FDA Label for Sumatriptan

1 Indications And Usage

Sumatriptan Succinate 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 Sumatriptan Succinate Injection, reconsider the diagnosis before Sumatriptan Succinate Injection is administered to treat any subsequent attacks.
• •Sumatriptan Succinate Injection is not indicated for the prevention of migraine or cluster headache attacks.

2.1 Dosing Information

The maximum single recommended adult dose of Sumatriptan Succinate 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 [see Clinical Studies (14.1)]. 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.

2.2 Administration Using The Autoinjector Pen

An autoinjector device 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 the autoinjector pen and direct them to use injection sites with an adequate skin and subcutaneous thickness to accommodate the length of the needle.

The needle shield of the prefilled syringe contains dry natural rubber (a latex derivative) [see Warnings and Precautions (5.9)].

2.3 Administration Of Doses Of Sumatriptan Succinate 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 autoinjector pen. Visually inspect the vial for particulate matter and discoloration before administration. Do not use if particulates and discolorations are noted.

3 Dosage Forms And Strengths

• •Injection: 4-mg and 6-mg single-dose prefilled syringe cartridges for use with the autoinjector pen.
• •Injection: 6-mg single-dose vial.

4 Contraindications

Sumatriptan Succinate 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 [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 or 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-hydroxytryptamine₁ (5‑HT₁) 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 (5.9)].
• •Severe hepatic impairment [see Clinical Pharmacology (12.3)].

5.1 Myocardial Ischemia, Myocardial Infarction, And Prinzmetal’S Angina

The use of Sumatriptan Succinate 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 Succinate Injection. Some of these reactions occurred in patients without known CAD. Sumatriptan Succinate 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 Sumatriptan Succinate Injection. If there is evidence of CAD or coronary artery vasospasm, Sumatriptan Succinate Injection is contraindicated. For patients with multiple cardiovascular risk factors who have a negative cardiovascular evaluation, consider administering the first dose of Sumatriptan Succinate Injection in a medically supervised setting and performing an electrocardiogram (ECG) immediately following administration of Sumatriptan Succinate Injection. For such patients, consider periodic cardiovascular evaluation in intermittent long‑term users of Sumatriptan Succinate 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 Sumatriptan Succinate Injection if these disturbances occur. Sumatriptan Succinate 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 Succinate Injection and are usually non-cardiac in origin. However, perform a cardiac evaluation if these patients are at high cardiac risk. The use of Sumatriptan Succinate 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 Sumatriptan Succinate 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. Sumatriptan Succinate Injection is contraindicated in patients with a history of stroke or TIA.

5.5 Other Vasospasm Reactions

Sumatriptan Succinate 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 injections of sumatriptan succinate.

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 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 Succinate Injection, 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 Succinate 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 Sumatriptan Succinate Injection. Sumatriptan Succinate 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. Sumatriptan Succinate Injection is contraindicated in patients with a history of hypersensitivity reaction to sumatriptan.

The needle shield of the prefilled syringe contains dry natural rubber (a latex derivative) that has the potential to cause allergic reactions in latex-sensitive individuals.

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. Sumatriptan Succinate Injection should be used with caution in patients with a history of epilepsy or conditions associated with a lowered seizure threshold.

6 Adverse Reactions

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

• •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)]
• •Hypersensitivity reactions [see Contraindications (4), Warnings and Precautions (5.9)]
• •Seizures [see Warnings and Precautions (5.10)]

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.

Migraine Headache

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

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 Sumatriptan Succinate 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 sumatriptan succinate 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% Sumatriptan Succinate Injection, 0% placebo), nausea and vomiting (4% Sumatriptan Succinate Injection, 0% placebo), and bronchospasm (1% Sumatriptan Succinate Injection, 0% placebo).

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.

Cardiovascular

Hypotension, palpitations.

Neurological

Dystonia, tremor.

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 Succinate Injection 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 Sumatriptan Succinate 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 Sumatriptan Succinate 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

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 (see Data). There are no data on the effects of sumatriptan on the breastfed infant or the effects of sumatriptan on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Sumatriptan Injection 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 Succinate Injection.

Data

Following subcutaneous administration of a 6-mg dose of sumatriptan injection in 5 lactating volunteers, sumatriptan was present in milk.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established. Sumatriptan Succinate 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 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 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 patients aged 12 to 17 years 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.

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. 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 succinate injection did not include sufficient numbers of patients aged 65 years 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 Sumatriptan Succinate Injection [see Warnings and Precautions (5.1)].

10 Overdosage

Coronary vasospasm was observed after intravenous administration of Sumatriptan Succinate Injection [see Contraindications (4)]. 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 [see Clinical Pharmacology (12.3)]; therefore, monitoring of patients after overdose with Sumatriptan Succinate 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.

