Generic Name: sumatriptan succinate
Dosage Form: injection
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 attack treated with sumatriptan, reconsider the diagnosis of migraine before sumatriptan is administered to treat any subsequent attacks.
- Sumatriptan is not indicated for the prevention of migraine attacks.
2. DOSAGE AND ADMINISTRATION
The maximum single recommended adult dose of Sumatriptan 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 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.
- 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) because these patients are at a higher risk of stroke [see Warnings and Precautions (5.4)] .
- History of hemiplegic or basilar migraine.
- 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 (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 [see Drug Interactions (7.1, 7.3)] .
- Concurrent administration of an MAO-A inhibitor or recent (within 2 weeks) use of an MAO-A inhibitor [see Drug Interactions (7.2) andClinical Pharmacology (12.3)] .
- Known hypersensitivity to sumatriptan [see Warnings and Precautions (5.9) and Adverse Reactions (6.2) ].
- Severe hepatic impairment [see Clinical Pharmacology (12.3)].
5. WARNINGS AND PRECAUTIONS
Myocardial Ischemia, Myocardial Infarction, and Prinzmetal’s Angina
The use of Sumatriptan 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 Sumatriptan 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 Injection. If there is evidence of CAD or coronary artery vasospasm, Sumatriptan Injection is contraindicated. For patients with multiple cardiovascular risk factors who have a negative cardiovascular evaluation, consider administering the first dose of Sumatriptan Injection in a medically supervised setting and performing an electrocardiogram (ECG) immediately following Sumatriptan Injection. For such patients, consider periodic cardiovascular evaluation in intermittent long-term users of Sumatriptan Injection.
Evaluate patients with signs or symptoms suggestive of angina following Sumatriptan Injection for the presence of CAD or Prinzmetal's angina before receiving additional doses of Sumatriptan Injection.
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 Injection if these disturbances occur. Sumatriptan Injection is contraindicated in patients with Wolff-Parkinson-White syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders
Chest, Throat, Neck, and/or Jaw Pain/Tightness/Pressure
As with other 5-HT1 agonists, 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 Sumatriptan Injection is contraindicated in patients shown to have CAD and those with Prinzmetal's variant angina.
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 Injection if a cerebrovascular event occurs.
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. Sumatriptan Injection is contraindicated in patients with a history of stroke or TIA.
Other Vasospasm Reactions
5-HT1 agonists, including Sumatriptan 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. Until further evaluation, Sumatriptan Injection is contraindicated in patients who experience symptoms or signs suggestive of non-coronary vasospasm reaction following the use of any 5-HT1 agonist.
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 may occur with triptans, including Sumatriptan 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 Injection if serotonin syndrome is suspected.
Increase in Blood Pressure
Significant elevation in blood pressure, including hypertensive crisis with acute impairment of organ systems, has been reported on rare occasions in patients treated with 5-HT1 agonists, including patients without a history of hypertension. Monitor blood pressure in patients treated with sumatriptan. Sumatriptan Injection is contraindicated in patients with uncontrolled hypertension.
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 Injection is contraindicated in patients with prior serious anaphylactic reaction.
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 Injection should be used with caution in patients with a history of epilepsy or conditions associated with a lowered seizure threshold.
6. ADVERSE REACTIONS
- 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)]
- Anaphylactic/anaphylactoid reactions [see Warnings and Precautions (5.9)]
- Seizures [see Warnings and Precautions (5.10)]
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 migraine subjects [Studies 2 and 3, see Clinical Studies (14.1)] following either a single 6 mg dose of Sumatriptan Injection or placebo. Only reactions that occurred at a frequency of 2% or more in groups treated with Sumatriptan Injection 6 mg and that occurred at a frequency greater than the placebo group are included in Table 1.
aThe sum of the percentages cited is greater than 100% because subjects may have experienced more than 1 type of adverse reaction. Only reactions that occurred at a frequency of 2% or more in groups treated with Sumatriptan Injection and occurred at a frequency greater than the placebo groups are included.
bIncludes injection site pain, stinging/burning, swelling, erythema, bruising, bleeding.
||Percent of Subjects Reporting
|Sumatriptan injection 6 mg Subcutaneous
(n = 547)
(n = 370)
|Feeling of heaviness
|Feeling of tightness
|Tight feeling in head
|Tightness in chest
|Pressure in chest
|Ear, nose, and throat
|Discomfort: nasal cavity/sinuses
|Injection site reactionb
The incidence of adverse reactions in controlled clinical trials was not affected by gender or age of the subjects. 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 Injection as a treatment for cluster headache [Studies 4 and 5, see Clinical Studies (14.2)], no new significant adverse reactions were detected that had not already been identified in trials of sumatriptan in subjects 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, 0% placebo), nausea and vomiting (4% sumatriptan, 0% placebo), and bronchospasm (1% sumatriptan, 0% placebo).
