of migraine or treatment with sumatriptan. This may influence the ability to drive and to operate machinery.

No studies on the effects on the ability to drive and use machines have been performed. Drowsiness may occur as a result of migraine or its treatment with Xibimer. This may influence the ability to drive and to operate machinery.

Adverse events are listed below by system organ class and frequency. Frequencies are defined as: very common (>1/10), common (>1/100 to <1/10), uncommon (>1/1000 to <1/100), rare (>1/10,000 to <1/1000) very rare (<1/10000), not known (cannot be estimated from the available data). Some of the symptoms reported as undesirable effects may be associated symptoms of migraine.

Adverse events reported in adults have also been observed in adolescents. These include very rare reports of coronary artery vasospasm and myocardial infarction.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard

The following serious adverse reactions are described below and elsewhere in the labeling:

• Myocardial ischemia, myocardial infarction, and Prinzmetal's angina
• Arrhythmias
• Chest, throat, neck, and/or jaw pain/tightness/pressure
• Cerebrovascular events
• Other vasospasm reactions
• Medication overuse headache
• Serotonin syndrome
• Increase in blood pressure
• Hypersensitivity reactions
• Seizures

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Migraine Headache

Table 1 lists adverse reactions that occurred in 2 US placebo-controlled clinical trials in migraine patients (Studies 2 and 3) following either a single 6-mg dose of Xibimer Injection or placebo. Only reactions that occurred at a frequency of 2% or more in groups treated with Xibimer Injection 6 mg and that occurred at a frequency greater than the placebo group are included in Table 1.

Table 1. Adverse Reactions in Pooled Placebo-Controlled Trials in Patients with Migraine (Studies 2 and 3)

The incidence of adverse reactions in controlled clinical trials was not affected by gender or age of the patients. There were insufficient data to assess the impact of race on the incidence of adverse reactions.

Cluster Headache

In the controlled clinical trials assessing the efficacy of Xibimer Injection as a treatment for cluster headache (Studies 4 and 5), no new significant adverse reactions were detected that had not already been identified in trials of Xibimer in patients with migraine.

Overall, the frequency of adverse reactions reported in the trials of cluster headache was generally lower than in the migraine trials. Exceptions include reports of paresthesia (5% Xibimer, 0% placebo), nausea and vomiting (4% Xibimer, 0% placebo), and bronchospasm (1% Xibimer, 0% placebo).

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of Xibimer Tablets, Xibimer Nasal Spray, and Xibimer Injection. 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.

Cardiovascular

Hypotension, palpitations.

Neurological

Dystonia, tremor.

Adverse events are listed below by system organ class and frequency. Frequencies are defined as:

very common (>1/10), common (>1/100, <1/10), uncommon (>1/1,000, <1/100), rare (>1/10,000, <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data). Some of the symptoms reported as undesirable effects may be associated symptoms of migraine.

Clinical Trial Data

Post-Marketing Data

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

The following serious adverse reactions are described below and elsewhere in the labeling:

• Myocardial ischemia, myocardial infarction, and Prinzmetal's angina
• Arrhythmias
• Chest, throat, neck, and/or jaw pain/tightness/pressure
• Cerebrovascular events
• Other vasospasm reactions
• Medication overuse headache
• Serotonin syndrome
• Increase in blood pressure
• Hypersensitivity reactions
• Seizures

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Migraine Headache

Table 1 lists adverse reactions that occurred in 2 US placebo-controlled clinical trials in migraine patients (Studies 2 and 3) following either a single 6-mg dose of IMITREX Injection or placebo. Only reactions that occurred at a frequency of 2% or more in groups treated with IMITREX Injection 6 mg and that occurred at a frequency greater than the placebo group are included in Table 1.

Table 1. Adverse Reactions in Pooled Placebo-Controlled Trials in Patients with Migraine (Studies 2 and 3)

The incidence of adverse reactions in controlled clinical trials was not affected by gender or age of the patients. There were insufficient data to assess the impact of race on the incidence of adverse reactions.

