Onzetra

Overdose

Coronary vasospasm was observed after intravenous administration of IMITREX Injection. 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 ; therefore, monitoring of patients after overdose with IMITREX Injection should continue for at least 10 hours or while symptoms or signs persist.

It is unknown what effect hemodialysis or peritoneal dialysis has on the serum concentrations of sumatriptan.

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Contraindications

IMITREX Injection is contraindicated in patients with:

• Ischemic coronary artery disease (CAD) (angina pectoris, history of myocardial infarction, or documented silent ischemia) or coronary artery vasospasm, including Prinzmetal's angina.
• 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.
• Peripheral vascular disease.
• Ischemic bowel disease.
• Uncontrolled hypertension.
• Recent use (i.e., within 24 hours) of ergotamine-containing medication, ergot-type medication (such as dihydroergotamine or methysergide), or another 5-hydroxytryptamine1 (5-HT1) agonist.
• Concurrent administration of a monoamine oxidase (MAO)-A inhibitor or recent (within 2 weeks) use of an MAO-A inhibitor.
• Hypersensitivity to IMITREX (angioedema and anaphylaxis seen).
• Severe hepatic impairment.

Pharmaceutical form

Undesirable effects

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

• Myocardial ischemia, myocardial infarction, and Prinzmetal's angina
• Arrhythmias
• Chest, throat, neck, and/or jaw pain/tightness/pressure
• Cerebrovascular events
• Other vasospasm reactions
• Medication overuse headache
• Serotonin syndrome
• Increase in blood pressure
• Hypersensitivity reactions
• Seizures

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Table 1 lists adverse reactions that occurred in 2 US placebo-controlled clinical trials in migraine patients (Studies 2 and 3) following either a single 6-mg dose of IMITREX Injection or placebo. Only reactions that occurred at a frequency of 2% or more in groups treated with IMITREX 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)

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.

In the controlled clinical trials assessing the efficacy of IMITREX Injection as a treatment for cluster headache (Studies 4 and 5), no new significant adverse reactions were detected that had not already been identified in trials of IMITREX in patients with migraine.

Overall, the frequency of adverse reactions reported in the trials of cluster headache was generally lower than in the migraine trials. Exceptions include reports of paresthesia (5% IMITREX, 0% placebo), nausea and vomiting (4% IMITREX, 0% placebo), and bronchospasm (1% IMITREX, 0% placebo).

The following adverse reactions have been identified during postapproval use of IMITREX Tablets, IMITREX Nasal Spray, and IMITREX 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.

Hypotension, palpitations.

Dystonia, tremor.

Therapeutic indications

IMITREX® Injection is indicated in adults for (1) the acute treatment of migraine, with or without aura, and (2) the acute treatment of cluster headache.

• Use only if a clear diagnosis of migraine or cluster headache has been established. If a patient has no response to the first migraine or cluster headache attack treated with IMITREX Injection, reconsider the diagnosis before IMITREX Injection is administered to treat any subsequent attacks.
• IMITREX Injection is not indicated for the prevention of migraine or cluster headache attacks.

Pharmacodynamic properties

Significant elevation in blood pressure, including hypertensive crisis, has been reported in patients with and without a history of hypertension.

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.

Transient increases in blood pressure observed in some patients in clinical trials carried out during sumatriptan's development as a treatment for migraine were not accompanied by any clinically significant changes in heart rate.

Pharmacokinetic properties

The bioavailability of sumatriptan via subcutaneous site injection to 18 healthy male subjects was 97% ± 16% of that obtained following intravenous injection.

After a single 6-mg subcutaneous manual injection into the deltoid area of the arm in 18 healthy males (age: 24 ± 6 years, weight: 70 kg), the maximum serum concentration (Cmax) of sumatriptan was (mean ± standard deviation) 74 ± 15 ng/mL and the time to peak concentration (Tmax) was 12 minutes after injection (range: 5 to 20 minutes). In this trial, the same dose injected subcutaneously in the thigh gave a Cmax of 61 ± 15 ng/mL by manual injection versus 52 ± 15 ng/mL by autoinjector techniques. The Tmax or amount absorbed was not significantly altered by either the site or technique of injection.

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.

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.

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.

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).

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 IMITREX Injection in this population is contraindicated.

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

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Qualitative and quantitative composition

Special warnings and precautions for use

Included as part of the PRECAUTIONS section.

The use of IMITREX Injection is contraindicated in patients with ischemic or vasospastic CAD. There have been rare reports of serious cardiac adverse reactions, including acute myocardial infarction, occurring within a few hours following administration of IMITREX Injection. Some of these reactions occurred in patients without known CAD. IMITREX Injection may cause coronary artery vasospasm (Prinzmetal's angina), even in patients without a history of CAD.