Other Adverse Reactions: In the paragraphs that follow, the frequencies of less commonly reported adverse reactions are presented. Reaction frequencies were calculated as the number of subjects reporting a reaction divided by the total number of subjects (N = 6,218) exposed to subcutaneous Sumatriptan Injection. All reported reactions are included except those already listed in the previous table. Reactions are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent are defined as those occurring in at least 1/100 subjects, infrequent are those occurring in 1/100 to 1/1,000 subjects, and rare are those occurring in fewer than 1/1,000 subjects.
Cardiovascular: Infrequent were hypertension, hypotension, bradycardia, tachycardia, palpitations, and syncope. Rare was arrhythmia.
Gastrointestinal: Frequent was abdominal discomfort.
Musculoskeletal: Frequent were muscle cramps.
Neurological: Frequent was anxiety. Infrequent were mental confusion, euphoria, agitation, tremor. Rare were myoclonia, sleep disturbance, and dystonia.
Respiratory: Infrequent was dyspnea.
Skin: Infrequent were erythema, pruritus, and skin rashes.
Miscellaneous: Infrequent was "serotonin agonist effect".
Adverse Events Observed With Other Formulations of Sumatriptan: The following adverse events occurred in clinical trials with sumatriptan tablets and sumatriptan nasal spray. Because the reports include events observed in open and uncontrolled trials, the role of sumatriptan in their causation cannot be reliably determined. All reported events are included except those already listed, those too general to be informative, and those not reasonably associated with the use of the drug.
Cardiovascular: Angina, cerebrovascular lesion, heart block, peripheral cyanosis, phlebitis, thrombosis.
Gastrointestinal: Abdominal distention and colitis.
Neurological: Convulsions, hallucinations, syncope, suicide, and twitching.
Miscellaneous: Edema, hypersensitivity, swelling of extremities, and swelling of face.
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.
Blood: Hemolytic anemia, pancytopenia, thrombocytopenia.
Ear, Nose, and Throat: Deafness.
Eye: Ischemic optic neuropathy, retinal artery occlusion, retinal vein thrombosis.
Neurological: Central nervous system vasculitis, cerebrovascular accident, serotonin syndrome, subarachnoid hemorrhage.
Non-Site Specific: Angioedema, cyanosis, temporal arteritis.
Skin: Exacerbation of sunburn, hypersensitivity reactions (allergic vasculitis, erythema, pruritus, rash, shortness of breath, urticaria), photosensitivity. Following subcutaneous administration of sumatriptan, pain, redness, stinging, induration, swelling, contusion, subcutaneous bleeding, and, on rare occasions, lipoatrophy (depression in the skin) or lipohypertrophy (enlargement or thickening of tissue) have been reported.
Urogenital: Acute renal failure.
To report SUSPECTED ADVERSE REACTIONS, contact Agila Specialties Private Limited at www.stridesarco.com or 1-877-244-9825 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
7. DRUG INTERACTIONS
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 Injection 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 Sumatriptan Injection in patients receiving MAO-A inhibitors is contraindicated [see Clinical Pharmacology (12.3)].
Other 5-HT1 Agonists
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, TCAs, and MAO inhibitors [see Warnings and Precautions (5.7)].
8. USE IN SPECIFIC POPULATIONS
Pregnancy Category C: There are no adequate and well-controlled trials of Sumatriptan Injection in pregnant women. Sumatriptan Injection 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. These doses were less than the maximum recommended human dose (MRHD) of 12 mg/day on a mg/m2 basis. 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 at doses that are approximately 10 times the MRHD on a mg/m2 basis, 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.
It is not known whether sumatriptan is excreted in human breast milk following subcutaneous administration. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from sumatriptan, 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.