Cluster Headache

In the controlled clinical trials assessing the efficacy of IMITREX Injection as a treatment for cluster headache (Studies 4 and 5), no new significant adverse reactions were detected that had not already been identified in trials of IMITREX in patients with migraine.

Overall, the frequency of adverse reactions reported in the trials of cluster headache was generally lower than in the migraine trials. Exceptions include reports of paresthesia (5% IMITREX, 0% placebo), nausea and vomiting (4% IMITREX, 0% placebo), and bronchospasm (1% IMITREX, 0% placebo).

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of IMITREX Tablets, IMITREX Nasal Spray, and IMITREX Injection. 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.

Cardiovascular

Hypotension, palpitations.

Neurological

Dystonia, tremor.

The following adverse reactions are discussed in more detail in other sections of the prescribing information:

• Allergic Contact Dermatitis
• Myocardial ischemia, myocardial infarction, and Prinzmetal's angina
• Arrhythmias
• Chest, throat, neck, and/or jaw pain/tightness/pressure
• Cerebrovascular events
• Other vasospasm reactions
• Medication overuse headache
• Serotonin syndrome
• Increase in blood pressure
• Anaphylactic/anaphylactoid reactions

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In two long-term, open-label studies in which patients were allowed to treat multiple migraine attacks for up to 1 year, 15% (99 out of 662) withdrew from the study because of adverse reaction. The most common adverse reactions leading to withdrawal from the study were contact dermatitis (4%) and application site pain (4%).

The most common adverse reactions (≥ 5%) in a controlled single dose study were application site pain, paresthesia, pruritus, warmth, and discomfort.

Controlled Single Dose Acute Migraine Study

Table 1 lists adverse reactions that occurred at a frequency of 2% or greater in a controlled clinical study of Xibimer in patients with acute migraine (Study 1). In that study, patients randomized to the control group used the same activated iontophoretic transdermal delivery system (TDS) as patients randomized to Xibimer, with the only difference being the absence of sumatriptan in the drug reservoir. Therefore, patients in the control group were exposed to same TDSrelated risks as patients in the Xibimer group, minus the risks related to sumatriptan. Only reactions that occurred at a frequency of 2% or more in patients treated with Xibimer or control are included in Table 1.

Table 1: Adverse Reactions Reported by at least 2% of Patients in Study 1

The incidence of “atypical sensations” adverse events (paresthesia, sensation warm/cold) and “pain and other pressure sensations” (chest pain/tightness/pressure/heaviness or neck/throat/jaw pain, tightness, pressure or heaviness) was 2% each in Xibimer-treated patients, vs. 0% in the control group. Application site bruising was reported in 2 Xibimer-treated patients (0.9%) vs. no patient in the control group.

Subgroup analyses of age (≤41 years, >41 years), race (Caucasian, non-Caucasian) and body mass index (BMI) (≤25.7 mg/kg², >25.7 mg/kg²) showed no difference between subgroups for adverse events.

Skin Irritation Examination

In Study 1, patients performed their own examination of the TDS application site at 4, 12, and 24 hours post TDS activation, and daily thereafter until resolution. Skin irritation examination scores are summarized in Table 2. The median time to “no redness” was 2.6 days for Xibimer compared with 0.3 day in the control group.

Table 2: Subject Self-examination Skin Irritation Scoring

Application Site Reactions Across Clinical Studies (Controlled Single Dose Acute Migraine Study And Long Term Safety Studies)

In the controlled and uncontrolled clinical studies combined (n = 796 unique Xibimer-treated subjects), the frequency of application site reactions of clinical interest is presented in Table 3.

Table 3: Application Site Reactions

The following adverse reactions are discussed in more detail in other sections of the prescribing information:

• Allergic Contact Dermatitis
• Myocardial ischemia, myocardial infarction, and Prinzmetal's angina
• Arrhythmias
• Chest, throat, neck, and/or jaw pain/tightness/pressure
• Cerebrovascular events
• Other vasospasm reactions
• Medication overuse headache
• Serotonin syndrome
• Increase in blood pressure
• Anaphylactic/anaphylactoid reactions

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In two long-term, open-label studies in which patients were allowed to treat multiple migraine attacks for up to 1 year, 15% (99 out of 662) withdrew from the study because of adverse reaction. The most common adverse reactions leading to withdrawal from the study were contact dermatitis (4%) and application site pain (4%).

