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| Product NDC Code | 0245-0812 | ||||
|---|---|---|---|---|---|
| Drug Name | Tosymra |
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| Type | Brand | ||||
| Pharm Class | Serotonin 1b Receptor Agonists [MoA], Serotonin 1d Receptor Agonists [MoA], Serotonin-1b and Serotonin-1d Receptor Agonist [EPC] |
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| Active Ingredients |
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| Route | NASAL | ||||
| Dosage Form | SPRAY | ||||
| RxCUI drug identifier | 401978, 2178073 |
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| Application Number | NDA210884 | ||||
| Labeler Name | Upsher-Smith Laboratories, LLC | ||||
| Packages |
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Overdosage of TOSYMRA
Information about signs, symptoms, and laboratory findings of acute ovedosage and the general principles of overdose treatment.10 OVERDOSAGE 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 TOSYMRA 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.
Adverse reactions
Information about undesirable effects, reasonably associated with use of the drug, that may occur as part of the pharmacological action of the drug or may be unpredictable in its occurrence. Adverse reactions include those that occur with the drug, and if applicable, with drugs in the same pharmacologically active and chemically related class. There is considerable variation in the listing of adverse reactions. They may be categorized by organ system, by severity of reaction, by frequency, by toxicological mechanism, or by a combination of these.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) ] Local Irritation [see Warnings and Precautions (5.11) ] Most common adverse reactions (≥5% and > placebo) with sumatriptan injection were tingling, dizziness/vertigo, warm/hot sensation, burning sensation, feeling of heaviness, pressure sensation, flushing, feeling of tightness, and numbness ( 6.1 ) Additional common adverse reactions with TOSYMRA include application site reactions, dysgeusia, and throat irritation. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Upsher-Smith Laboratories, LLC at 1-855-899-9180 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. Adverse Reactions in Placebo-Controlled Trials with Sumatriptan Injection Table 1 lists adverse reactions that occurred in 2 placebo-controlled clinical trials in patients with migraine (Studies 2 and 3) 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. Table 1: Adverse Reactions in Pooled Placebo-Controlled Trials in Patients with Migraine (Studies 2 and 3) Adverse Reaction Sumatriptan Injection 6 mg Subcutaneous (n = 547) % Placebo (n = 370) % Atypical sensations 42 9 Tingling 14 3 Warm/hot sensation 11 4 Burning sensation 7 <1 Feeling of heaviness 7 1 Pressure sensation 7 2 Feeling of tightness 5 <1 Numbness 5 2 Feeling strange 2 <1 Tight feeling in head 2 <1 Cardiovascular Flushing 7 2 Chest discomfort 5 1 Tightness in chest 3 <1 Pressure in chest 2 <1 Ear, nose, and throat Throat discomfort 3 <1 Discomfort: nasal cavity/sinuses 2 <1 Miscellaneous Jaw discomfort 2 0 Musculoskeletal Weakness 5 <1 Neck pain/stiffness 5 <1 Myalgia 2 <1 Neurological Dizziness/vertigo 12 4 Drowsiness/sedation 3 2 Headache 2 <1 Skin Sweating 2 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. Adverse Reactions in Studies with TOSYMRA In an open-label study that was designed to evaluate the local tolerability of TOSYMRA, repeated use of TOSYMRA was allowed over the course of 6 months. In this study, local irritative symptoms were reported in approximately 46% of patients treated with TOSYMRA, the most common of which were application site reactions (e.g., burning sensations in the nose), dysgeusia, and throat irritation [see Warnings and Precautions (5.11) ] . 6.2 Post-marketing Experience The following adverse reactions have been identified during post-approval use of sumatriptan tablets, sumatriptan nasal spray, and sumatriptan injection. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Cardiovascular : Hypotension, palpitations. Neurological : Dystonia, tremor.
| Adverse Reaction | Sumatriptan Injection 6 mg Subcutaneous (n = 547) % | Placebo (n = 370) % |
|---|---|---|
| Atypical sensations | 42 | 9 |
| Tingling | 14 | 3 |
| Warm/hot sensation | 11 | 4 |
| Burning sensation | 7 | <1 |
| Feeling of heaviness | 7 | 1 |
| Pressure sensation | 7 | 2 |
| Feeling of tightness | 5 | <1 |
| Numbness | 5 | 2 |
| Feeling strange | 2 | <1 |
| Tight feeling in head | 2 | <1 |
| Cardiovascular | ||
| Flushing | 7 | 2 |
| Chest discomfort | 5 | 1 |
| Tightness in chest | 3 | <1 |
| Pressure in chest | 2 | <1 |
| Ear, nose, and throat | ||
| Throat discomfort | 3 | <1 |
| Discomfort: nasal cavity/sinuses | 2 | <1 |
| Miscellaneous | ||
| Jaw discomfort | 2 | 0 |
| Musculoskeletal | ||
| Weakness | 5 | <1 |
| Neck pain/stiffness | 5 | <1 |
| Myalgia | 2 | <1 |
| Neurological | ||
| Dizziness/vertigo | 12 | 4 |
| Drowsiness/sedation | 3 | 2 |
| Headache | 2 | <1 |
| Skin | ||
| Sweating | 2 | 1 |
TOSYMRA Drug Interactions
Information about and practical guidance on preventing clinically significant drug/drug and drug/food interactions that may occur in people taking the drug.7 DRUG INTERACTIONS 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 TOSYMRA 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 TOSYMRA 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 TOSYMRA 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 co-administration of triptans and SSRIs, SNRIs, TCAs, and MAO inhibitors [see Warnings and Precautions (5.7) ] .