11 Description

Sumatriptan Succinate Injection contains sumatriptan succinate, a selective 5-HT_1B/1D receptor agonist. Sumatriptan succinate is chemically designated as 3-[2-(dimethylamino)ethyl]-N-methyl-indole-5-methanesulfonamide succinate (1:1), and it has the following structure:

The empirical formula is C₁₄H₂₁N₃O₂S•C₄H₆O₄, representing a molecular weight of 413.5. Sumatriptan succinate is a white to off-white powder that is readily soluble in water and in saline.

Sumatriptan Succinate Injection is a clear, colorless to pale yellow, sterile, nonpyrogenic solution for subcutaneous injection. Each 0.5 mL of Sumatriptan Succinate Injection 8-mg/mL solution contains 4 mg of sumatriptan (base) as the succinate salt and 3.8 mg of sodium chloride, USP in Water for Injection, USP. Each 0.5 mL of Sumatriptan Succinate Injection 12-mg/mL solution contains 6 mg of sumatriptan (base) as the succinate salt and 3.5 mg of sodium chloride, USP in Water for Injection, USP. The pH range of both solutions is approximately 4.2 to 5.3. The osmolality of both injections is 291 mOsmol.

12.1 Mechanism Of Action

Sumatriptan binds with high affinity to human cloned 5‑HT_1B/1D receptors. Sumatriptan presumably exerts its therapeutic effects in the treatment of migraine and cluster headaches 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.

12.2 Pharmacodynamics

Blood Pressure

Significant elevation in blood pressure, including hypertensive crisis, has been reported in patients with and without a history of hypertension [see Warnings and Precautions (5.8)].

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 patients 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.

12.3 Pharmacokinetics

Absorption

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 (C_max) of sumatriptan was (mean ± standard deviation) 74 ± 15 ng/mL and the time to peak concentration (T_max) was 12 minutes after injection (range: 5 to 20 minutes). In this trial, the same dose injected subcutaneously in the thigh gave a C_max of 61 ± 15 ng/mL by manual injection versus 52 ± 15 ng/mL by autoinjector techniques. The T_max 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).

Patients with 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 Sumatriptan Succinate Injection in this population is contraindicated [see Contraindications (4)].

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

Drug Interaction Studies

Monoamine Oxidase-A Inhibitors: In a trial of 14 healthy females, pretreatment with an MAO-A inhibitor decreased the clearance of subcutaneous sumatriptan, resulting in a 2-fold increase in the area under the sumatriptan plasma concentration-time curve (AUC), corresponding to a 40% increase in elimination half-life.

13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

In carcinogenicity studies in mouse and rat, sumatriptan was administered orally for 78 weeks and 104 weeks, respectively, at doses up to 160 mg/kg/day (the high 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 (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.

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.

13.2 Animal Toxicology And/Or Pharmacology

Corneal Opacities

Dogs receiving oral sumatriptan developed corneal opacities and defects in the corneal epithelium. Corneal opacities were seen at the lowest dose tested, 2 mg/kg/day, and were present after 1 month of treatment. Defects in the corneal epithelium were noted in a 60-week study. Earlier examinations for these toxicities were not conducted and no-effect doses were not established; however, the relative plasma exposure at the lowest dose tested was approximately 3 times the human exposure after a 6-mg subcutaneous dose.

14.1 Migraine

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 Succinate Injection. Lower doses of Sumatriptan Succinate 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 Succinate 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 Succinate 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 Succinate Injection. Approximately 82% and 65% of patients treated with Sumatriptan Succinate Injection 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 Succinate Injection 6 mg in Studies 2 and 3.

Sumatriptan Succinate Injection also relieved photophobia, phonophobia (sound sensitivity), nausea, and vomiting associated with migraine attacks. Similar efficacy was seen when patients self‑administered Sumatriptan Succinate Injection using the autoinjector pen.

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

14.2 Cluster Headache

The efficacy of Sumatriptan Succinate Injection in the acute treatment of cluster headache was demonstrated in 2 randomized, double-blind, placebo-controlled, 2-period crossover trials (Studies 4 and 5). Patients aged 21 to 65 years were enrolled and were instructed to treat a moderate to very severe headache within 10 minutes of onset. Headache relief was defined as a reduction in headache severity to mild or no pain. In both trials, the proportion of individuals gaining relief at 10 or 15 minutes was significantly greater among patients receiving 6 mg of Sumatriptan Succinate Injection compared with those who received placebo (see Table 4).

An estimate of the cumulative probability of a patient with a cluster headache obtaining relief after being treated with either sumatriptan succinate injection or placebo is presented in Figure 1.

