Sumatriptan

Sumatriptan Nasal Spray 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 headache has been established. If a patient has no response to the first migraine attack treated with Sumatriptan Nasal Spray, reconsider the diagnosis of migraine before Sumatriptan Nasal Spray is administered to treat any subsequent attacks.
• Sumatriptan is not indicated for the prevention of migraine attacks.
• Safety and effectiveness of Sumatriptan Nasal Spray have not been established for cluster headache. Sumatriptan is a serotonin (5-HT 1B/1D ) receptor agonist (triptan) indicated for acute treatment of migraine with or without aura in adults. ( 1 ) Limitations of Use:
• Use only if a clear diagnosis of migraine headache has been established. ( 1 )
• Not indicated for the prophylactic therapy of migraine attacks. ( 1 )
• Not indicated for the treatment of cluster headache. ( 1 )

Unit dose nasal spray devices containing 5 mg or 20 mg sumatriptan. Nasal spray: 5 mg and 20 mg ( 3 , 16 )

Sumatriptan Nasal Spray 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 [see Warnings and Precautions ( 5.1 )]
• Wolff-Parkinson-White syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders [see Warnings and Precautions ( 5.2 )]
• History of stroke, transient ischemic attack (TIA), or history of hemiplegic or basilar migraine because these patients are at a higher risk of stroke [see Warnings and Precautions ( 5.4 )]
• Peripheral vascular disease [see Warnings and Precautions ( 5.5 )]
• Ischemic bowel disease [see Warnings and Precautions ( 5.5 )]
• Uncontrolled hypertension [see Warnings and Precautions ( 5.8 )]
• Recent use (i.e., within 24 hours) of ergotamine-containing medication, ergot-type medication (such as dihydroergotamine or methysergide), or another 5-hydroxytryptamine 1 (5-HT 1 ) agonist [see Drug Interactions ( 7.1 , 7.3 )]
• Concurrent administration of a monoamine oxidase (MAO)-A inhibitor or recent (within 2 weeks) use of an MAO-A inhibitor [see Drug Interactions ( 7.2 ), Clinical Pharmacology ( 12.3 )]
• Hypersensitivity to sumatriptan (angioedema and anaphylaxis seen) [see Warnings and Precautions ( 5.10 )]
• Severe hepatic impairment [see Clinical Pharmacology ( 12.3 )]
• History of coronary artery disease or coronary artery vasospasm ( 4 )
• Wolff-Parkinson-White syndrome or other cardiac accessory conduction pathway disorders ( 4 )
• History of stroke, transient ischemic attack, or hemiplegic or basilar migraine ( 4 )
• Peripheral vascular disease ( 4 )
• Ischemic bowel disease ( 4 )
• Uncontrolled hypertension ( 4 )
• Recent (within 24 hours) use of another 5-HT 1 agonist (e.g., another triptan) or of an ergotamine-containing medication. ( 4 )
• Concurrent or recent (past 2 weeks) use of monoamine oxidase-A inhibitor. ( 4 )
• Hypersensitivity to sumatriptan (angioedema and anaphylaxis seen). ( 4 )
• Severe hepatic impairment ( 4 )

• Myocardial ischemia/infarction and Prinzmetal’s angina: Perform cardiac evaluation in patients with multiple cardiovascular risk factors. ( 5.1 )
• Arrhythmias: Discontinue Sumatriptan Nasal Spray if occurs. ( 5.2 )
• Chest/throat/neck/jaw pain, tightness, pressure, or heaviness: Generally not associated with myocardial ischemia; evaluate for coronary artery disease in patients at high risk. ( 5.3 )
• Cerebral hemorrhage, subarachnoid hemorrhage, and stroke: Discontinue Sumatriptan Nasal Spray if occurs. ( 5.4 )
• Gastrointestinal ischemic reactions and peripheral vasospastic reactions: Discontinue Sumatriptan Nasal Spray if occurs. ( 5.5 )
• Medication overuse headache: Detoxification may be necessary. ( 5.6 )
• Serotonin syndrome: Discontinue Sumatriptan Nasal Spray if occurs. ( 5.7 )
• Seizures: Use with caution in patients with epilepsy or a lowered seizure threshold. ( 5.11 )

5.1 Myocardial Ischemia, Myocardial Infarction, and Prinzmetal’s Angina The use of Sumatriptan Nasal Spray 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 Nasal Spray. Some of these reactions occurred in patients without known CAD. Sumatriptan Nasal Spray 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 Sumatriptan Nasal Spray. If there is evidence of CAD or coronary artery vasospasm, Sumatriptan Nasal Spray is contraindicated. For patients with multiple cardiovascular risk factors who have a negative cardiovascular evaluation, consider administering the first dose of Sumatriptan Nasal Spray in a medically supervised setting and performing an electrocardiogram (ECG) immediately following administration of Sumatriptan Nasal Spray. For such patients, consider periodic cardiovascular evaluation in intermittent long-term users of Sumatriptan Nasal Spray.