Safety and effectiveness of Sumatriptan Injection in pediatric patients under 18 years of age have not been established; therefore, Sumatriptan Injection is not recommended for use in patients under 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 subjects 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 subjects appeared to be both dose- and age-dependent, with younger subjects 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. 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 sumatriptan in patients under 18 years of age is not recommended.
Clinical trials of Sumatriptan Injection 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 receiving Sumatriptan Injection [see Warnings and Precautions (5.1)].
No gross overdoses in clinical practice have been reported. Coronary vasospasm was observed after intravenous administration of Sumatriptan 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)], and therefore monitoring of patients after overdose with Sumatriptan 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.
Sumatriptan Injection, USP contains sumatriptan (as the succinate), a selective 5-HT1B/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:
Sumatriptan Injection, USP is a clear, colorless to pale yellow, sterile, nonpyrogenic solution for subcutaneous injection. Each 0.5 mL of Sumatriptan Injection, USP 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 the solution is approximately 4.2 to 5.3. The osmolality of the injection is 270 to 330 mOsmol.
12. CLINICAL PHARMACOLOGY
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 by binding to 5-HT1B/1D receptors located on intracranial blood vessels and sensory nerves of the trigeminal system.
Current theories proposed to explain the etiology of migraine headache suggest that symptoms are due to local cranial vasodilatation and/or to the release of sensory neuropeptides (including substance P and calcitonin gene-related peptide) through nerve endings in the trigeminal system. The therapeutic activity of sumatriptan for the treatment of migraine and cluster headaches is thought to be due to the agonist effects at the 5-HT1B/1D receptors on intracranial blood vessels (including the arteriovenous anastomoses) and sensory nerves of the trigeminal system, which result in cranial vessel constriction and inhibition of pro-inflammatory neuropeptide release.
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 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.
After a single 6 mg subcutaneous manual injection into the deltoid area of the arm in 18 healthy males (age: 24 ± 6 years, weight: 70 kg), the maximum serum concentration (Cmax) of sumatriptan was (mean ± standard deviation) 74 ± 15 ng/mL and the time to peak concentration (Tmax) was 12 minutes after injection (range: 5 to 20 minutes). In this trial, the same dose injected subcutaneously in the thigh gave a Cmax of 61 ± 15 ng/mL by manual injection versus 52 ± 15 ng/mL by autoinjector techniques. The Tmax or amount absorbed was not significantly altered by either the site or technique of injection.
Distribution: Protein binding, determined by equilibrium dialysis over the concentration range of 10 to 1,000 ng/mL, is low, approximately 14% to 21%. The effect of sumatriptan on the protein binding of other drugs has not been evaluated.
Following a 6 mg subcutaneous injection into the deltoid area of the arm in 9 males (mean age: 33 years, mean weight: 77 kg) the volume of distribution central compartment of sumatriptan was 50 ± 8 liters and the distribution half-life was 15 ± 2 minutes.
Metabolism: In vitro studies with human microsomes suggest that sumatriptan is metabolized by MAO, predominantly the A isoenzyme. Most of a radiolabeled dose of sumatriptan excreted in the urine is the major metabolite indole acetic acid (IAA) or the IAA glucuronide, both of which are inactive.
Elimination: After a single 6 mg subcutaneous dose, 22% ± 4% was excreted in the urine as unchanged sumatriptan and 38% ± 7% as the IAA metabolite.
Following a 6 mg subcutaneous injection into the deltoid area of the arm, the systemic clearance of sumatriptan was 1,194 ± 149 mL/min and the terminal half-life was 115 ± 19 minutes.
Special 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).
Renal Impairment: The effect of renal impairment on the pharmacokinetics of sumatriptan has not been examined.
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 Injection in this population is contraindicated [see Contraindications (4)].
Race: The systemic clearance and Cmax of 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 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. 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. Average exposures achieved in mice receiving the highest dose were approximately 110 times the exposure attained in humans after the maximum recommended single dose of 6 mg. The highest dose to rats was approximately 260 times the maximum single dose of 6 mg on a mg/m2 basis. 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 2 gene mutation assays (the Ames test and the in vitro mammalian Chinese hamster V79/HGPRT assay). It was not clastogenic in 2 cytogenetics assays (the in vitro human lymphocyte assay and the in vivo rat micronucleus assay).