The most common adverse reactions (≥ 5%) in a controlled single dose study were application site pain, paresthesia, pruritus, warmth, and discomfort.

Controlled Single Dose Acute Migraine Study

Table 1 lists adverse reactions that occurred at a frequency of 2% or greater in a controlled clinical study of ZECUITY in patients with acute migraine (Study 1). In that study, patients randomized to the control group used the same activated iontophoretic transdermal delivery system (TDS) as patients randomized to ZECUITY, with the only difference being the absence of sumatriptan in the drug reservoir. Therefore, patients in the control group were exposed to same TDSrelated risks as patients in the ZECUITY group, minus the risks related to sumatriptan. Only reactions that occurred at a frequency of 2% or more in patients treated with ZECUITY or control are included in Table 1.

Table 1: Adverse Reactions Reported by at least 2% of Patients in Study 1

The incidence of “atypical sensations” adverse events (paresthesia, sensation warm/cold) and “pain and other pressure sensations” (chest pain/tightness/pressure/heaviness or neck/throat/jaw pain, tightness, pressure or heaviness) was 2% each in ZECUITY-treated patients, vs. 0% in the control group. Application site bruising was reported in 2 ZECUITY-treated patients (0.9%) vs. no patient in the control group.

Subgroup analyses of age (≤41 years, >41 years), race (Caucasian, non-Caucasian) and body mass index (BMI) (≤25.7 mg/kg², >25.7 mg/kg²) showed no difference between subgroups for adverse events.

Skin Irritation Examination

In Study 1, patients performed their own examination of the TDS application site at 4, 12, and 24 hours post TDS activation, and daily thereafter until resolution. Skin irritation examination scores are summarized in Table 2. The median time to “no redness” was 2.6 days for ZECUITY compared with 0.3 day in the control group.

Table 2: Subject Self-examination Skin Irritation Scoring

Application Site Reactions Across Clinical Studies (Controlled Single Dose Acute Migraine Study And Long Term Safety Studies)

In the controlled and uncontrolled clinical studies combined (n = 796 unique ZECUITY-treated subjects), the frequency of application site reactions of clinical interest is presented in Table 3.

Table 3: Application Site Reactions

Single doses of sumatriptan up to 40 mg intranasally, in excess of 16 mg subcutaneously and 400 mg orally have not been associated with side effects other than those mentioned.

In clinical studies volunteers have received 20 mg of sumatriptan by the intranasal route three times a day for a period of 4 days without significant adverse effects.

If overdosage occurs, the patient should be monitored for at least 10 hours and standard supportive treatment applied as required. It is unknown what effect haemodialysis or peritoneal dialysis has on the plasma concentrations of sumatriptan.

Coronary vasospasm was observed after intravenous administration of Xibimer Injection. Overdoses would be expected from animal data (dogs at 0.1 g/kg, rats at 2 g/kg) to possibly cause convulsions, tremor, inactivity, erythema of the extremities, reduced respiratory rate, cyanosis, ataxia, mydriasis, injection site reactions (desquamation, hair loss, and scab formation), and paralysis.

The elimination half-life of sumatriptan is about 2 hours ; therefore, monitoring of patients after overdose with Xibimer Injection should continue for at least 10 hours or while symptoms or signs persist.

It is unknown what effect hemodialysis or peritoneal dialysis has on the serum concentrations of sumatriptan.

Doses in excess of 400 mg orally were not associated with side effects other than those mentioned.

If overdosage occurs, the patient should be monitored for at least 10 hours and standard supportive treatment applied as required.

It is unknown what effect hemodialysis or peritoneal dialysis has on the plasma concentrations of Xibimer.

Coronary vasospasm was observed after intravenous administration of IMITREX Injection. Overdoses would be expected from animal data (dogs at 0.1 g/kg, rats at 2 g/kg) to possibly cause convulsions, tremor, inactivity, erythema of the extremities, reduced respiratory rate, cyanosis, ataxia, mydriasis, injection site reactions (desquamation, hair loss, and scab formation), and paralysis.