Perform a cardiovascular evaluation in triptan-naive patients who have multiple cardiovascular risk factors (e.g., increased age, diabetes, hypertension, smoking, obesity, strong family history of CAD) prior to receiving IMITREX Injection. If there is evidence of CAD or coronary artery vasospasm, IMITREX Injection is contraindicated. For patients with multiple cardiovascular risk factors who have a negative cardiovascular evaluation, consider administering the first dose of IMITREX Injection in a medically supervised setting and performing an electrocardiogram (ECG) immediately following administration of IMITREX Injection. For such patients, consider periodic cardiovascular evaluation in intermittent long-term users of IMITREX Injection.

Life-threatening disturbances of cardiac rhythm, including ventricular tachycardia and ventricular fibrillation leading to death, have been reported within a few hours following the administration of 5-HT1 agonists. Discontinue IMITREX Injection if these disturbances occur. IMITREX Injection is contraindicated in patients with Wolff-Parkinson-White syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders.

Sensations of tightness, pain, pressure, and heaviness in the precordium, throat, neck, and jaw commonly occur after treatment with IMITREX Injection and are usually non-cardiac in origin. However, perform a cardiac evaluation if these patients are at high cardiac risk. The use of IMITREX Injection is contraindicated in patients with CAD and those with Prinzmetal's variant angina.

Cerebral hemorrhage, subarachnoid hemorrhage, and stroke have occurred in patients treated with 5-HT1 agonists, and some have resulted in fatalities. In a number of cases, it appears possible that the cerebrovascular events were primary, the 5-HT1 agonist having been administered in the incorrect belief that the symptoms experienced were a consequence of migraine when they were not. Also, patients with migraine may be at increased risk of certain cerebrovascular events (e.g., stroke, hemorrhage, TIA). Discontinue IMITREX Injection if a cerebrovascular event occurs.

Before treating headaches in patients not previously diagnosed with migraine or cluster headache or in patients who present with atypical symptoms, exclude other potentially serious neurological conditions. IMITREX Injection is contraindicated in patients with a history of stroke or TIA.

IMITREX Injection may cause non-coronary vasospastic reactions, such as peripheral vascular ischemia, gastrointestinal vascular ischemia and infarction (presenting with abdominal pain and bloody diarrhea), splenic infarction, and Raynaud's syndrome. In patients who experience symptoms or signs suggestive of non-coronary vasospasm reaction following the use of any 5-HT1 agonist, rule out a vasospastic reaction before receiving additional IMITREX Injections.

Reports of transient and permanent blindness and significant partial vision loss have been reported with the use of 5-HT1 agonists. Since visual disorders may be part of a migraine attack, a causal relationship between these events and the use of 5-HT1 agonists have not been clearly established.

Overuse of acute migraine drugs (e.g., ergotamine, triptans, opioids, or combination of these drugs for 10 or more days per month) may lead to exacerbation of headache (medication overuse headache). Medication overuse headache may present as migraine-like daily headaches, or as a marked increase in frequency of migraine attacks. Detoxification of patients, including withdrawal of the overused drugs, and treatment of withdrawal symptoms (which often includes a transient worsening of headache) may be necessary.

Serotonin syndrome may occur with IMITREX Injection, particularly during co-administration with selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and MAO inhibitors. 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 IMITREX Injection if serotonin syndrome is suspected.

Significant elevation in blood pressure, including hypertensive crisis with acute impairment of organ systems, has been reported on rare occasions in patients treated with 5-HT1 agonists, including patients without a history of hypertension. Monitor blood pressure in patients treated with IMITREX. IMITREX Injection is contraindicated in patients with uncontrolled hypertension.

Anaphylactic/anaphylactoid reactions have occurred in patients receiving IMITREX. 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. IMITREX Injection is contraindicated in patients with a history of hypersensitivity reaction to IMITREX.

Seizures have been reported following administration of IMITREX. 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. IMITREX Injection should be used with caution in patients with a history of epilepsy or conditions associated with a lowered seizure threshold.

Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION and Instructions for Use).

Inform patients that IMITREX Injection may cause serious cardiovascular side effects such as myocardial infarction or stroke. Although serious cardiovascular events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, irregular heartbeat, significant rise in blood pressure, weakness, and slurring of speech, and should ask for medical advice if any indicative sign or symptoms are observed. Apprise patients of the importance of this follow-up.

Inform patients that anaphylactic/anaphylactoid reactions have occurred in patients receiving IMITREX Injection. Such reactions can be life threatening or fatal. In general, anaphylactic reactions to drugs are more likely to occur in individuals with a history of sensitivity to multiple allergens.

Inform patients that use of IMITREX Injection within 24 hours of another triptan or an ergot-type medication (including dihydroergotamine or methysergide) is contraindicated.

Caution patients about the risk of serotonin syndrome with the use of IMITREX Injection or other triptans, particularly during combined use with SSRIs, SNRIs, TCAs, and MAO inhibitors.

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).

Inform patients that IMITREX Injection should not be used during pregnancy unless the potential benefit justifies the potential risk to the fetus.

Advise patients to notify their healthcare provider if they are breastfeeding or plan to breastfeed.

Treatment with IMITREX Injection may cause somnolence and dizziness; instruct patients to evaluate their ability to perform complex tasks after administration of IMITREX Injection.