Impairment of Fertility: A fertility study (Segment I) by the subcutaneous route, during which male and female rats were dosed daily with sumatriptan prior to and throughout the mating period, has shown no evidence of impaired fertility at doses equivalent to approximately 100 times the maximum recommended single human dose of 6 mg on a mg/m2 basis. 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. The no-effect dose for this finding was approximately 8 times the maximum recommended single human dose of 6 mg on a mg/m2 basis. It is not clear whether the problem is associated with the treatment of males or females or both.
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 dosage 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 exposure at the lowest dose tested was approximately 5 times the human exposure after a 100 mg oral dose or 3 times the human exposure after a 6 mg subcutaneous dose.
Melanin Binding: In rats with a single subcutaneous dose (0.5 mg/kg) of radiolabeled sumatriptan, the elimination half-life of radioactivity from the eye was 15 days, suggesting that sumatriptan and its metabolites bind to the melanin of the eye. The clinical significance of this binding is unknown.
14. CLINICAL STUDIES
In controlled clinical trials enrolling more than 1,000 subjects 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 subjects 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.
a Relief is defined as the reduction of moderate or severe pain to no or mild pain after dosing without use of rescue medication.
|Dose of Sumatriptan Injection
Percent Subjects With Relief a
|Adverse Events Incidence (%)
|at 10 Minutes
||at 30 Minutes
||at 1 Hour
||at 2 Hours
In 2 randomized, placebo-controlled clinical trials of Sumatriptan Injection 6 mg in 1,104 subjects 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 subjects within 1 hour of a single 6 mg subcutaneous dose of Sumatriptan Injection. Approximately 82% and 65% of subjects 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.
aP<0.05 versus placebo
b A successful outcome in terms of clinical disability was defined prospectively as ability to work mildly impaired or ability to work and function normally.
c Includes subjects that may have received an additional placebo injection 1 hour after the initial injection.
dIncludes subjects that may have received an additional 6 mg of Sumatriptan Injection 1 hour after the initial injection.
|Placebo (n = 190)
||Sumatriptan 6 mg (n = 384)
||Placebo (n = 180)
||Sumatriptan 6 mg (n = 350)
|Subjects with pain relief (grade 0/1)
|Subjects with no pain
|Subjects without nausea
|Subjects without photophobia
|Subjects with little or no clinical disabilityb
||Sumatriptan 6 mgd
||Sumatriptan 6 mgd
|Subjects with pain relief (grade 0/1)
|Subjects with no pain
|Subjects without nausea
|Subjects without photophobia
|Subjects with little or no clinical disabilityb
The efficacy of Sumatriptan Injection 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).
The efficacy of Sumatriptan 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). Subjects 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 subjects receiving 6 mg of Sumatriptan Injection compared with those who received placebo (see Table 4).
(n = Number of headaches treated.)
(n = 39)
|Sumatriptan 6 mg (n = 39)
||Placebo (n = 88)
||Sumatriptan 6 mg (n = 92)
|Subjects with pain relief (no/mild)
|5 Minutes post-injection
|10 Minutes post-injection
|15 Minutes post-injection
Figure 1. Time to Relief of Cluster Headache from Time of Injectiona
The plot was constructed with data from subjects 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 Injection).
Other data suggest that treatment with Sumatriptan 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 Injection, USP
||6 mg per 0.5 mL Single-Dose Vial
||5 vials per carton
Store between 2°C and 30°C (36°F and 86°F). Protect from light.
Protect from light. Retain in carton until time of use.
17. PATIENT COUNSELING INFORMATION
Risk of Myocardial Ischemia and/or Infarction, Prinzmetal’s Angina, Other Vasospasm-Related Events, Arrhythmias, and Cerebrovascular Events
Inform patients that Sumatriptan 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. Patients should be apprised of the importance of this follow-up [see Warnings and Precautions (5.1, 5.2, 5.4, 5.5, 5.8)].
Inform patients that anaphylactic/anaphylactoid 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 Warnings and Precautions (5.9)].
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)].
Inform patients that Sumatriptan Injection should not be used during pregnancy unless the potential benefit justifies the potential risk to the fetus [see Use in Specific Populations (8.1)].