The elimination half-life of sumatriptan is about 2 hours ; therefore, monitoring of patients after overdose with IMITREX Injection should continue for at least 10 hours or while symptoms or signs persist.

It is unknown what effect hemodialysis or peritoneal dialysis has on the serum concentrations of sumatriptan.

No gross overdoses in clinical practice have been reported. Coronary vasospasm was observed after intravenous administration of sumatriptan injection. Overdoses would be expected from animal data (dogs at 0.1 g/kg, rats at 2 g/kg) to possibly cause convulsions, tremor, inactivity, erythema of the extremities, reduced respiratory rate, cyanosis, ataxia, mydriasis, injection site reactions (desquamation, hair loss, and scab formation), and paralysis.

The apparent elimination half-life of sumatriptan after Xibimer administration is about 3 hours , and therefore monitoring of patients after overdose with Xibimer should continue for at least 15 hours or while symptoms or signs persist.

It is unknown what effect hemodialysis or peritoneal dialysis has on the serum concentrations of sumatriptan.

No gross overdoses in clinical practice have been reported. Coronary vasospasm was observed after intravenous administration of sumatriptan injection. Overdoses would be expected from animal data (dogs at 0.1 g/kg, rats at 2 g/kg) to possibly cause convulsions, tremor, inactivity, erythema of the extremities, reduced respiratory rate, cyanosis, ataxia, mydriasis, injection site reactions (desquamation, hair loss, and scab formation), and paralysis.

The apparent elimination half-life of sumatriptan after ZECUITY administration is about 3 hours , and therefore monitoring of patients after overdose with ZECUITY should continue for at least 15 hours or while symptoms or signs persist.

It is unknown what effect hemodialysis or peritoneal dialysis has on the serum concentrations of sumatriptan.

After intranasal administration, sumatriptan is rapidly absorbed, median times to maximum plasma concentrations being 1.5 (range: 0.25-3) hours in adults and 2 (range: 0.5-3) hours in adolescents. After a 20 mg dose, the mean maximum concentration is 13ng/mL. Mean intranasal bioavailability, relative to subcutaneous administration is about 16%, partly due to pre-systemic metabolism.

Plasma protein binding is low (14-21%) and the mean volume of distribution is 170L. The elimination half-life is approximately 2 hours. The mean total plasma clearance is approximately 1160mL/min and the mean renal plasma clearance is approximately 260mL/min.

A pharmacokinetic study in adolescent subjects (12-17 years) indicated that the mean maximum plasma concentration was 13.9ng/mL and mean elimination half-life was approximately 2 hours following a 20 mg intranasal dose. Population pharmacokinetic modelling indicated that clearance and volume of distribution both increase with body size in the adolescent population resulting in higher exposure in lower bodyweight adolescents.

Non-renal clearance accounts for about 80% of the total clearance. Sumatriptan is eliminated primarily by oxidative metabolism mediated by monoamine oxidase A. The major metabolite, the indole acetic acid analogue of sumatriptan, is mainly excreted in urine, where it is present as a free acid and the glucuronide conjugate. It has no known 5-HT1 or 5-HT2 activity. Minor metabolites have not been identified. The pharmacokinetic profile of intranasal sumatriptan does not appear to be significantly affected by migraine attacks.

Special Patient Populations

Elderly (over 65)

The kinetics in the elderly have been insufficiently studied to justify a statement on possible differences in kinetics between elderly and young volunteers.

Hepatic impairment

Sumatriptan pharmacokinetics after an oral dose (50 mg) and a subcutaneous dose (6 mg) were studied in 8 patients with mild to moderate hepatic impairment matched for sex, age, and weight with 8 healthy subjects. Following an oral dose, sumatriptan plasma exposure (AUC and Cmax) almost doubled (increased approximately 80%) in patients with mild to moderate hepatic impairment compared to the control subjects with normal hepatic function. There was no difference between the patients with hepatic impairment and control subjects after the s.c. dose. This indicates that mild to moderate hepatic impairment reduces presystemic clearance and increases the bioavailability and exposure to sumatriptan compared to healthy subjects.