Clinical pharmacology
Information about the clinical pharmacology and actions of the drug in humans.12 CLINICAL PHARMACOLOGY 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 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. 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 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. 12.3 Pharmacokinetics Following nasal administration of 10 mg TOSYMRA in 73 healthy subjects, the relative bioavailability of TOSYMRA was approximately 87% [90% confidence interval (CI) 82 to 94] of that obtained following 4 mg subcutaneous injection of sumatriptan. The relative bioavailability of TOSYMRA was 58% [90% CI 55 to 62] following 6 mg subcutaneous injection of sumatriptan. Absorption Peak plasma concentration of sumatriptan was observed in a median time of 10 minutes (range 5 to 23 minutes). After single nasal administration of the 10 mg dose, the mean (CV%) C max and AUC were 51.8 ng/mL (58%) and 60.70 ng∙hr/mL (42%), respectively. Distribution Sumatriptan 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. Elimination The elimination half-life of sumatriptan following administration of TOSYMRA is 2.44 ± 1.00 hours. 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. Excretion 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 hepatic disease on the pharmacokinetics of TOSYMRA has not been evaluated. 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 TOSYMRA 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. TOSYMRA has not been evaluated for race differences. 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.
Mechanism of action
Information about the established mechanism(s) of the drugÕs action in humans at various levels (for example receptor, membrane, tissue, organ, whole body). If the mechanism of action is not known, this field contains a statement about the lack of information.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 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.
Pharmacodynamics
Information about any biochemical or physiologic pharmacologic effects of the drug or active metabolites related to the drugÕs clinical effect in preventing, diagnosing, mitigating, curing, or treating disease, or those related to adverse effects or toxicity.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 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.
Pharmacokinetics
Information about the clinically significant pharmacokinetics of a drug or active metabolites, for instance pertinent absorption, distribution, metabolism, and excretion parameters.12.3 Pharmacokinetics Following nasal administration of 10 mg TOSYMRA in 73 healthy subjects, the relative bioavailability of TOSYMRA was approximately 87% [90% confidence interval (CI) 82 to 94] of that obtained following 4 mg subcutaneous injection of sumatriptan. The relative bioavailability of TOSYMRA was 58% [90% CI 55 to 62] following 6 mg subcutaneous injection of sumatriptan. Absorption Peak plasma concentration of sumatriptan was observed in a median time of 10 minutes (range 5 to 23 minutes). After single nasal administration of the 10 mg dose, the mean (CV%) C max and AUC were 51.8 ng/mL (58%) and 60.70 ng∙hr/mL (42%), respectively. Distribution Sumatriptan 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. Elimination The elimination half-life of sumatriptan following administration of TOSYMRA is 2.44 ± 1.00 hours. 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. Excretion 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 hepatic disease on the pharmacokinetics of TOSYMRA has not been evaluated. 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 TOSYMRA 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. TOSYMRA has not been evaluated for race differences. 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.
