Included as part of the PRECAUTIONS section.
Myocardial Ischemia, Myocardial Infarction, And Prinzmetal’s
The use of ONZETRA Xsail 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-HT1 agonists, including
ONZETRA Xsail, may cause coronary artery vasospasm (Prinzmetal’s angina), even
in patients without a history of CAD.
Perform a cardiovascular evaluation in triptan-naÃ¯ve
patients who have multiple cardiovascular risk factors (e.g., increased age,
diabetes, hypertension, smoking, obesity, strong family history of CAD) prior
to receiving ONZETRA Xsail. If there is evidence of CAD or coronary artery
vasospasm, ONZETRA Xsail is contraindicated. For patients with multiple
cardiovascular risk factors who have a negative cardiovascular evaluation,
consider administering the first dose of ONZETRA Xsail in a medically
supervised setting and performing an electrocardiogram (ECG) immediately
following administration of ONZETRA Xsail. For such patients, consider periodic
cardiovascular evaluation in intermittent longterm users of ONZETRA Xsail.
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 ONZETRA Xsail if these disturbances occur. ONZETRA
Xsail is contraindicated in patients with Wolff-Parkinson-White syndrome or
arrhythmias associated with other cardiac accessory conduction pathway
Chest, Throat, Neck, And/Or Jaw Pain/Tightness/Pressure
Sensations of tightness, pain, pressure, and heaviness in
the chest, throat, neck, and jaw commonly occur after treatment with 5-HT1
agonists including other products containing sumatriptan and are usually
non-cardiac in origin. However, perform a cardiac evaluation if these patients
are at high cardiac risk. The use of ONZETRA Xsail is contraindicated in
patients with known CAD and those with Prinzmetal’s variant angina.
Cerebral hemorrhage, subarachnoid hemorrhage, stroke, and
other cerebrovascular events have occurred in patients treated with 5-HT1
agonists including other products containing sumatriptan, 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. Patients with migraine may be at increased risk of
certain cerebrovascular events (e.g., stroke, hemorrhage, TIA). ONZETRA Xsail
is contraindicated in patients with a history of stroke or TIA. Discontinue
ONZETRA Xsail if a cerebrovascular event occurs.
Before treating headaches in patients not previously
diagnosed as migraineurs, and in migraineurs who present with atypical
symptoms, exclude other potentially serious neurological conditions.
Other Vasospasm Reactions
5-HT1 agonists, including ONZETRA Xsail, 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 a non-coronary
vasospastic reaction following the use of any 5-HT1 agonist, rule out a
vasospastic reaction before using ONZETRA Xsail.
Transient and permanent blindness and significant partial
vision loss have been reported with the use of 5-HT1 agonists including
sumatriptan. 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
Medication Overuse Headache
Overuse of acute migraine drugs (e.g., ergotamine,
triptans, opioids, nonsteroidal anti-inflammatory drugs or combinations 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 triptans, including
ONZETRA Xsail, particularly during co-administration with selective serotonin
reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors
(SNRIs), tricyclic antidepressants (TCAs), and MAO inhibitors [see DRUG
INTERACTIONS]. Serotonin syndrome symptoms may include mental status
changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g.,
tachycardia, labile blood pressure, hyperthermia), neuromuscular abnormalities
(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 ONZETRA Xsail if serotonin syndrome is suspected.
Increase In Blood Pressure
Significant elevation in blood pressure, including
hypertensive crisis with acute impairment of organ systems, has been reported
on rare occasions in patients treated with 5-HT1 agonists, including patients
without a history of hypertension. Monitor blood pressure in patients treated
with ONZETRA Xsail. ONZETRA Xsail is contraindicated in patients with
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. ONZETRA Xsail
is contraindicated in patients with a history of hypersensitivity reaction to
Seizures have been reported following administration of
sumatriptan. Some have occurred in patients with either a history of seizures
or concurrent conditions predisposing to seizures. There are also reports in
patients where no such predisposing factors are apparent. ONZETRA Xsail should
be used with caution in patients with a history of epilepsy or conditions
associated with a lowered seizure threshold.
Patient Counseling Information
Advise the patient to read the FDA-approved patient
labeling (PATIENT INFORMATION and Instructions for Use).
Only patients who are able to understand and follow the
instructions should use ONZETRA Xsail.
Instructions on the proper use of ONZETRA Xsail from a
physician or healthcare professional prior to administration for the first time
may be helpful. For support, healthcare professionals and patients can call
1-844-ONZETRA or see www.ONZETRA.com.
Risk Of Myocardial Ischemia And/Or Infarction,
Prinzmetal’s Angina, Other Vasospasm-Related Events, Arrhythmias, And Cerebrovascular
Inform patients that triptan medications, including
ONZETRA Xsail, may cause serious cardiovascular side effects such as myocardial
infarction or stroke, which may result in hospitalization and even death.
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 signs or
symptoms are observed. Apprise patients of the importance of this follow-up [see
WARNINGS AND PRECAUTIONS].
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 WARNINGS
Concomitant Use With Other Triptans And Ergot Medications
Inform patients that use of ONZETRA Xsail within 24 hours
of another triptan or an ergot-type medication (including dihydroergotamine or
methysergide) is contraindicated [see CONTRAINDICATIONS and DRUG
Caution patients about the risk of serotonin syndrome
with the use of ONZETRA Xsail or other triptans, particularly during combined
use with SSRIs, SNRIs, TCAs, and MAO inhibitors [see WARNINGS AND
PRECAUTIONS and DRUG INTERACTIONS].
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].