Following oral administration, pre-systemic clearance is reduced in patients with mild to moderate hepatic impairment and plasma exposure, measured by Cmax and AUC, almost doubled.).

Absorption and Bioavailability

The bioavailability of sumatriptan via subcutaneous site injection to 18 healthy male subjects was 97% ± 16% of that obtained following intravenous injection.

After a single 6-mg subcutaneous manual injection into the deltoid area of the arm in 18 healthy males (age: 24 ± 6 years, weight: 70 kg), the maximum serum concentration (Cmax) of sumatriptan was (mean ± standard deviation) 74 ± 15 ng/mL and the time to peak concentration (Tmax) was 12 minutes after injection (range: 5 to 20 minutes). In this trial, the same dose injected subcutaneously in the thigh gave a Cmax of 61 ± 15 ng/mL by manual injection versus 52 ± 15 ng/mL by autoinjector techniques. The Tmax or amount absorbed was not significantly altered by either the site or technique of injection.

Distribution

Protein binding, determined by equilibrium dialysis over the concentration range of 10 to 1,000 ng/mL is low, approximately 14% to 21%. The effect of sumatriptan on the protein binding of other drugs has not been evaluated.

Following a 6-mg subcutaneous injection into the deltoid area of the arm in 9 males (mean age: 33 years, mean weight: 77 kg) the volume of distribution central compartment of sumatriptan was 50 ± 8 liters and the distribution half-life was 15 ± 2 minutes.

Metabolism

In vitro studies with human microsomes suggest that sumatriptan is metabolized by MAO, predominantly the A isoenzyme. Most of a radiolabeled dose of sumatriptan excreted in the urine is the major metabolite indole acetic acid (IAA) or the IAA glucuronide, both of which are inactive.

Elimination

After a single 6-mg subcutaneous dose, 22% ± 4% was excreted in the urine as unchanged sumatriptan and 38% ± 7% as the IAA metabolite.

Following a 6-mg subcutaneous injection into the deltoid area of the arm, the systemic clearance of sumatriptan was 1,194 ± 149 mL/min and the terminal half-life was 115 ± 19 minutes.

Specific Populations

Age

The pharmacokinetics of sumatriptan in the elderly (mean age: 72 years, 2 males and 4 females) and in subjects with migraine (mean age: 38 years, 25 males and 155 females) were similar to that in healthy male subjects (mean age: 30 years).

Hepatic Impairment

The effect of mild to moderate hepatic disease on the pharmacokinetics of subcutaneously administered sumatriptan has been evaluated. There were no significant differences in the pharmacokinetics of subcutaneously administered sumatriptan in moderately hepatically impaired subjects compared with healthy controls. The pharmacokinetics of subcutaneously administered sumatriptan in patients with severe hepatic impairment has not been studied. The use of Xibimer Injection in this population is contraindicated.

Race

The systemic clearance and Cmax of subcutaneous sumatriptan were similar in black (n = 34) and Caucasian (n = 38) healthy male subjects.

Following oral administration, Xibimer is rapidly absorbed, 70% of maximum concentration occurring at 45 minutes. After 100mg dose, the maximum plasma concentration is 54ng/ml. Mean absolute oral bioavailability is 14% partly due to presystemic metabolism and partly due to incomplete absorption. The elimination phase half-life is approximately 2 hours, although there is an indication of a longer terminal phase. Plasma protein binding is low (14-21%), mean volume of distribution is 170 litres. Mean total plasma clearance is approximately 1160ml/min and the mean renal plasma clearance is approximately 260ml/min. Non-renal clearance accounts for about 80 % of the total clearance. Xibimer is eliminated primarily by oxidative metabolism mediated by monoamine oxidase A. The major metabolite, the indole acetic acid analogue of Xibimer is mainly excreted in the urine, where it is present as a free acid and the glucuronide conjugate. It has no known 5HT1 or 5HT2 activity. Minor metabolites have not been identified. The pharmacokinetics of oral Xibimer do not appear to be significantly affected by migraine attacks.

