Tosymra
(Sumatriptan)Dosage & 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.
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Tosymra Prescribing Information
TOSYMRA is indicated for the acute treatment of migraine with or without aura in adults.
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 nasal spray device delivering 10 mg of sumatriptan.
Pregnancy: Based on animal data, may cause fetal harm (
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
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.
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.
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.
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.]
5.1 Myocardial Ischemia, Myocardial Infarction, and Prinzmetal's AnginaThe use of TOSYMRA 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. Some of these reactions occurred in patients without known CAD. 5-HT1agonists, including TOSYMRA, 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 TOSYMRA. If there is evidence of CAD or coronary artery vasospasm, TOSYMRA is contraindicated. For patients with multiple cardiovascular risk factors who have a negative cardiovascular evaluation, consider administering the first dose of TOSYMRA in a medically supervised setting and performing an electrocardiogram (ECG) immediately following administration of TOSYMRA. For such patients, consider periodic cardiovascular evaluation in intermittent long-term users of TOSYMRA.
- Wolff-Parkinson-White syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders[see.]
5.2 ArrhythmiasLife-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-HT1agonists. Discontinue TOSYMRA if these disturbances occur.
TOSYMRA is contraindicated in patients with Wolff-Parkinson-White syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders.
- 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.]
5.4 Cerebrovascular EventsCerebral hemorrhage, subarachnoid hemorrhage, and stroke have occurred in patients treated with 5-HT1agonists, and some have resulted in fatalities. In a number of cases, it appears possible that the cerebrovascular events were primary, the 5-HT1agonist 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 TOSYMRA if a cerebrovascular event occurs.
Before treating headaches in patients not previously diagnosed with migraine or in patients who present with atypical symptoms, exclude other potentially serious neurological conditions. TOSYMRA is contraindicated in patients with a history of stroke or TIA.
- Peripheral vascular disease[see.]
5.5 Other Vasospasm ReactionsTOSYMRA may cause non-coronary vasospastic reactions, such as peripheral vascular ischemia, gastrointestinal vascular ischemia and infarction (presenting with abdominal pain and bloody diarrhea), splenic infarction, and Raynaud's syndrome. In patients who experience symptoms or signs suggestive of non-coronary vasospasm reaction following the use of any 5-HT1agonist, rule out a vasospastic reaction before receiving additional TOSYMRA.
Reports of transient and permanent blindness and significant partial vision loss have been reported with the use of 5-HT1agonists. Since visual disorders may be part of a migraine attack, a causal relationship between these events and the use of 5-HT1agonists have not been clearly established.
- Ischemic bowel disease[see.]
5.5 Other Vasospasm ReactionsTOSYMRA may cause non-coronary vasospastic reactions, such as peripheral vascular ischemia, gastrointestinal vascular ischemia and infarction (presenting with abdominal pain and bloody diarrhea), splenic infarction, and Raynaud's syndrome. In patients who experience symptoms or signs suggestive of non-coronary vasospasm reaction following the use of any 5-HT1agonist, rule out a vasospastic reaction before receiving additional TOSYMRA.
Reports of transient and permanent blindness and significant partial vision loss have been reported with the use of 5-HT1agonists. Since visual disorders may be part of a migraine attack, a causal relationship between these events and the use of 5-HT1agonists have not been clearly established.
- Uncontrolled hypertension[see.]
5.8 Increase in Blood PressureSignificant elevation in blood pressure, including hypertensive crisis with acute impairment of organ systems, has been reported on rare occasions in patients treated with 5-HT1agonists, including patients without a history of hypertension. Monitor blood pressure in patients treated with TOSYMRA. TOSYMRA is contraindicated in patients with uncontrolled hypertension.
- 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.,7.1 Ergot-Containing DrugsErgot-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.
]7.3 Other 5-HT1AgonistsBecause their vasospastic effects may be additive, coadministration of TOSYMRA and other 5-HT1agonists (e.g., triptans) within 24 hours of each other is contraindicated.
- Concurrent administration of a monoamine oxidase (MAO)-A inhibitor or recent (within 2 weeks) use of an MAO-A inhibitor[see.and
7.2 Monoamine Oxidase-A InhibitorsMAO-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)].]12.3 PharmacokineticsFollowing 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.
AbsorptionPeak 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%) Cmaxand AUC were 51.8 ng/mL (58%) and 60.70 ng∙hr/mL (42%), respectively.
DistributionSumatriptan 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.
EliminationThe elimination half-life of sumatriptan following administration of TOSYMRA is 2.44 ± 1.00 hours.
MetabolismIn vitrostudies 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.ExcretionAfter 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 PopulationsAgeThe 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 ImpairmentThe 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 GroupsThe systemic clearance and Cmaxof 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 StudiesMonoamine Oxidase-A InhibitorsIn 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.
- Hypersensitivity to sumatriptan (angioedema and anaphylaxis seen)[see.]
5.9 Hypersensitivity ReactionsHypersensitivity reactions, including angioedema and anaphylaxis, have occurred in patients receiving sumatriptan. Such reactions can be life threatening or fatal. In general, anaphylactic reactions to drugs are more likely to occur in individuals with a history of sensitivity to multiple allergens. TOSYMRA is contraindicated in patients with a history of hypersensitivity reaction to sumatriptan.
- Severe hepatic impairment[see.]
12.3 PharmacokineticsFollowing 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.
AbsorptionPeak 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%) Cmaxand AUC were 51.8 ng/mL (58%) and 60.70 ng∙hr/mL (42%), respectively.
DistributionSumatriptan 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.
EliminationThe elimination half-life of sumatriptan following administration of TOSYMRA is 2.44 ± 1.00 hours.