Contraindications
Information about situations in which the drug product is contraindicated or should not be used because the risk of use clearly outweighs any possible benefit, including the type and nature of reactions that have been reported.4 CONTRAINDICATIONS TOSYMRA 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-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) and 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) ] . History of coronary artery disease or coronary 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 )
Description
General information about the drug product, including the proprietary and established name of the drug, the type of dosage form and route of administration to which the label applies, qualitative and quantitative ingredient information, the pharmacologic or therapeutic class of the drug, and the chemical name and structural formula of the drug.11 DESCRIPTION TOSYMRA contains sumatriptan, a selective 5-HT 1B/1D receptor agonist. Sumatriptan is chemically designated as 1-[3-[2-(dimethylamino)ethyl]-1H-indol-5-yl]- N -methylmethanesulfonamide, and it has the following structure: The empirical formula is C 14 H 21 N 3 O 2 S, representing a molecular weight of 295.40. Sumatriptan is a white to pale yellow powder that is very slightly soluble in water. TOSYMRA nasal spray is a clear, pale yellow to yellow colored liquid. Each 100 uL of TOSYMRA contains 10 mg of sumatriptan in single-dose aqueous buffered solution containing citric acid monohydrate, n-Dodecyl beta-D-maltoside, potassium phosphate monobasic, sodium chloride, and sodium phosphate dibasic anhydrous in water for injection. The pH range of solution is approximately 5.0 to 6.0 and the osmolality is between 270 to 330 mOsmol. Chemical Structure
Dosage and administration
Information about the drug product’s dosage and administration recommendations, including starting dose, dose range, titration regimens, and any other clinically sigificant information that affects dosing recommendations.2 DOSAGE AND ADMINISTRATION The recommended dose of TOSYMRA is 10 mg given as a single spray in one nostril. The maximum cumulative dose that may be given in a 24-hour period is 30 mg, with doses of TOSYMRA separated by at least 1 hour. TOSYMRA may also be given at least 1 hour following a dose of another sumatriptan product. Single dose of 10 mg of nasal spray ( 2 ) Maximum dose in a 24-hour period: 30 mg; separate doses by at least one hour ( 2 )
Dosage forms and strengths
Information about all available dosage forms and strengths for the drug product to which the labeling applies. This field may contain descriptions of product appearance.3 DOSAGE FORMS AND STRENGTHS Single-dose nasal spray device delivering 10 mg of sumatriptan. Nasal Spray, 10 mg ( 3 )
Indications and usage
A statement of each of the drug products indications for use, such as for the treatment, prevention, mitigation, cure, or diagnosis of a disease or condition, or of a manifestation of a recognized disease or condition, or for the relief of symptoms associated with a recognized disease or condition. This field may also describe any relevant limitations of use.1 INDICATIONS AND USAGE TOSYMRA is indicated for the acute treatment of migraine with or without aura in adults. TOSYMRA is a serotonin (5-HT 1B/1D ) receptor agonist (triptan) indicated for the acute treatment of migraine with or without aura in adults ( 1 ) Limitations of Use : Use only if a clear diagnosis of migraine has been established ( 1 ) Not indicated for the preventive treatment of migraine ( 1 ) Not indicated for the treatment of cluster headache ( 1 ) Limitations of Use : Use only if a clear diagnosis of migraine has been established. If a patient has no response to the first migraine attack treated with TOSYMRA, reconsider the diagnosis before TOSYMRA is administered to treat any subsequent attacks. TOSYMRA is not indicated for the preventive treatment of migraine. TOSYMRA is not indicated for the treatment of cluster headache.
Spl product data elements
Usually a list of ingredients in a drug product.TOSYMRA sumatriptan Sumatriptan Sumatriptan CITRIC ACID MONOHYDRATE N-DODECYL .BETA.-D-MALTOSIDE MONOBASIC POTASSIUM PHOSPHATE sodium chloride SODIUM PHOSPHATE, DIBASIC, ANHYDROUS water
Animal pharmacology and or toxicology
Information from studies of the drug in animals, if the data were not relevant to nor included in other parts of the labeling. Most labels do not contain this field.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.
Carcinogenesis and mutagenesis and impairment of fertility
Information about carcinogenic, mutagenic, or fertility impairment potential revealed by studies in animals. Information from human data about such potential is part of the warnings field.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 highest dose in rat was reduced from 360 mg/kg/day during Week 21). 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 (0, 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.
Nonclinical toxicology
Information about toxicology in non-human subjects.13 NONCLINICAL TOXICOLOGY 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 highest dose in rat was reduced from 360 mg/kg/day during Week 21). 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 (0, 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.