In a pilot study, no significant differences were found in the pharmacokinetic parameters between the elderly and young healthy volunteers.

Absorption and Bioavailability

The bioavailability of sumatriptan via subcutaneous site injection to 18 healthy male subjects was 97% ± 16% of that obtained following intravenous injection.

After a single 6-mg subcutaneous manual injection into the deltoid area of the arm in 18 healthy males (age: 24 ± 6 years, weight: 70 kg), the maximum serum concentration (Cmax) of sumatriptan was (mean ± standard deviation) 74 ± 15 ng/mL and the time to peak concentration (Tmax) was 12 minutes after injection (range: 5 to 20 minutes). In this trial, the same dose injected subcutaneously in the thigh gave a Cmax of 61 ± 15 ng/mL by manual injection versus 52 ± 15 ng/mL by autoinjector techniques. The Tmax or amount absorbed was not significantly altered by either the site or technique of injection.

Distribution

Protein binding, determined by equilibrium dialysis over the concentration range of 10 to 1,000 ng/mL is low, approximately 14% to 21%. The effect of sumatriptan on the protein binding of other drugs has not been evaluated.

Following a 6-mg subcutaneous injection into the deltoid area of the arm in 9 males (mean age: 33 years, mean weight: 77 kg) the volume of distribution central compartment of sumatriptan was 50 ± 8 liters and the distribution half-life was 15 ± 2 minutes.

Metabolism

In vitro studies with human microsomes suggest that sumatriptan is metabolized by MAO, predominantly the A isoenzyme. Most of a radiolabeled dose of sumatriptan excreted in the urine is the major metabolite indole acetic acid (IAA) or the IAA glucuronide, both of which are inactive.

Elimination

After a single 6-mg subcutaneous dose, 22% ± 4% was excreted in the urine as unchanged sumatriptan and 38% ± 7% as the IAA metabolite.

Following a 6-mg subcutaneous injection into the deltoid area of the arm, the systemic clearance of sumatriptan was 1,194 ± 149 mL/min and the terminal half-life was 115 ± 19 minutes.

Specific Populations

Age

The pharmacokinetics of sumatriptan in the elderly (mean age: 72 years, 2 males and 4 females) and in subjects with migraine (mean age: 38 years, 25 males and 155 females) were similar to that in healthy male subjects (mean age: 30 years).

Hepatic Impairment

The effect of mild to moderate hepatic disease on the pharmacokinetics of subcutaneously administered sumatriptan has been evaluated. There were no significant differences in the pharmacokinetics of subcutaneously administered sumatriptan in moderately hepatically impaired subjects compared with healthy controls. The pharmacokinetics of subcutaneously administered sumatriptan in patients with severe hepatic impairment has not been studied. The use of IMITREX Injection in this population is contraindicated.

Race

The systemic clearance and Cmax of subcutaneous sumatriptan were similar in black (n = 34) and Caucasian (n = 38) healthy male subjects.

Absorption And Bioavailability

Following Xibimer administration to the upper arm the maximum mean sumatriptan serum concentration (Cmax) was 22 ng/mL, the mean total area under the curve (AUC 0-inf) was 110 hr*ng/mL, and the median tmax was 1.1 hours. The mean Cmax and mean AUC0-inf measured after Xibimer administration were approximately 37% and 45% of the values measured after administration of 100 mg Imitrex® tablets, respectively.

The effect of Xibimer application to the upper arm versus thigh was assessed in 19 healthy subjects. The application sites are considered interchangeable as the relative bioavailability of sumatriptan following application of the Xibimer TDS to these two sites was comparable.

Distribution

Protein binding, determined by equilibrium dialysis over the concentration range of 10 to 1000 ng/mL, is between 14% and 21%. The effect of sumatriptan on the protein binding of other drugs has not been evaluated. The apparent volume of distribution of sumatriptan is 2.4 L/kg.

