Zecuity (Transdermal)

Dosage Forms And Strengths

Iontophoretic transdermal system: 6.5 mg over 4 hours.

Storage And Handling

ZECUITY contains 86 mg sumatriptan that delivers 6.5 mg of sumatriptan over 4 hours.

After use, fold used system so the adhesive side sticks to itself and safely discard away from children and pets. ZECUITY contains lithium-manganese dioxide batteries; dispose in accordance with state and local regulations.

Store at room temperature, between 20°C to 25°C (68°F to 77°F), with excursions permitted between 15°C to 30°C (59°F to 86°F). Do not store in the refrigerator or freezer.

ZECUITY is packaged individually in a sealed pouch. ZECUITY is supplied in cartons of 4 systems, NDC 51759-101-04.

Manufactured for : Teva Pharmaceuticals International GmbH by LTS, Lohmann Therapie-Systeme AG, D-56626, Andernach, Germany and by LTS Lohmann Therapy Systems Corp., West Caldwell, NJ 07006. Distributed by: Teva Pharmaceuticals USA, Inc., North Wales, PA 19454. Revised: Feb 2017

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.

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.

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.

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 .

SIDE EFFECTS

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

DRUG INTERACTIONS

Ergot-Containing Drugs

Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because these effects may be additive, use of ergotamine-containing or ergot-type medications (like dihydroergotamine or methysergide) and ZECUITY within 24 hours of each other is contraindicated.

Monoamine Oxidase-A Inhibitors

MAO-A inhibitors increase systemic exposure by 2-fold. Therefore, the use of ZECUITY in patients receiving MAO-A inhibitors is contraindicated.

Other 5-HT₁ Agonists

Because their vasospastic effects may be additive, coadministration of ZECUITY and other 5-HT₁ agonists (e.g., triptans) within 24 hours of each other is contraindicated.

Selective Serotonin Reuptake Inhibitors /Serotonin Norepinephrine Reuptake Inhibitors And Serotonin Syndrome

Cases of serotonin syndrome have been reported during coadministration of triptans and SSRIs or SNRIs, SNRIs, TCAs, and MAO inhibitors.

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.

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

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.

Blood Pressure

Significant elevation in blood pressure, including hypertensive crisis, has been reported in patients treated with sumatriptan, with and without a history of hypertension.

Peripheral (Small) Arteries

In healthy volunteers (N = 18), a trial evaluating the effects of sumatriptan on peripheral (small vessel) arterial reactivity failed to detect a clinically significant increase in peripheral resistance.

Heart Rate

Transient increases in blood pressure observed in some subjects in clinical trials carried out during sumatriptan's development as a treatment for migraine were not accompanied by any clinically significant changes in heart rate.

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).