Package label principal display panel
The content of the principal display panel of the product package, usually including the product’s name, dosage forms, and other key information about the drug product.PRINCIPAL DISPLAY PANEL - 6 Bottle Blister Pack Carton UPSHER-SMITH NDC 0245-0812-61 Rx only tosymra ® (sumatriptan nasal spray) 10 mg This box contains six (6) unit-dose nasal spray devices. Each unit-dose contains 10 mg of sumatriptan in 0.1 mL. For Intranasal Use Only 1 spray per unit. Do not test before use. PRINCIPAL DISPLAY PANEL - 6 Bottle Blister Pack Carton
Spl unclassified section
Information not classified as belonging to one of the other fields. Approximately 40% of labeling with effective_time between June 2009 and August 2014 have information in this field.Manufactured for UPSHER-SMITH LABORATORIES, LLC Maple Grove, MN 55369 TOSYMRA is a registered trademark of Upsher-Smith Laboratories, LLC. This product may be covered by one or more U.S. patent(s). See www.uslpatents.com. Revised: 2/2021
TOSYMRA: Information for patients
Information necessary for patients to use the drug safely and effectively, such as precautions concerning driving or the concomitant use of other substances that may have harmful additive effects.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 TOSYMRA may cause serious cardiovascular side effects such as myocardial infarction or stroke. Although serious cardiovascular events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, irregular heartbeat, significant rise in blood pressure, weakness, and slurring of speech and should ask for medical advice when observing any indicative sign or symptoms are observed. Apprise patients of the importance of this follow-up [see Warnings and Precautions (5.1 , 5.2 , 5.4 , 5.5 , 5.8) ] . Hypersensitivity Reactions Inform patients that anaphylactic reactions have occurred in patients receiving sumatriptan. Such reactions can be life threatening or fatal. In general, anaphylactic reactions to drugs are more likely to occur in individuals with a history of sensitivity to multiple allergens [see Contraindications (4) and Warnings and Precautions (5.9) ] . Concomitant Use with Other Triptans or Ergot Medications Inform patients that use of TOSYMRA within 24 hours of another triptan or an ergot-type medication (including dihydroergotamine or methylsergide) is contraindicated [see Contraindications (4) , Drug Interactions (7.1 , 7.3) ] . Serotonin Syndrome Caution patients about the risk of serotonin syndrome with the use of TOSYMRA 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 TOSYMRA may cause somnolence and dizziness; instruct patients to evaluate their ability to perform complex tasks during migraine attacks and after administration of TOSYMRA. Local Irritation Inform patients that they may experience local irritation of their nose, mouth, and throat; and changes in taste [see Warnings and Precautions (5.11) ] . How to Use TOSYMRA Provide patients instruction on the proper use of TOSYMRA. Caution patients to avoid spraying the contents of the device in their eyes.
Instructions for use
Information about safe handling and use of the drug product.This Instructions for Use has been approved by the U.S. Food and Drug Administration. Revised: 2/202 Instructions for Use TOSYMRA ® (toe-SIM-ruh) (sumatriptan) Nasal Spray About TOSYMRA Important Information Read this Instructions for Use before you start using TOSYMRA and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment. If you have any questions about TOSYMRA, ask your healthcare provider or pharmacist. Only 1 device is needed to deliver a full dose (See Figure A ). The device gives a single spray that should be delivered into 1 nostril. Never use more than 1 device or dose into more than 1 nostril. Keep TOSYMRA and all medicines out of reach of children. Do not remove the device from its packaging until ready to use. Do not test the spray or press the plunger before giving a dose into the nostril. Do not use after the expiration date has passed. Storage Information The device should be stored at room temperature between 68° to 77°F (20° to 25°C). Do not store in the refrigerator or freezer. Always keep the device in the sealed blister package until time of use. Instructions for Use Step 1 – Gently Blow Your Nose While sitting upright, gently blow your nose to clear your nostrils (See Figure B ) . Step 2 – Remove 1 Device from Carton Remove only 1 device from the carton (See Figure C ) . Do not use more than 1 device to get your dose. Step 3 – Check the Expiration Date on Back of Blister Package Check the expiration date on the back of the blister package (See Figure D ) . Do not use if the expiration date has passed. Throw away the expired device in the household trash if the expiration date has passed. Step 4 – Remove Device from Blister Package Peel off the paper backing completely from the blister package. Flip the blister package onto your hand to remove the device from its packaging (See Figure E ) . Step 5 – Check the Expiration Date on the Device Check the expiration date on the device (See Figure F ) . Do not use the device if the expiration date has passed. Throw away the expired device in the household trash if the expiration date has passed. Step 6 – Close 1 Nostril Gently press 1 nostril with your finger to keep it closed (See Figure G ) . Step 7 – Place Spray Nozzle in Open Nostril Hold the device upright between your thumb and first 2 fingers (See Figure H ) . Insert half of the spray nozzle into the open nostril and angle outward (See Figure I ) . Step 8 – Tilt Head Back Slightly While keeping the device in your nose, tilt your head back slightly (See Figure J ) . This will allow the medicine to go into