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 ZEMBRACE SymTouch, reconsider the diagnosis before ZEMBRACE SymTouch is administered to treat any subsequent attacks.
• ZEMBRACE SymTouch injection is not indicated for the prevention of migraine attacks.

2.1 Dosing Information

The recommended dose of ZEMBRACE SymTouch is 3 mg injected subcutaneously.

The maximum cumulative injected dose that may be given in 24 hours is 12 mg, with doses of ZEMBRACE SymTouch separated by at least 1 hour. ZEMBRACE SymTouch may also be given at least 1 hour following a dose of another sumatriptan product.

2.2 Administration Using ZEMBRACE SymTouch

ZEMBRACE SymTouch is available as a prefilled, ready-to-use, single dose, disposable auto-injector containing 3 mg sumatriptan. With ZEMBRACE SymTouch, the needle penetrates approximately ¼ inch (6 mm). The injection is intended to be given subcutaneously. Do not administer by any other route. Instruct patients on the proper use of ZEMBRACE SymTouch and direct them to use injection sites with an adequate skin and subcutaneous thickness to accommodate the length of the needle.

5.1 Myocardial Ischemia, Myocardial Infarction, and Prinzmetal's Angina

The use of ZEMBRACE SymTouch 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 sumatriptan injection. Some of these reactions occurred in patients without known CAD. 5-HT1 agonists, including ZEMBRACE SymTouch 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 ZEMBRACE SymTouch injection. If there is evidence of CAD or coronary artery vasospasm, ZEMBRACE SymTouch injection is contraindicated. For patients with multiple cardiovascular risk factors who have a negative cardiovascular evaluation, consider administering the first dose of ZEMBRACE SymTouch injection in a medically supervised setting and performing an electrocardiogram (ECG) immediately following ZEMBRACE SymTouch injection. For such patients, consider periodic cardiovascular evaluation in intermittent long-term users of ZEMBRACE SymTouch injection.

5.2 Arrhythmias

Life-threatening disturbances of cardiac rhythm, including ventricular tachycardia and ventricular fibrillation leading to death, have been reported within a few hours following the administration of 5-HT1 agonists.

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

5.3 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 sumatriptan injection and are usually non-cardiac in origin. However, perform a cardiac evaluation if these patients are at high cardiac risk. The use of ZEMBRACE SymTouch injection is contraindicated in patients with CAD and those with Prinzmetal's variant angina.

5.4 Cerebrovascular Events

Cerebral hemorrhage, subarachnoid hemorrhage, and stroke have occurred in patients treated with 5-HT1 agonists, and some have resulted in fatalities. In a number of cases, it appears possible that the cerebrovascular events were primary, the 5-HT1 agonist having been administered in the incorrect belief that the symptoms experienced were a consequence of migraine when they were not. Also, patients with migraine may be at increased risk of certain cerebrovascular events (e.g., stroke, hemorrhage, TIA). Discontinue ZEMBRACE SymTouch injection if a cerebrovascular event occurs.

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

5.5 Other Vasospasm Reactions

ZEMBRACE SymTouch 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 ZEMBRACE SymTouch 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.

5.6 Medication Overuse Headache

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

5.7 Serotonin Syndrome

Serotonin syndrome may occur with ZEMBRACE SymTouch injection, particularly during co-administration with selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and MAO inhibitors [see Drug Interactions (7.4)]. 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 ZEMBRACE SymTouch injection if serotonin syndrome is suspected.

5.8 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 ZEMBRACE SymTouch. ZEMBRACE SymTouch injection is contraindicated in patients with uncontrolled hypertension.

5.9 Hypersensitivity Reactions

Hypersensitivity reactions, including angioedema and anaphylaxis, 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. ZEMBRACE SymTouch injection is contraindicated in patients with a history of hypersensitivity reaction to sumatriptan.

5.10 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. ZEMBRACE SymTouch injection should be used with caution in patients with a history of epilepsy or conditions associated with a lowered seizure threshold.

6.1 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.

6.2 Post-marketing Experience

The following adverse reactions have been identified during post-approval use of sumatriptan tablets, sumatriptan nasal spray, and sumatriptan 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.

7.1 Ergot-Containing Drugs

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

7.2 Monoamine Oxidase-A Inhibitors

MAO-A inhibitors increase systemic exposure by 2-fold. Therefore, the use of ZEMBRACE SymTouch injection in patients receiving MAO-A inhibitors is contraindicated [see Clinical Pharmacology (12.3)].

7.3 Other 5-HT1 Agonists

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

7.4 Selective Serotonin Reuptake Inhibitors/Serotonin Norepinephrine Reuptake Inhibitors and Serotonin Syndrome

Cases of serotonin syndrome have been reported during coadministration of triptans and SSRIs, SNRIs, TCAs, and MAO inhibitors [see Warnings and Precautions (5.7)].

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

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

Two controlled clinical trials evaluated sumatriptan 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 sumatriptan 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 sumatriptan (25 to 100 mg) in pediatric subjects 12 to 17 years of age enrolled a total of 701 pediatric migraineurs. These trials did not establish the efficacy of oral sumatriptan 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.

Post-marketing experience documents that serious adverse reactions have occurred in the pediatric population after use of subcutaneous, oral, and/or intranasal sumatriptan. 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 sumatriptan; 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 sumatriptan are not presently available.

8.5 Geriatric Use

Clinical trials of sumatriptan injection did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger patients. 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 receiving ZEMBRACE SymTouch injection [see Warnings and Precautions (5.1)].