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-HT 1 agonists. Discontinue Sumatriptan Nasal Spray if these disturbances occur. Sumatriptan Nasal Spray 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 may occur after treatment with Sumatriptan Nasal Spray and are usually non-cardiac in origin. However, perform a cardiac evaluation if these patients are at high cardiac risk. The use of Sumatriptan Nasal Spray 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-HT 1 agonists, and some have resulted in fatalities. In a number of cases, it appears possible that the cerebrovascular events were primary, the 5-HT 1 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 Sumatriptan Nasal Spray if a cerebrovascular event occurs. Before treating headaches in patients not previously diagnosed as migraineurs, and in migraineurs who present with atypical symptoms, exclude other potentially serious neurological conditions. Sumatriptan Nasal Spray is contraindicated in patients with a history of stroke or TIA.

5.5 Other Vasospasm Reactions Sumatriptan Nasal Spray 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-HT 1 agonist, rule out a vasospastic reaction before using additional Sumatriptan Nasal Spray. Reports of transient and permanent blindness and significant partial vision loss have been reported with the use of 5‑HT 1 agonists. Since visual disorders may be part of a migraine attack, a causal relationship between these events and the use of 5-HT 1 agonists has not been clearly established.

5.6 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.

5.7 Serotonin Syndrome Serotonin syndrome may occur with Sumatriptan Nasal Spray, particularly during coadministration 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 Sumatriptan Nasal Spray 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-HT 1 agonists, including patients without a history of hypertension. Monitor blood pressure in patients treated with sumatriptan. Sumatriptan Nasal Spray is contraindicated in patients with uncontrolled hypertension.

5.9 Local Irritation Local irritative symptoms such as burning, numbness, paresthesia, discharge, and pain or soreness were reported in approximately 5% of patients in controlled clinical trials and were noted to be severe in about 1%. The symptoms were transient and generally resolved in less than 2 hours. Limited examinations of the nose and throat did not reveal any clinically noticeable injury in these patients. The consequences of extended and repeated use of Sumatriptan Nasal Spray on the nasal and/or respiratory mucosa have not been systematically evaluated in patients.

5.10 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. Sumatriptan Nasal Spray is contraindicated in patients with a history of hypersensitivity reaction to sumatriptan.

5.11 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. […]

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

• Myocardial ischemia, myocardial infarction, and Prinzmetal’s angina [see Warnings and Precautions ( 5.1 )]
• Arrhythmias [see Warnings and Precautions ( 5.2 )]
• Chest, throat, neck, and/or jaw pain/tightness/pressure [see Warnings and Precautions ( 5.3 )]
• Cerebrovascular events [see Warnings and Precautions ( 5.4 )]
• Other vasospasm reactions [see Warnings and Precautions ( 5.5 )]
• Medication overuse headache [see Warnings and Precautions ( 5.6 )]
• Serotonin syndrome [see Warnings and Precautions ( 5.7 )]
• Increase in blood pressure [see Warnings and Precautions ( 5.8 )]
• Local irritation [see Warnings and Precautions ( 5.9 )]
• Hypersensitivity reactions [see Contraindications ( 4 ), Warnings and Precautions ( 5.10 )]
• Seizures [see Warnings and Precautions ( 5.11 )] Most common adverse reactions (≥1% and >placebo) were burning sensation, disorder/discomfort of nasal cavity/sinuses, throat discomfort, nausea and/or vomiting, bad/unusual taste, and dizziness/vertigo. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Prasco Laboratories at 1-866-525-0688 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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. Table 1 lists adverse reactions that occurred in worldwide placebo-controlled clinical trials in 3,419 patients with migraine. Only treatment-emergent adverse reactions that occurred at a frequency of 1% or more in the group treated with Sumatriptan Nasal Spray 20 mg and that occurred at a frequency greater than the placebo group are included in Table 1 . Table 1. Adverse Reactions Reported by at Least 1% of Patients and at a Greater Frequency than Placebo in Controlled Migraine Clinical Trials Adverse Reaction Percent of Patients Reporting Sumatriptan Nasal Spray 5 mg (n = 496) Sumatriptan Nasal Spray 10 mg (n = 1,007) Sumatriptan Nasal Spray 20 mg (n = 1,212) Placebo (n = 704) Atypical sensations Burning sensation 0.4 0.6 1.4

0.1 Ear, nose, and throat Disorder/discomfort of nasal cavity/sinuses 2.8 2.5 3.8

2.4 Throat discomfort 0.8 1.8 2.4

0.9 Gastrointestinal Nausea and/or vomiting 12.2 11.0 13.5

11.3 Neurological Bad/unusual taste 13.5 19.3 24.5

1.7 Dizziness/vertigo 1.0 1.7 1.4

0.9 The incidence of adverse reactions in controlled clinical trials was not affected by gender, weight, or age of the patients; use of prophylactic medications; or presence of aura. There were insufficient data to assess the impact of race on the incidence of adverse reactions.

6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval 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. These reactions have been chosen for inclusion due to either their seriousness, frequency of reporting, or causal connection to sumatriptan or a combination of these factors. Cardiovascular Hypotension, palpitations. Neurological Dystonia, tremor. Reproductive System and Breast Disorders Breast pain [see Use in Specific Populations ( 8.2 )] .