your nasal passage without dripping out. Step 9 – Deliver the Dose As you slowly breathe through your nose, firmly press the plunger all the way up to release the dose (See Figure K ) . Note: The plunger is stiff so make sure to press firmly. Step 10 – Remove Device and Breathe Gently for 10 to 20 Seconds Remove the device from your nostril. While keeping your head upright, gently breathe in through your nose and breathe out through your mouth. Repeat this for 10 to 20 seconds (See Figure L ) . It is normal for you to feel liquid in your nose or at the back of your throat. Do not look down because the medicine may drip from your nose. Do not breathe in deeply. Step 11 – Dispose of the Used Device Throw away the used device and its packaging into your household trash (See Figure M ) . You have received your full dose, if you have: ✓ Used 1 device ✓ Given 1 spray into 1 nostril Manufactured for UPSHER-SMITH LABORATORIES, LLC Maple Grove, MN 55369 TOSYMRA is a registered trademark of Upsher-Smith Laboratories, LLC. This product may be covered by one or more U.S. patent(s). See www.uslpatents.com. Figure A Figure B Figure C Figure D Figure E Figure F Figure G Figure H Figure I Figure J Figure K Figure L Figure M
| This Instructions for Use has been approved by the U.S. Food and Drug Administration. | Revised: 2/202 | ||
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| While sitting upright, gently blow your nose to clear your nostrils | |||
| Remove only 1 device from the carton | |||
| Check the expiration date on the back of the blister package | |||
| Peel off the paper backing completely from the blister package. Flip the blister package onto your hand to remove the device from its packaging | |||
| Check the expiration date on the device | |||
| Gently press 1 nostril with your finger to keep it closed | |||
| Hold the device upright between your thumb and first 2 fingers | |||
| While keeping the device in your nose, tilt your head back slightly | |||
| As you slowly breathe through your nose, firmly press the plunger all the way up to release the dose | |||
| Remove the device from your nostril. While keeping your head upright, gently breathe in through your nose and breathe out through your mouth. Repeat this for 10 to 20 seconds | |||
Throw away the used device and its packaging into your household trash
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Spl patient package insert
Information necessary for patients to use the drug safely and effectively.This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: 2/2021 Patient Information TOSYMRA ® (toe-SIM-ruh) (sumatriptan) Nasal Spray What is the most important information I should know about TOSYMRA? TOSYMRA can cause serious side effects, including: Heart attack and other heart problems. Heart problems may lead to death. Stop taking TOSYMRA 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 TOSYMRA is not for people with risk factors for heart disease unless a heart exam is done and shows no problem. You have a higher risk for heart disease if you: have high blood pressure have high cholesterol levels smoke are overweight have diabetes have a family history of heart disease What is TOSYMRA? TOSYMRA is a prescription medicine used to treat acute migraine headaches with or without aura in adults. TOSYMRA 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. TOSYMRA is not used to prevent or decrease the number of migraines you have. TOSYMRA is not used to treat cluster headaches. It is not known if TOSYMRA is safe and effective in children under 18 years of age. Do not take TOSYMRA if you have: 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 severe liver problems 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 eletriptan frovatriptan naratriptan rizatriptan ergotamines dihydroergotamine Ask your healthcare provider if you are not sure if your medicine is listed above. are taking certain antidepressants, known as monoamine oxidase (MAO)-A inhibitors or it has been 2 weeks or less since you stopped taking a MAO-A inhibitor. Ask your healthcare provider or pharmacist for a list of these medicines if you are not sure. an allergy to sumatriptan or any of the ingredients in TOSYMRA. See the end of this Patient Information leaflet for a complete list of ingredients in TOSYMRA. Before taking TOSYMRA, tell your healthcare provider about all of your medical conditions, including if you: have high blood pressure. have high cholesterol. have diabetes. smoke. are overweight. have heart problems or family history of heart problems or stroke. have kidney problems. have liver problems. have had epilepsy or seizures. are not using effective birth control. are pregnant or plan to become pregnant. It is not known if TOSYMRA can harm your unborn baby. are breastfeeding or plan to breastfeed. TOSYMRA passes into your breast milk. It is not known if this can harm your baby. Talk with your healthcare provider about the best way to feed your baby if you take TOSYMRA. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. TOSYMRA and certain other medicines can affect each other, causing serious side effects. Especially tell your healthcare provider if you take anti-depressant medicines called: selective serotonin reuptake inhibitors (SSRIs) serotonin norepinephrine reuptake inhibitors (SNRIs) tricyclic antidepressants (TCAs) monoamine oxidase inhibitors (MAOIs) Ask your healthcare provider or pharmacist for a list of these medicines if you are not sure. 