MetabolismIn vitrostudies 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.ExcretionAfter 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 PopulationsAgeThe 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 ImpairmentThe 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 GroupsThe systemic clearance and Cmaxof 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 StudiesMonoamine Oxidase-A InhibitorsIn 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.
- Myocardial ischemia/infarction and Prinzmetal's angina: Perform cardiac evaluation in patients with multiple cardiovascular risk factors ()
5.1 Myocardial Ischemia, Myocardial Infarction, and Prinzmetal's AnginaThe use of TOSYMRA 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. Some of these reactions occurred in patients without known CAD. 5-HT1agonists, including TOSYMRA, 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 TOSYMRA. If there is evidence of CAD or coronary artery vasospasm, TOSYMRA is contraindicated. For patients with multiple cardiovascular risk factors who have a negative cardiovascular evaluation, consider administering the first dose of TOSYMRA in a medically supervised setting and performing an electrocardiogram (ECG) immediately following administration of TOSYMRA. For such patients, consider periodic cardiovascular evaluation in intermittent long-term users of TOSYMRA.
- Arrhythmias: Discontinue TOSYMRA if occurs ()
5.2 ArrhythmiasLife-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-HT1agonists. Discontinue TOSYMRA if these disturbances occur.
TOSYMRA is contraindicated in patients with Wolff-Parkinson-White syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders.
- Chest/throat/neck/jaw pain, tightness, pressure, or heaviness: Generally, not associated with myocardial ischemia; evaluate for coronary artery disease in patients at high risk ()
5.3 Chest, Throat, Neck, and/or Jaw Pain/Tightness/PressureSensations 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 TOSYMRA is contraindicated in patients shown to have CAD and those with Prinzmetal's variant angina.
- Cerebral hemorrhage, subarachnoid hemorrhage, and stroke: Discontinue TOSYMRA if occurs ()
5.4 Cerebrovascular EventsCerebral hemorrhage, subarachnoid hemorrhage, and stroke have occurred in patients treated with 5-HT1agonists, and some have resulted in fatalities. In a number of cases, it appears possible that the cerebrovascular events were primary, the 5-HT1agonist 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 TOSYMRA if a cerebrovascular event occurs.
Before treating headaches in patients not previously diagnosed with migraine or in patients who present with atypical symptoms, exclude other potentially serious neurological conditions. TOSYMRA is contraindicated in patients with a history of stroke or TIA.
- Gastrointestinal ischemia and reactions, peripheral vasospastic reactions: Discontinue TOSYMRA if occurs ()
5.5 Other Vasospasm ReactionsTOSYMRA may cause non-coronary vasospastic reactions, such as peripheral vascular ischemia, gastrointestinal vascular ischemia and infarction (presenting with abdominal pain and bloody diarrhea), splenic infarction, and Raynaud's syndrome. In patients who experience symptoms or signs suggestive of non-coronary vasospasm reaction following the use of any 5-HT1agonist, rule out a vasospastic reaction before receiving additional TOSYMRA.
Reports of transient and permanent blindness and significant partial vision loss have been reported with the use of 5-HT1agonists. Since visual disorders may be part of a migraine attack, a causal relationship between these events and the use of 5-HT1agonists have not been clearly established.
- Medication overuse headache: Detoxification may be necessary ()
5.6 Medication Overuse HeadacheOveruse of acute migraine drugs (e.g., ergotamine, triptans, opioids, or combination of these drugs for 10 or more days per month) may lead to exacerbation of headache (medication overuse headache). Medication overuse headache may present as migraine-like daily headaches, or as a marked increase in frequency of migraine attacks. Detoxification of patients, including withdrawal of the overused drugs, and treatment of withdrawal symptoms (which often includes a transient worsening of headache) may be necessary.
- Serotonin syndrome: Discontinue TOSYMRA if occurs ()
5.7 Serotonin SyndromeSerotonin syndrome may occur with TOSYMRA, particularly during co-administration with selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and MAO inhibitors
[see Drug Interactions (7.4)]. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The onset of symptoms usually occurs within minutes to hours of receiving a new or a greater dose of a serotonergic medication. Discontinue TOSYMRA if serotonin syndrome is suspected. - Increase in blood pressure: Hypertensive crisis can occur ()
5.8 Increase in Blood PressureSignificant elevation in blood pressure, including hypertensive crisis with acute impairment of organ systems, has been reported on rare occasions in patients treated with 5-HT1agonists, including patients without a history of hypertension. Monitor blood pressure in patients treated with TOSYMRA. TOSYMRA is contraindicated in patients with uncontrolled hypertension.
- Hypersensitivity reactions: Angioedema and anaphylaxis can occur ()
5.9 Hypersensitivity ReactionsHypersensitivity reactions, including angioedema and anaphylaxis, have occurred in patients receiving sumatriptan. Such reactions can be life threatening or fatal. In general, anaphylactic reactions to drugs are more likely to occur in individuals with a history of sensitivity to multiple allergens. TOSYMRA is contraindicated in patients with a history of hypersensitivity reaction to sumatriptan.
- Seizures: Use with caution in patients with epilepsy or a lowered seizure threshold ()
5.10 SeizuresSeizures 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. TOSYMRA should be used with caution in patients with a history of epilepsy or conditions associated with a lowered seizure threshold.
- Local irritation: Burning and abnormal taste can occur ()
5.11 Local IrritationLocal irritative symptoms were reported in approximately 46% of patients treated with TOSYMRA in an open-label trial which allowed repeated use of TOSYMRA over the course of 6 months. Of these, the most common local irritative symptoms were application site reaction (36%), dysgeusia (21%), and throat irritation (5%). Approximately 0.5% of the cases were reported as severe.