Inform patients that ONZETRA Xsail should not be used
during pregnancy unless the potential benefit justifies the potential risk to the
fetus [see Use In Specific Populations].
Advise patients to notify their healthcare provider if
they are breastfeeding or plan to breastfeed [see Use In Specific
Ability To Perform Complex Tasks
Treatment with sumatriptan may cause somnolence and
dizziness; instruct patients to evaluate their ability to perform complex tasks
during migraine attacks and after administration of ONZETRA Xsail.
Inform patients that they may experience local irritation
of their nose and throat. The symptoms will generally resolve in less than 2
How To Use ONZETRA Xsail With The Breath Powered Device
Provide patients with instructions on the proper use of
ONZETRA Xsail with the breath powered device.
Advise patients that use of the breath powered device is
for ONZETRA Xsail only. No other product or substance is approved for use in
the breath powered device.
Advise patients to remove a disposable nosepiece from the
foil pouch, remove the clear device cap from the reusable device, and click the
nosepiece into the device body.
Advise the patient to fully press and release the white
piercing button on the device body to pierce the capsule inside the nosepiece.
Instruct the patient to press the white piercing button only once.
Advise the patient to insert the nosepiece into the
nostril so that it makes a tight seal. The device is then rotated and the
mouthpiece inserted between the lips.
Instruct the patient to blow forcefully through the
mouthpiece to deliver the sumatriptan powder into the nasal cavity. Vibration
(e.g., a rattling noise) may occur, and indicates that the patient is blowing
forcefully, as directed.
Advise the patient to remove and discard the nosepiece in
the trash once the medication has been administered.
Instruct the patient to follow the same process using a
second nosepiece in the other nostril to administer the remainder of the total
ONZETRA, Xsail, and AVANIR are trademarks and/or
registered trademarks of Avanir Pharmaceuticals, Inc. in the United States and
Carcinogenesis, Mutagenesis, Impairment Of Fertility
In carcinogenicity studies in mouse and rat in which
sumatriptan was administered orally for 78 weeks and 104 weeks, respectively,
there was no evidence in either species of an increase in tumors related to
Carcinogenicity studies of sumatriptan using the nasal
route have not been conducted.
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 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 of up to 60 mg/kg/day. When sumatriptan
(5, 50, or 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.
Fertility studies of sumatriptan using the intranasal
route have not been conducted.
Use In Specific Populations
Pregnancy Category C
There are no adequate and well-controlled trials 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. Developmental
toxicity studies of sumatriptan by the intranasal route have not been
conducted. ONZETRA Xsail 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 rats was 60 mg/kg/day.
Oral administration of sumatriptan to pregnant rabbits during the period of
organogenesis resulted in increased incidences of embryolethality and fetal
cervicothoracic vascular and skeletal abnormalities. Intravenous administration
of sumatriptan to pregnant rabbits during the period of organogenesis resulted
in an increased incidence of embryolethality. The highest oral and intravenous
no-effect doses for developmental toxicity in rabbits were 15 and 0.75
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.
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 ONZETRA Xsail.
Safety and effectiveness has not been established in
pediatric patients younger than 18 years of age.
Two controlled clinical trials evaluated sumatriptan
nasal spray (5 to 20 mg) in 1,248 adolescent migraineurs aged 12 to 17 years
who treated a single attack. The trials did not establish the efficacy of
sumatriptan nasal spray compared with placebo in the treatment of migraine in
adolescents. Adverse reactions observed in these clinical trials were similar
in nature to those reported in clinical trials in adults.
Five controlled clinical trials (2 single-attack studies,
3 multiple-attack studies) evaluating oral sumatriptan (25 to 100 mg) in
pediatric patients aged 12 to 17 years enrolled a total of 701 adolescent
migraineurs. These studies did not establish the efficacy of oral sumatriptan
compared to placebo in the treatment of migraine in adolescents. Adverse
reactions observed in these clinical trials were similar in nature to those
reported in clinical trials in adults. The frequency of all adverse reactions
in these patients appeared to be both dose-and age-dependent, with younger
patients reporting reactions more commonly than older adolescents.
Postmarketing experience documents that serious adverse
reactions have occurred in the pediatric population after use of subcutaneous,
oral, and/or intranasal sumatriptan. These reports include reactions similar in
nature to those reported rarely in adults, including stroke, visual loss, and
death. A myocardial infarction has been reported in a 14-year-old male
following the use of oral sumatriptan; clinical signs occurred within 1 day of
drug administration. Clinical data to determine the frequency of serious adverse
reactions in pediatric patients who might receive subcutaneous, oral, or nasal
sumatriptan are not presently available.
Clinical trials of ONZETRA Xsail did not include
sufficient numbers of subjects aged 65 and over to determine whether they
respond differently from younger subjects. Other reported clinical experience
with subcutaneous, oral, and liquid nasal spray sumatriptan has not identified
differences in responses between the elderly and younger patients. In general,
treatment for an elderly patient should be cautious, reflecting the greater
frequency of decreased or abnormal hepatic function, renal function, or cardiac
function, more pronounced blood pressure increases, higher risks for
unrecognized CAD, and/or 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 ONZETRA Xsail [see WARNINGS AND PRECAUTIONS].
The clearance of oral sumatriptan was reduced in patients
with moderate hepatic impairment [see CLINICAL PHARMACOLOGY]. Similar
changes can be expected following intranasal administration. The effect of
severe hepatic impairment was NOT evaluated using oral formulation. The use of
ONZETRA Xsail in patients with severe hepatic impairment is contraindicated [see