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 TOSYMRA? See the Instructions for Use for complete information on how to use TOSYMRA nasal spray. Certain people should take their first dose of TOSYMRA 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 TOSYMRA exactly as your healthcare provider tells you to use it. You should take TOSYMRA as soon as the symptoms of your headache start, but it may be taken at any time during a migraine. If your headache comes back after the first nasal spray or you only get some relief from your headache, you can use a second nasal spray 1 hour after the first nasal spray. Do not use more than 30 mg of TOSYMRA Nasal Spray in a 24-hour period. If you use too much TOSYMRA, 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 TOSYMRA, so you can talk with your healthcare provider about how TOSYMRA is working for you. What should I avoid while taking TOSYMRA? TOSYMRA can cause dizziness, weakness, or drowsiness. If you have these symptoms, do not drive a car, use machinery, or do anything where you need to be alert. What are the possible side effects of TOSYMRA? TOSYMRA may cause serious side effects. See " What is the most important information I should know about TOSYMRA? " 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 fever 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 much migraine medicine, such as TOSYMRA, for 10 or more days each month may have worse headaches (medication overuse headache). If your headaches get worse, your healthcare provider may decide to stop your treatment with TOSYMRA. serotonin syndrome. Serotonin syndrome is a rare but serious problem that can happen in people using TOSYMRA, especially if TOSYMRA is used with anti-depressant medicines called SSRIs or SNRIs. Call your healthcare provider right away if you have any of the following symptoms of serotonin syndrome: 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 increased blood pressure including a sudden severe increase (hypertensive crisis) even if you have no history of high blood pressure. hives (itchy bumps); swelling of your tongue, mouth, or throat. seizures. Seizures have happened in people taking TOSYMRA who have never had seizures before. Talk with your healthcare provider about your chance of having seizures while you take TOSYMRA. The most common side effects of TOSYMRA include: tingling feeling of heaviness numbness dizziness feeling of pressure application site (nasal) reactions feeling warm or hot flushing abnormal taste burning feeling feeling of tightness throat irritation Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of TOSYMRA. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store TOSYMRA? Store between 68° to 77°F (20° to 25°C) Do not store in the refrigerator or freeze. Do not test before use. Keep TOSYMRA and all medicines out of the reach of children. General information about the safe and effective use of TOSYMRA. Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflets. Do not use TOSYMRA for a condition for which it was not prescribed. Do not give TOSYMRA to other people, even if they have the same symptoms you have. It may harm them. You can ask your healthcare provider or pharmacist for information about TOSYMRA that is written for healthcare professionals. For more information, go to www.upsher-smith.com or call 1-888-650-3789. What are the ingredients in TOSYMRA? Active ingredient: sumatriptan Inactive ingredients: citric acid monohydrate, n-Dodecyl beta-D-maltoside, potassium phosphate monobasic, sodium chloride, and sodium phosphate dibasic anhydrous in water for injection. Manufactured for UPSHER-SMITH LABORATORIES, LLC Maple Grove, MN 55369 TOSYMRA is a registered trademark of Upsher-Smith Laboratories, LLC. This product may be covered by one or more U.S. patent(s). See www.uslpatents.com.
| This Patient Information has been approved by the U.S. Food and Drug Administration. | Revised: 2/2021 | ||
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Clinical studies
This field may contain references to clinical studies in place of detailed discussion in other sections of the labeling.14 CLINICAL STUDIES The efficacy of TOSYMRA is based on the relative bioavailability of TOSYMRA nasal spray compared to sumatriptan subcutaneous injection (4 mg) in healthy adults [see Clinical Pharmacology (12.3) ] . In controlled clinical trials enrolling more than 1,000 patients during migraine attacks who were experiencing moderate or severe pain and 1 or more of the symptoms enumerated in Table 3, onset of relief began as early as 10 minutes following a 6 mg sumatriptan injection. Lower doses of sumatriptan injection may also prove effective, although the proportion of patients obtaining adequate relief was decreased and the latency to that relief is greater with lower doses. In Study 1, 6 different doses of sumatriptan injection (n = 30 each group) were compared with placebo (n = 62) in a single-attack, parallel-group design; the dose-response relationship was found to be as shown in Table 2. Table 2: Proportion of Patients with Migraine Relief and Incidence of Adverse Reactions by Time and by Sumatriptan Dose in Study 1 Dose of sumatriptan Injection Percent Patients with Relief Relief is defined as the reduction of moderate or severe pain to no or mild pain after dosing without use of rescue medication. Adverse Reactions Incidence (%) at 10 Minutes at 30 Minutes at 1 Hour at 2 Hours Placebo 5 15 24 21 55 1 mg 10 40 43 40 63 2 mg 7 23 57 43 63 3 mg 17 47 57 60 77 4 mg Efficacy of Tosymra nasal spray was demonstrated based on bioavailability to 4 mg sumatriptan SC injection. 