Advice patients to notify their healthcare provider if they are breastfeeding or plan to breastfeed [see Use in Specific Populations (8.3)].
Ability To Perform Complex Tasks
Since migraines or treatment with Sumatriptan Injection may cause somnolence and dizziness, instruct patients to evaluate their ability to perform complex tasks during migraine attacks and after administration of Sumatriptan Injection.
Patients should be cautioned about the risk of serotonin syndrome with the use of Sumatriptan Injection or other triptans, particularly during combined use with SSRIs, SNRIs, TCAs, and MAO inhibitors [see Warnings and Precautions (5.7) and Drug Interactions (7.4)].
How to Use Sumatriptan Injection
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.
Agila Specialties Private Limited
Made in India
Sumatriptan Injection, USP
Read this Patient Information before you start taking Sumatriptan Injection and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or treatment.
What is the most important information I should know about sumatriptan?
Sumatriptan can cause serious side effects, including:
Heart attack and other heart problems. Heart problems may lead to death.
Stop taking sumatriptan and get emergency medical help right away if you have any of the following symptoms of a heart attack:
- discomfort in the center of your chest that lasts for more than a few minutes, or that goes away and comes back
- severe tightness, pain, pressure, or heaviness in your chest, throat, neck, or jaw
- pain or discomfort in your arms, back, neck, jaw, or stomach
- shortness of breath with or without chest discomfort
- breaking out in a cold sweat
- nausea or vomiting
- feeling lightheaded
- have high blood pressure
- have high cholesterol levels
- are overweight
- have diabetes
- have a family history of heart disease
What is sumatriptan?
Sumatriptan is not used to treat other types of headaches such as hemiplegic (that make you unable to move on one side of your body) or basilar (rare form of migraine with aura) migraines.
Sumatriptan is not used to prevent or decrease the number of migraine or cluster headaches you have.
It is not known if sumatriptan is safe and effective in children under 18 years of age.
Who should not take sumatriptan?
- heart problems or a history of heart problems
- narrowing of blood vessels to your legs, arms, stomach, or kidney (peripheral vascular disease)
- uncontrolled high blood pressure
- hemiplegic migraines or basilar migraines. If you are not sure if you have these types of migraines, ask your healthcare provider.
- had a stroke, transient ischemic attacks (TIAs), or problems with your blood circulation
- taken any of the following medicines in the last 24 hours:
- almotriptan (AXERT®)
- eletriptan (RELPAX®)
- frovatriptan (FROVA®)
- naratriptan (AMERGE®)
- rizatriptan (MAXALT®, MAXALT-MLT®)
- sumatriptan and naproxen (TREXIMET®)
- ergotamines (CAFERGOT®, ERGOMAR®, MIGERGOT®)
- dihydroergotamine (D.H.E. 45®, MIGRANAL®)
- an allergy to sumatriptan or any of the ingredients in Sumatriptan Injection. See the end of this leaflet for a complete list of ingredients in Sumatriptan Injection.
What should I tell my healthcare provider before taking sumatriptan?
- have high blood pressure
- have high cholesterol
- have diabetes
- are overweight
- have heart problems or family history of heart problems or stroke
- have liver problems
- have had epilepsy or seizures
- are not using effective birth control
- become pregnant while taking sumatriptan
- are breastfeeding or plan to breastfeed. Sumatriptan passes into your breast milk and may harm your baby. Talk with your healthcare provider about the best way to feed your baby if you take sumatriptan.
Tell your healthcare provider about all the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal supplements.
Especially tell your healthcare provider if you take antidepressant medicines called:
- selective serotonin reuptake inhibitors (SSRIs)
- serotonin norepinephrine reuptake inhibitors (SNRIs)
- tricyclic antidepressants (TCAs)
- monoamine oxidase inhibitors (MAOIs)
Know the medicines you take. Keep a list of them to show your healthcare provider or pharmacist when you get a new medicine.
How should I take sumatriptan?
- Certain people should take their first dose of sumatriptan in their healthcare provider's office or in another medical setting. Ask your healthcare provider if you should take your first dose in a medical setting.
- Use sumatriptan exactly as your healthcare provider tells you to use it.
- Your healthcare provider may change your dose. Do not change your dose without first talking with your healthcare provider.
- For adults, the usual dose is a single injection given just below the skin.