Figure 1. Time to Relief of Cluster Headache from Time of Injection^a

^a The figure uses Kaplan-Meier (product limit) Survivorship Plot. Patients taking rescue medication were censored at 15 minutes.

The plot was constructed with data from patients who either experienced relief or did not require (request) rescue medication within a period of 2 hours following treatment. As a consequence, the data in the plot are derived from only a subset of the 258 headaches treated (rescue medication was required in 52 of the 127 placebo-treated headaches and 18 of the 131 headaches treated with Sumatriptan Succinate Injection).

Other data suggest that treatment with Sumatriptan Succinate Injection is not associated with an increase in early recurrence of headache and has little effect on the incidence of later-occurring headaches (i.e., those occurring after 2, but before 18 or 24 hours).

16 How Supplied/Storage And Handling

Sumatriptan Succinate Injection contains sumatriptan (base) as the succinate salt and is supplied as a clear, colorless to pale yellow, sterile, nonpyrogenic solution as follows:

Prefilled Syringe and/or Autoinjector Pen:

The needle shield of the prefilled syringe contains dry natural rubber (a latex derivative) that has the potential to cause allergic reactions in latex-sensitive individuals.

Each pack contains a Patient Information and Instructions for Use leaflet.

• •Sumatriptan Succinate Injection Kit, 4 mg, containing 1 autoinjector pen, 2 prefilled single-dose syringe cartridges, and 1 carrying case (NDC 66993-083-98).
• •Sumatriptan Succinate Injection Kit, 6 mg, containing 1 autoinjector pen, 2 prefilled single-dose syringe cartridges, and 1 carrying case (NDC 66993-084-98).
• •Two 4-mg single-dose prefilled syringe cartridges for use with Sumatriptan Succinate Injection Kit (NDC 66993-083-79).
• •Two 6-mg single-dose prefilled syringe cartridges for use with Sumatriptan Succinate Injection Kit (NDC 66993-084-79).

Single-Dose Vial:

• •Sumatriptan Succinate Injection single-dose vial (6 mg/0.5 mL) in cartons containing 5 vials (NDC 66993-085-95).

Store between 2° and 30°C (36° and 86°F). Protect from light.

17 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 Sumatriptan Succinate 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 [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 Succinate 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), Warnings and Precautions (5.9)]. Inform latex-sensitive patients that the needle shield of the Sumatriptan Succinate Injection prefilled syringe contains dry natural rubber (a derivative of latex) that may cause allergic reactions in individuals sensitive to latex.

Concomitant Use with Other Triptans or Ergot Medications

Inform patients that use of Sumatriptan Succinate Injection within 24 hours of another triptan or an ergot-type medication (including dihydroergotamine or methysergide) 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 Sumatriptan Succinate 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 Sumatriptan Succinate Injection may cause somnolence and dizziness; instruct patients to evaluate their ability to perform complex tasks after administration of Sumatriptan Succinate Injection.

How to Use Sumatriptan Succinate Injection

Instruct patients to read the Instructions for Use before starting therapy. Provide patients instruction on the proper use of Sumatriptan Succinate Injection if they are able to self-administer Sumatriptan Succinate Injection in medically unsupervised situations. Instruct patients on storage and disposal of the pen [see How Supplied/Storage and Handling (16)].

Inform patients that the needle in the autoinjector 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.

Manufactured by:

GlaxoSmithKline

Research Triangle Park, NC 27709

Manufactured for:

Prasco Laboratories

Mason, OH 45040 USA

SMJ-PS:1PI

Package Label.Principal Display Panel

Principal Display Panel

NDC 66993-083-98

Sumatriptan Succinate Injection

PRASCO

This carton contains:

• •Sumatriptan Succinate Injection
•  2 prefilled 0.5-mL syringe cartridges, each containing 4 mg of sumatriptan for subcutaneous injection only
• •1 Sumatriptan Autoinjector Pen
• •1 Carrying Case
• •Instructions for Use/Information for the Patient
• •Prescribing Information

This Product Contains Dry Natural Rubber

Rx Only

4 mg

Made in India

Rev. 9/19

62000000042108

Principal Display Panel

NDC 66993-084-98

Sumatriptan Succinate Injection

PRASCO

This carton contains:

• •Sumatriptan Succinate Injection
•  2 prefilled 0.5-mL syringe cartridges, each containing 6 mg of sumatriptan for subcutaneous injection only
• •1 Sumatriptan Autoinjector Pen
• •1 Carrying Case
• •Instructions for Use/Information for the Patient
• •Prescribing Information

This Product Contains Dry Natural Rubber

Rx Only

6 mg

Made in India

Rev. 9/19

62000000042064