13 37 50 57 80 6 mg 10 63 73 70 83 8 mg 23 57 80 83 93 In 2 randomized, placebo-controlled clinical trials of sumatriptan injection 6 mg in 1,104 patients with moderate or severe migraine pain (Studies 2 and 3), the onset of relief was less than 10 minutes. Headache relief, as defined by a reduction in pain from severe or moderately severe to mild or no headache, was achieved in 70% of the patients within 1 hour of a single 6 mg subcutaneous dose of sumatriptan injection. Approximately 82% and 65% of patients treated with sumatriptan 6 mg had headache relief and were pain free within 2 hours, respectively. Table 3 shows the 1- and 2-hour efficacy results for sumatriptan injection 6 mg in Studies 2 and 3. Table 3: Proportion of Patients with Pain Relief and Relief of Migraine Symptoms after 1 and 2 Hours of Treatment in Studies 2 and 3 1-Hour Data Study 2 Study 3 Placebo (n = 190) Sumatriptan Injection 6 mg (n = 384) Placebo (n = 180) Sumatriptan Injection 6 mg (n = 350) Patients with pain relief (Grade 0/1) 18% 70% P<0.05 versus placebo. 26% 70% Patients with no pain 5% 48% 13% 49% Patients without nausea 48% 73% 50% 73% Patients without photophobia 23% 56% 25% 58% Patients with little or no clinical disability A successful outcome in terms of clinical disability was defined prospectively as ability to work mildly impaired or ability to work and function normally. 34% 76% 34% 76% 2-Hour Data Study 2 Study 3 Placebo Includes patients that may have received an additional placebo injection 1 hour after the initial injection. Sumatriptan Injection 6 mg Includes patients that may have received an additional 6 mg of sumatriptan injection 1 hour after the initial injection. Placebo Sumatriptan Injection 6 mg Patients with pain relief (Grade 0/1) 31% 81% 39% 82% Patients with no pain 11% 63% 19% 65% Patients without nausea 56% 82% 63% 81% Patients without photophobia 31% 72% 35% 71% Patients with little or no clinical disability 42% 85% 49% 84% Sumatriptan injection also relieved photophobia, phonophobia (sound sensitivity), nausea, and vomiting associated with migraine attacks. 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 patient, or concomitant use of common migraine prophylactic drugs (e.g., beta-blockers).
| Dose of sumatriptan Injection | Percent Patients with Relief | Adverse Reactions Incidence (%) | |||
|---|---|---|---|---|---|
| at 10 Minutes | at 30 Minutes | at 1 Hour | at 2 Hours | ||
| Placebo | 5 | 15 | 24 | 21 | 55 |
| 1 mg | 10 | 40 | 43 | 40 | 63 |
| 2 mg | 7 | 23 | 57 | 43 | 63 |
| 3 mg | 17 | 47 | 57 | 60 | 77 |
| 6 mg | 10 | 63 | 73 | 70 | 83 |
| 8 mg | 23 | 57 | 80 | 83 | 93 |
| Patients with pain relief (Grade 0/1) | 18% | 70% | 26% | 70% |
| Patients with no pain | 5% | 48% | 13% | 49% |
| Patients without nausea | 48% | 73% | 50% | 73% |
| Patients without photophobia | 23% | 56% | 25% | 58% |
| Patients with little or no clinical disability | 34% | 76% | 34% | 76% |
| Patients with pain relief (Grade 0/1) | 31% | 81% | 39% | 82% |
| Patients with no pain | 11% | 63% | 19% | 65% |
| Patients without nausea | 56% | 82% | 63% | 81% |
| Patients without photophobia | 31% | 72% | 35% | 71% |
| Patients with little or no clinical disability | 42% | 85% | 49% | 84% |
Geriatric use
Information about any limitations on any geriatric indications, needs for specific monitoring, hazards associated with use of the drug in the geriatric population.8.5 Geriatric Use Clinical trials of sumatriptan did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy. A cardiovascular evaluation is recommended for geriatric patients who have other cardiovascular risk factors (e.g., diabetes, hypertension, smoking, obesity, strong family history of CAD) prior to receiving TOSYMRA [see Warnings and Precautions (5.1) ] .
Pediatric use
Information about any limitations on any pediatric indications, needs for specific monitoring, hazards associated with use of the drug in any subsets of the pediatric population (such as neonates, infants, children, or adolescents), differences between pediatric and adult responses to the drug, and other information related to the safe and effective pediatric use of the drug.8.4 Pediatric Use Safety and effectiveness of TOSYMRA in pediatric patients have not been established. TOSYMRA is not recommended for use in patients younger than 18 years of age. Two controlled clinical trials evaluated sumatriptan nasal spray (5 mg to 20 mg) in 1,248 pediatric migraineurs 12 to 17 years of age who treated a single attack. The trials did not establish the efficacy of sumatriptan nasal spray compared with placebo in the treatment of migraine in pediatric patients. Adverse reactions observed in these clinical trials were similar in nature to those reported in clinical trials in adults. Five controlled clinical trials (2 single-attack trials, 3 multiple-attack trials) evaluating oral sumatriptan (25 mg to 100 mg) in pediatric subjects 12 to 17 years of age enrolled a total of 701 pediatric migraineurs. These trials did not establish the efficacy of oral sumatriptan compared with placebo in the treatment of migraine in pediatric patients. Adverse reactions observed in these clinical trials were similar in nature to those reported in clinical trials in adults. The frequency of all adverse reactions in these patients appeared to be both dose- and age-dependent, with younger patients reporting reactions more commonly than older pediatric patients. Post-marketing experience documents that serious adverse reactions have occurred in the pediatric population after use of subcutaneous, oral, and/or intranasal sumatriptan. These reports include reactions similar in nature to those reported rarely in adults, including stroke, visual loss, and death. A myocardial infarction has been reported in a 14-year-old male following the use of oral sumatriptan; clinical signs occurred within 1 day of drug administration. Clinical data to determine the frequency of serious adverse reactions in pediatric patients who might receive subcutaneous, oral, or intranasal sumatriptan are not presently available.