- You should give an injection as soon as the symptoms of your headache start, but it may be given at any time during a migraine attack.
- If you did not get any relief after the first injection, do not give a second injection without first talking with your healthcare provider.
- You can take a second injection 1 hour after the first injection, but not sooner, if your headache came back after your first injection.
- Do not take more than 12 mg in a 24-hour period.
- If you use too much sumatriptan, call your healthcare provider or go to the nearest hospital emergency room right away.
- You should write down when you have headaches and when you take sumatriptan so you can talk with your healthcare provider about how sumatriptan is working for you.
What should I avoid while taking sumatriptan?
What are the possible side effects of sumatriptan?
These serious side effects include:
- changes in color or sensation in your fingers and toes (Raynaud's syndrome)
- stomach and intestinal problems (gastrointestinal and colonic ischemic events). Symptoms of gastrointestinal and colonic ischemic events include:
- sudden or severe stomach pain
- stomach pain after meals
- weight loss
- nausea or vomiting
- constipation or diarrhea
- bloody diarrhea
- problems with blood circulation to your legs and feet (peripheral vascular ischemia). Symptoms of peripheral vascular ischemia include:
- cramping and pain in your legs or hips
- feeling of heaviness or tightness in your leg muscles
- burning or aching pain in your feet or toes while resting
- numbness, tingling, or weakness in your legs
- cold feeling or color changes in 1 or both legs or feet
- medication overuse headaches. Some people who use too many Sumatriptan Injections may have worse headaches (medication overuse headache). If your headaches get worse, your healthcare provider may decide to stop your treatment with sumatriptan.
- serotonin syndrome. Serotonin syndrome is a rare but serious problem that can happen in people using sumatriptan, especially if sumatriptan is used with antidepressant medicines called SSRIs or SNRIs.
- mental changes such as seeing things that are not there (hallucinations), agitation, or coma
- fast heartbeat
- changes in blood pressure
- high body temperature
- tight muscles
- trouble walking
- seizures. Seizures have happened in people taking sumatriptan who have never had seizures before. Talk with your healthcare provider about your chance of having seizures while you take sumatriptan.
- pain or redness at your injection site
- tingling or numbness in your fingers or toes
- warm, hot, burning feeling to your face (flushing)
- discomfort or stiffness in your neck
- feeling weak, drowsy, or tired
These are not all the possible side effects of Sumatriptan Injection. For more information, ask your healthcare provider or pharmacist.
Call your doctor for medical advice about side effects. You may report side effects to Agila Specialties Private Limited at www.stridesarco.com or FDA at 1-800-FDA-1088.
How should I store Sumatriptan Injection, USP?
- Store Sumatriptan Injection between 36°F and 86°F (2°C and 30°C).
- Store your medicine away from light.
- Keep your medicine in the packaging provided with it.
General information about the safe and effective use of sumatriptan
Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflets. Do not use sumatriptan for a condition for which it was not prescribed. Do not give sumatriptan to other people, even if they have the same symptoms you have. It may harm them.
This Patient Information leaflet summarizes the most important information about sumatriptan. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about sumatriptan that is written for healthcare professionals.
What are the ingredients in Sumatriptan Injection,USP ?
Inactive ingredients: sodium chloride, water for injection
This Patient Information has been approved by the U.S. Food and Drug Administration.
AXERT® is the trade mark of Ortho-McNeil-Janssen Pharmaceuticals, Inc.
RELPAX® is the trade mark of Pfizer Pharmaceuticals LLC
FROVA® is the trade mark of - Vernalis Development Limited
AMERGE® is the trade mark of GlaxoSmithKline LLC
MAXALT® & MAXALT-MLT® is the trade mark of Merck & Co., Inc.
TREXIMET® is the trade mark of GlaxoSmithKline LLC
CAFERGOT® is the trade mark of Sandoz Inc
ERGOMAR® is the trade mark of Rosedale Therapeutic
MIGERGOT® is the trade mark of G&W Laboratories, Inc.
D.H.E. 45® and MIGRANAL® are the trade mark of Valeant Pharmaceuticals North America
Agila Specialties Private Limited
Made in India.
|Labeler - AGILA SPECIALTIES PRIVATE LIMITED (650548014)|
|Registrant - AGILA SPECIALTIES PRIVATE LIMITED (650548014)|
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