Metabolism

In vitro studies with human microsomes suggest that sumatriptan is metabolized by MAO, predominantly the A isoenzyme. No new metabolites were identified in comparison with the oral sumatriptan tablets. Most of a radiolabeled sumatriptan dose that is excreted in the urine is the major metabolite indole acetic acid (IAA) or the IAA glucuronide, both of which are inactive.

Elimination

After a single Xibimer dose in 9 subjects, 11% of the sumatriptan dose was excreted in the urine as unchanged sumatriptan and 69% as the indole acetic acid metabolite. After a single Xibimer dose, the mean sumatriptan half-life was 3.1 hours.

Migraine Effect

Similar pharmacokinetic values were observed during a migraine attack compared to a migraine-free period following Xibimer administration on the upper arm in 18 patients with a diagnosis of migraine.

External Heat Source

A heat effect study in 12 healthy adult subjects demonstrated similar pharmacokinetic values without and with the application of an external heat source (40°C heat wrap placed over top of the Xibimer TDS for the 4 hour dosing period).

Absorption And Bioavailability

Following ZECUITY administration to the upper arm the maximum mean sumatriptan serum concentration (Cmax) was 22 ng/mL, the mean total area under the curve (AUC 0-inf) was 110 hr*ng/mL, and the median tmax was 1.1 hours. The mean Cmax and mean AUC0-inf measured after ZECUITY administration were approximately 37% and 45% of the values measured after administration of 100 mg Imitrex® tablets, respectively.

The effect of ZECUITY application to the upper arm versus thigh was assessed in 19 healthy subjects. The application sites are considered interchangeable as the relative bioavailability of sumatriptan following application of the ZECUITY TDS to these two sites was comparable.

Distribution

Protein binding, determined by equilibrium dialysis over the concentration range of 10 to 1000 ng/mL, is between 14% and 21%. The effect of sumatriptan on the protein binding of other drugs has not been evaluated. The apparent volume of distribution of sumatriptan is 2.4 L/kg.

Metabolism

In vitro studies with human microsomes suggest that sumatriptan is metabolized by MAO, predominantly the A isoenzyme. No new metabolites were identified in comparison with the oral sumatriptan tablets. Most of a radiolabeled sumatriptan dose that is excreted in the urine is the major metabolite indole acetic acid (IAA) or the IAA glucuronide, both of which are inactive.

Elimination

After a single ZECUITY dose in 9 subjects, 11% of the sumatriptan dose was excreted in the urine as unchanged sumatriptan and 69% as the indole acetic acid metabolite. After a single ZECUITY dose, the mean sumatriptan half-life was 3.1 hours.

Migraine Effect

Similar pharmacokinetic values were observed during a migraine attack compared to a migraine-free period following ZECUITY administration on the upper arm in 18 patients with a diagnosis of migraine.

External Heat Source

A heat effect study in 12 healthy adult subjects demonstrated similar pharmacokinetic values without and with the application of an external heat source (40°C heat wrap placed over top of the ZECUITY TDS for the 4 hour dosing period).

In non-clinical studies carried out to test for local and ocular irritancy, following administration of sumatriptan nasal spray, there was no nasal irritancy seen in laboratory animals and no ocular irritancy observed when the spray was applied directly to the eyes of rabbits.

Experimental studies of acute and chronic toxicity showed no evidence of toxic effects within the human therapeutic dose range. In a rat fertility study a reduction in success of insemination was seen at exposures sufficiently in excess of the maximum human exposure. In rabbits, embryo-lethality without marked teratogenic defects was seen.

Sumatriptan was devoid of genotoxic and carcinogenic activity in in-vitro systems and animal studies.

Xibimer was devoid of genotoxic and carcinogenic activity in in-vitro systems and animal studies.

In a rat fertility study oral doses of Xibimer resulting in plasma levels approximately 200 times those seen in man after a 100 mg oral dose were associated with a reduction in the success of insemination.

This effect did not occur during a subcutaneous study where maximum plasma levels achieved approximately 150 times those in man by the oral route.

In rabbits embryolethality, without marked teratogenic defects, was seen. The relevance for humans of these findings is unknown.

Not applicable

Not applicable.

No special requirements.

No special requirements