Pregnancy
Information about effects the drug may have on pregnant women or on a fetus. This field may be ommitted if the drug is not absorbed systemically and the drug is not known to have a potential for indirect harm to the fetus. It may contain information about the established pregnancy category classification for the drug. (That information is nominally listed in the teratogenic_effects field, but may be listed here instead.)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 embryo lethality, fetal abnormalities, and pup mortality. When administered by the intravenous route to pregnant rabbits, sumatriptan was embryo lethal (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 embryo lethality 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 embryo lethality. 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.
Use in specific populations
Information about use of the drug by patients in specific populations, including pregnant women and nursing mothers, pediatric patients, and geriatric patients.8 USE IN SPECIFIC POPULATIONS 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 embryo lethality, fetal abnormalities, and pup mortality. When administered by the intravenous route to pregnant rabbits, sumatriptan was embryo lethal (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 embryo lethality 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 embryo lethality. 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 TOSYMRA 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 TOSYMRA. 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 of TOSYMRA in pediatric patients have not been established. TOSYMRA is not recommended for use in patients younger than 18 years of age. Two controlled clinical trials evaluated sumatriptan nasal spray (5 mg to 20 mg) in 1,248 pediatric migraineurs 12 to 17 years of age who treated a single attack. The trials did not establish the efficacy of sumatriptan nasal spray compared with placebo in the treatment of migraine in pediatric patients. Adverse reactions observed in these clinical trials were similar in nature to those reported in clinical trials in adults. Five controlled clinical trials (2 single-attack trials, 3 multiple-attack trials) evaluating oral sumatriptan (25 mg to 100 mg) in pediatric subjects 12 to 17 years of age enrolled a total of 701 pediatric migraineurs. These trials did not establish the efficacy of oral sumatriptan compared with placebo in the treatment of migraine in pediatric patients. Adverse reactions observed in these clinical trials were similar in nature to those reported in clinical trials in adults. The frequency of all adverse reactions in these patients appeared to be both dose- and age-dependent, with younger patients reporting reactions more commonly than older pediatric patients. Post-marketing experience documents that serious adverse reactions have occurred in the pediatric population after use of subcutaneous, oral, and/or intranasal sumatriptan. These reports include reactions similar in nature to those reported rarely in adults, including stroke, visual loss, and death. A myocardial infarction has been reported in a 14-year-old male following the use of oral sumatriptan; clinical signs occurred within 1 day of drug administration. Clinical data to determine the frequency of serious adverse reactions in pediatric patients who might receive subcutaneous, oral, or intranasal sumatriptan are not presently available. 8.5 Geriatric Use Clinical trials of sumatriptan did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy. A cardiovascular evaluation is recommended for geriatric patients who have other cardiovascular risk factors (e.g., diabetes, hypertension, smoking, obesity, strong family history of CAD) prior to receiving TOSYMRA [see Warnings and Precautions (5.1) ] .
How supplied
Information about the available dosage forms to which the labeling applies, and for which the manufacturer or distributor is responsible. This field ordinarily includes the strength of the dosage form (in metric units), the units in which the dosage form is available for prescribing, appropriate information to facilitate identification of the dosage forms (such as shape, color, coating, scoring, and National Drug Code), and special handling and storage condition information.16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied TOSYMRA ® 10 mg (NDC 0245-0812-89) contains sumatriptan and is supplied as a ready-to-use, single-dose, disposable unit. Each carton contains 6 units (NDC 0245-0812-61) and a Patient Information and Instructions for Use leaflet. 16.2 Storage and Handling Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F). Do not store in the refrigerator or freezer. Do not test before use.
Storage and handling
Information about safe storage and handling of the drug product.16.2 Storage and Handling Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F). Do not store in the refrigerator or freezer. Do not test before use.
Disclaimer: Do not rely on openFDA or Phanrmacy Near Me to make decisions regarding medical care. While we make every effort to ensure that data is accurate, you should assume all results are unvalidated. Source: OpenFDA, Healthporta Drugs API