Provide patients instruction on the proper use of IMITREX Injection if they are able to self-administer IMITREX Injection in medically unsupervised situations.

Inform patients that the needle in the IMITREX STATdose Pen penetrates approximately 1/4 of an inch (5 to 6 mm). Inform patients that the injection is intended to be given subcutaneously and intramuscular or intravascular delivery should be avoided. Instruct patients to use injection sites with an adequate skin and subcutaneous thickness to accommodate the length of the needle.

In carcinogenicity studies in mouse and rat in which 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). The highest dose to mice and rats was approximately 130 and 260 times the single MRHD of 6 mg administered subcutaneously on a mg/m² basis. There was no evidence in either species of an increase in tumors related to sumatriptan administration.

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.

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 or approximately 100 times the single human dose of 6 mg on a mg/m² basis. When sumatriptan (5, 50, 500 mg/kg/day) was administered orally to male and female rats prior to and throughout the mating period, there was a treatment-related decrease in fertility secondary to a decrease in mating in animals treated with doses greater than 5 mg/kg/day. It is not clear whether this finding was due to an effect on males or females or both.

There are no adequate and well-controlled trials of IMITREX Injection in pregnant women. In developmental toxicity studies in rats and rabbits, oral administration of sumatriptan to pregnant animals was associated with embryolethality, fetal abnormalities, and pup mortality. When administered by the intravenous route to pregnant rabbits, sumatriptan was embryolethal. IMITREX Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

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 rates was 60 mg/kg/day, or approximately 100 times the single maximum recommended human dose (MRHD) of 6 mg administered subcutaneously on a mg/m² basis. Oral administration of sumatriptan to pregnant rabbits during the period of organogenesis resulted in increased incidences of embryolethality and fetal cervicothoracic vascular and skeletal abnormalities. Intravenous administration of sumatriptan to pregnant rabbits during the period of organogenesis resulted in an increased incidence of embryolethality. The highest oral and intravenous no-effect doses for developmental toxicity in rabbits were 15 and 0.75 mg/kg/day, or approximately 50 and 2 times, respectively, the single MRHD of 6 mg administered subcutaneously on a mg/m² basis.

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, or approximately 80 times the single MRHD of 6 mg administered subcutaneously on a mg/m² basis. 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, or approximately 100 times the single MRHD of 6 mg administered subcutaneously on a mg/m² basis. 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, or approximately 160 times the single MRHD of 6 mg administered subcutaneously on a mg/m² basis.

Sumatriptan is excreted in human milk following subcutaneous administration. Infant exposure to sumatriptan can be minimized by avoiding breastfeeding for 12 hours after treatment with IMITREX Injection.

Safety and effectiveness in pediatric patients have not been established. IMITREX Injection is not recommended for use in patients younger than 18 years of age.

Two controlled clinical trials evaluated IMITREX Nasal Spray (5 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 IMITREX 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 IMITREX (25 to 100 mg) in pediatric patients 12 to 17 years of age enrolled a total of 701 pediatric migraineurs. These trials did not establish the efficacy of oral IMITREX compared with placebo in the treatment of migraine in pediatric patients. Adverse reactions observed in these clinical trials were similar in nature to those reported in clinical trials in adults. The frequency of all adverse reactions in these patients appeared to be both dose- and age-dependent, with younger patients reporting reactions more commonly than older pediatric patients.

Postmarketing experience documents that serious adverse reactions have occurred in the pediatric population after use of subcutaneous, oral, and/or intranasal IMITREX. 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 IMITREX; 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 IMITREX are not presently available.

Clinical trials of IMITREX Injection did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.

A cardiovascular evaluation is recommended for geriatric patients who have other cardiovascular risk factors (e.g., diabetes, hypertension, smoking, obesity, strong family history of CAD) prior to receiving IMITREX Injection.

Dosage (Posology) and method of administration

The maximum single recommended adult dose of IMITREX Injection for the acute treatment of migraine or cluster headache is 6 mg injected subcutaneously. For the treatment of migraine, if side effects are dose limiting, lower doses (1 mg to 5 mg) may be used. For the treatment of cluster headache, the efficacy of lower doses has not been established.

The maximum cumulative dose that may be given in 24 hours is 12 mg, two 6-mg injections separated by at least 1 hour. A second 6-mg dose should only be considered if some response to a first injection was observed.

An autoinjector device (IMITREX STATdose Pen) is available for use with 4- mg and 6-mg prefilled syringe cartridges. With this device, the needle penetrates approximately 1/4 inch (5 to 6 mm). The injection is intended to be given subcutaneously, and intramuscular or intravascular delivery must be avoided. Instruct patients on the proper use of IMITREX STATdose Pen and direct them to use injection sites with an adequate skin and subcutaneous thickness to accommodate the length of the needle.

In patients receiving doses other than 4 mg or 6 mg, use the 6-mg single-dose vial; do not use the IMITREX STATdose Pen. Visually inspect the vial for particulate matter and discoloration before administration. Do not use if particulates and discolorations are noted.