12.1 Mechanism of Action

Sumatriptan binds with high affinity to human cloned 5-HT1B/1D receptors. Sumatriptan presumably exerts its therapeutic effects in the treatment of migraine headache through agonist effects at the 5-HT1B/1D receptors on intracranial blood vessels and sensory nerves of the trigeminal system, which result in cranial vessel constriction and inhibition of pro-inflammatory neuropeptide release.

12.2 Pharmacodynamics

12.3 Pharmacokinetics

After a single 3 mg dose, ZEMBRACE SymTouch was bioequivalent to IMITREX subcutaneous injection.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

13.2 Animal Toxicology and/or Pharmacology

Clinical Studies with Sumatriptan Injection

In controlled clinical trials enrolling more than 1,000 patients during migraine attacks who were experiencing moderate or severe pain and 1 or more of the symptoms enumerated in Table 3, onset of relief began as early as 10 minutes following a 6-mg sumatriptan injection. Lower doses of sumatriptan injection may also prove effective, although the proportion of patients obtaining adequate relief was decreased and the latency to that relief is greater with lower doses.

In Study 1, 6 different doses of sumatriptan injection (n = 30 each group) were compared with placebo (n = 62), in a single-attack, parallel-group design, the dose response relationship was found to be as shown in Table 2.

In 2 randomized, placebo-controlled clinical trials of sumatriptan injection 6 mg in 1,104 patients with moderate or severe migraine pain (Studies 2 and 3), the onset of relief was less than 10 minutes. Headache relief, as defined by a reduction in pain from severe or moderately severe to mild or no headache, was achieved in 70% of the patients within 1 hour of a single 6-mg subcutaneous dose of sumatriptan injection. Approximately 82% and 65% of patients treated with sumatriptan 6 mg had headache relief and were pain free within 2 hours, respectively.

Table 3 shows the 1- and 2-hour efficacy results for sumatriptan injection 6 mg in Studies 2 and 3.

Sumatriptan injection also relieved photophobia, phonophobia (sound sensitivity), nausea, and vomiting associated with migraine attacks.

The efficacy of sumatriptan injections was unaffected by whether or not the migraine was associated with aura, duration of attack, gender or age of the subject, or concomitant use of common migraine prophylactic drugs (e.g., beta-blockers).

Clinical Study with ZEMBRACE SymTouch

In a double-blind, randomized, placebo-controlled clinical trial of ZEMBRACE SymTouch, 230 patients with migraine with or without aura received either ZEMBRACE SymTouch (N=111) or placebo (N=119) for a single migraine attack. The patients had a mean age of 41 years (range 18 to 65 years); approximately 76% were White and 85% were female.

The study excluded patients with medication overuse headache, treatment with onabotulinumtoxin A within 180 days, and patients with a history of cluster headache.

The primary efficacy endpoint was the proportion of patients who were pain-free (defined as a reduction from pre-dose moderate [Grade 2] or severe [Grade 3] pain to none [Grade 0]) 2 hours after the first dose. Of the ZEMBRACE SymTouch-treated patients, 46% were pain free at 2 hours after treatment compared to 27% of the placebo-treated patients.

16.1 How Supplied

• ZEMBRACE® SymTouch® 3 mg/0.5 mL Injection contains sumatriptan as the succinate salt and is supplied as a clear, colorless to pale yellow, sterile, nonpyrogenic solution in a prefilled, ready-to-use, single dose, disposable auto-injector unit (NDC # 0245-0809-89).
• Each carton contains 4 units (NDC # 0245-0809-38) and a Patient Information and Instructions for Use leaflet.

16.2 Storage and Handling

Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F). Protect from light.

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

Inform patients that ZEMBRACE SymTouch 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 when observing any indicative sign or symptoms are observed. Apprise patients of the importance of this follow-up [see Warnings and Precautions (5.1, 5.2, 5.4, 5.5, 5.8)].

Hypersensitivity Reactions

Inform patients that anaphylactic reactions have occurred in patients receiving sumatriptan 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 [see Contraindications (4) and Warnings and Precautions (5.9)].

Concomitant Use with Other Triptans or Ergot Medications

Inform patients that use of ZEMBRACE SymTouch injection within 24 hours of another triptan or an ergot-type medication (including dihydroergotamine or methylsergide) is contraindicated [see Contraindications (4), Drug Interactions (7.1, 7.3)].

Serotonin Syndrome

Caution patients about the risk of serotonin syndrome with the use of ZEMBRACE SymTouch injection or other triptans, particularly during combined use with SSRIs, SNRIs, TCAs, and MAO inhibitors [see Warnings and Precautions (5.7), Drug Interactions (7.4)].

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) [see Warnings and Precautions (5.6)].

Pregnancy

Advise patients to notify their healthcare provider if they become pregnant during treatment or plan to become pregnant [see Use in Specific Populations (8.1)].

Lactation

Advise patients to notify their healthcare provider if they are breastfeeding or plan to breastfeed [see Use in Specific Populations (8.2)].

Ability to Perform Complex Tasks

Treatment with ZEMBRACE SymTouch injection may cause somnolence and dizziness; instruct patients to evaluate their ability to perform complex tasks during migraine attacks and after administration of ZEMBRACE SymTouch injection.

How to Use ZEMBRACE SymTouch

Provide patients instruction on the proper use of ZEMBRACE SymTouch injection if they are able to self-administer ZEMBRACE SymTouch injection in medically unsupervised conditions.

Inform patients that the needle in the ZEMBRACE SymTouch penetrates approximately ¼ of an inch (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.