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 Sumatriptan Nasal Spray within 24 hours of each other is contraindicated.

7.2 Monoamine Oxidase-A Inhibitors MAO-A inhibitors increase systemic exposure by up to 7-fold. Therefore, the use of Sumatriptan Nasal Spray in patients receiving MAO-A inhibitors is contraindicated [see Clinical Pharmacology ( 12.3 )] .

7.3 Other 5-HT 1 Agonists Because their vasospastic effects may be additive, coadministration of Sumatriptan Nasal Spray and other 5-HT 1 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 )] .

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

8.1 Pregnancy Risk Summary Data from a prospective pregnancy exposure registry and epidemiological studies of pregnant women have not detected an increased frequency of birth defects or a consistent pattern of birth defects among women exposed to sumatriptan compared with the general population (see Data) . 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 (see Data ). In the U.S. general population, the estimated background risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. The reported rate of major birth defects among deliveries to women with migraine ranged from 2.2% to 2.9% and the reported rate of miscarriage was 17%, which were similar to rates reported in women without migraine. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk: Several studies have suggested that women with migraine may be at increased risk of preeclampsia during pregnancy. Data Human Data: The Sumatriptan/Naratriptan/TREXIMET (sumatriptan and naproxen sodium) Pregnancy Registry, a population-based international prospective study, collected data for sumatriptan from January 1996 to September 2012. The Registry documented outcomes of 626 infants and fetuses exposed to sumatriptan during pregnancy (528 with earliest exposure during the first trimester, 78 during the second trimester, 16 during the third trimester, and 4 unknown). The occurrence of major birth defects (excluding fetal deaths and induced abortions without reported defects and all spontaneous pregnancy losses) during first-trimester exposure to sumatriptan was 4.2% (20/478 [95% CI: 2.6% to 6.5%]) and during any trimester of exposure was 4.2% (24/576 [95% CI: 2.7% to 6.2%]). The sample size in this study had 80% power to detect at least a 1.73- to 1.91-fold increase in the rate of major malformations. The number of exposed pregnancy outcomes accumulated during the registry was insufficient to support definitive conclusions about overall malformation risk or for making comparisons of the frequencies of specific birth defects. Of the 20 infants with reported birth defects after exposure to sumatriptan in the first trimester, 4 infants had ventricular septal defects, including one infant who was exposed to both sumatriptan and naratriptan, and 3 infants had pyloric stenosis. No other birth defect was reported for more than 2 infants in this group. In a study using data from the Swedish Medical Birth Register, live births to women who reported using triptans or ergots during pregnancy were compared with those of women who did not. Of the 2,257 births with first-trimester exposure to sumatriptan, 107 infants were born with malformations (relative risk 0.99 [95% CI: 0.91 to 1.21]). A study using linked data from the Medical Birth Registry of Norway to the Norwegian Prescription Database compared pregnancy outcomes in women who redeemed prescriptions for triptans during pregnancy, as well as a migraine disease comparison group who redeemed prescriptions for sumatriptan before pregnancy only, compared with a population control group. Of the 415 women who redeemed prescriptions for sumatriptan during the first trimester, 15 had infants with major congenital malformations (OR 1.16 [95% CI: 0.69 to 1.94]) while for the 364 women who redeemed prescriptions for sumatriptan before, but not during, pregnancy, 20 had infants with major congenital malformations (OR 1.83 [95% CI: 1.17 to 2.88]), each compared with the population comparison group. Additional smaller observational studies evaluating use of sumatriptan during pregnancy have not suggested an increased risk of teratogenicity. Animal Data: 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 rats was 60 mg/kg/day. 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, respectively. 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. 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. 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.

8.2 Lactation Risk Summary Sumatriptan is excreted in human milk following subcutaneous administration. There is no information regarding sumatriptan concentrations in milk from lactating women following administration of Sumatriptan Nasal Spray. There are no data on the effects of sumatriptan on the breastfed infant or the effects of sumatriptan on milk production. Use of sumatriptan may be associated with transient breast pain [see Adverse Reactions ( 6.2 )] . The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Sumatriptan Nasal Spray and any potential adverse effects on the breastfed infant from sumatriptan or from the underlying maternal condition. Clinical Considerations Infant exposure to sumatriptan can be minimized by avoiding breastfeeding for 12 hours after treatment with Sumatriptan Nasal Spray.

8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. Sumatriptan Nasal Spray 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 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 trials, 3 multiple-attack trials) evaluating oral sumatriptan (25 to 100 mg) in pediatric patients aged 12 to 17 years enrolled a total of 701 adolescent migraineurs. These trials did not establish the efficacy of oral sumatriptan 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. 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 adolescents. Postmarketing 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. […]

Sumatriptan binds with high affinity to human cloned 5-HT 1B/1D receptors. Sumatriptan presumably exerts its therapeutic effects in the treatment of migraine headache through agonist effects at the 5‑HT 1B/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.