ZEMBRACE SymTouch (sumatriptan) injection, solution
Promius Pharma, LLC
1 INDICATIONS AND USAGE
ZEMBRACE SymTouch is indicated for the acute treatment of migraine with or without aura in adults.
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 ZEMBRACE SymTouch, reconsider the diagnosis before ZEMBRACE SymTouch is administered to treat any subsequent attacks.
- ZEMBRACE SymTouch injection is not indicated for the prevention of migraine attacks.
ZEMBRACE SymTouch is a serotonin (5-HT1B/1D) receptor agonist (triptan) indicated for:
- Acute treatment of migraine with or without aura in adults (1)
- Use only if a clear diagnosis of migraine has been established. (1)
- Not indicated for the prophylactic therapy of migraine. (1)
2 DOSAGE AND ADMINISTRATION
- For subcutaneous use only. (2.1)
- Acute treatment of migraine: 3 mg Single dose. (2.1)
- Maximum dose in a 24-hour period: 12 mg. Separate doses by at least 1 hour. (2.1)
2.1 Dosing Information
The recommended dose of ZEMBRACE SymTouch is 3 mg injected subcutaneously.
The maximum cumulative injected dose that may be given in 24 hours is 12 mg, with doses of ZEMBRACE SymTouch separated by at least 1 hour. ZEMBRACE SymTouch may also be given at least 1 hour following a dose of another sumatriptan product.
2.2 Administration Using ZEMBRACE SymTouch
ZEMBRACE SymTouch is available as a prefilled, ready-to-use, single dose, disposable auto-injector containing 3 mg sumatriptan. With ZEMBRACE SymTouch, the needle penetrates approximately ¼ inch (6 mm). The injection is intended to be given subcutaneously. Do not administer by any other route. Instruct patients on the proper use of ZEMBRACE SymTouch and direct them to use injection sites with an adequate skin and subcutaneous thickness to accommodate the length of the needle.
3 DOSAGE FORMS AND STRENGTHS
Injection: 3 mg sumatriptan in 0.5 mL prefilled, ready-to-use, single dose, disposable auto-injector.
- Injection: 3-mg prefilled, ready-to use, single-dose disposable autoinjector. (3)
ZEMBRACE SymTouch 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 [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 (i.e., within 24 hours) use of ergotamine-containing medication, ergot-type medication (such as dihydroergotamine or methysergide), or another 5-hydroxytryptamine1 (5-HT1) agonist [see Drug Interactions (7.1, 7.3)].
- Concurrent administration of an MAO-A inhibitor or recent (within 2 weeks) use of an MAO-A inhibitor [see Drug Interactions (7.2) and Clinical Pharmacology (12.3)].
- Known 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-HT1 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)
5 WARNINGS AND PRECAUTIONS
- Myocardial ischemia/infarction and Prinzmetal’s angina: Perform cardiac evaluation in patients with multiple cardiovascular risk factors. (5.1)
- Arrhythmias: Discontinue ZEMBRACE SymTouch if occurs. (5.2)
- 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)
- Cerebral hemorrhage, subarachnoid hemorrhage, and stroke: Discontinue ZEMBRACE SymTouch if occurs. (5.4)
- Gastrointestinal ischemia and reactions, peripheral vasospastic reactions: Discontinue ZEMBRACE SymTouch if occurs. (5.5)
- Medication overuse headache: Detoxification may be necessary. (5.6)
- Serotonin syndrome: Discontinue ZEMBRACE SymTouch if occurs. (5.7)
- Seizures: Use with caution in patients with epilepsy or a lowered seizure threshold. (5.10)
5.1 Myocardial Ischemia, Myocardial Infarction, and Prinzmetal’s Angina
The use of ZEMBRACE SymTouch injection is contraindicated in patients with ischemic or vasospastic CAD. There have been rare reports of serious cardiac adverse reactions, including acute myocardial infarction, occurring within a few hours following administration of sumatriptan injection. Some of these reactions occurred in patients without known CAD. 5-HT1 agonists, including ZEMBRACE SymTouch 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 ZEMBRACE SymTouch injection. If there is evidence of CAD or coronary artery vasospasm, ZEMBRACE SymTouch injection is contraindicated. For patients with multiple cardiovascular risk factors who have a negative cardiovascular evaluation, consider administering the first dose of ZEMBRACE SymTouch injection in a medically supervised setting and performing an electrocardiogram (ECG) immediately following ZEMBRACE SymTouch injection. For such patients, consider periodic cardiovascular evaluation in intermittent long-term users of ZEMBRACE SymTouch 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 ZEMBRACE SymTouch injection if these disturbances occur. ZEMBRACE SymTouch injection is contraindicated in patients with Wolff-Parkinson-White syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders.
5.3 Chest, Throat, Neck, and/or Jaw Pain/Tightness/Pressure
Sensations of tightness, pain, pressure, and heaviness in the precordium, throat, neck, and jaw commonly occur after treatment with sumatriptan injection and are usually non-cardiac in origin. However, perform a cardiac evaluation if these patients are at high cardiac risk. The use of ZEMBRACE SymTouch injection is contraindicated in patients with CAD and those with Prinzmetal’s variant angina.
5.4 Cerebrovascular Events
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 ZEMBRACE SymTouch injection 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. ZEMBRACE SymTouch injection is contraindicated in patients with a history of stroke or TIA.
5.5 Other Vasospasm Reactions
ZEMBRACE SymTouch 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 ZEMBRACE SymTouch 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.
5.6 Medication Overuse Headache
Overuse of acute migraine drugs (e.g., ergotamine, triptans, opioids, 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.
5.7 Serotonin Syndrome
Serotonin syndrome may occur with ZEMBRACE SymTouch injection, 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 ZEMBRACE SymTouch injection if serotonin syndrome is suspected.
5.8 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 ZEMBRACE SymTouch. ZEMBRACE SymTouch injection is contraindicated in patients with uncontrolled hypertension.
5.9 Hypersensitivity Reactions
Hypersensitivity 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. ZEMBRACE SymTouch injection is contraindicated in patients with a history of hypersensitivity reaction to sumatriptan.
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. ZEMBRACE SymTouch injection should be used with caution in patients with a history of epilepsy or conditions associated with a lowered seizure threshold.
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)]
Most common adverse reactions (≥5% and > placebo) were injection site reactions, tingling, dizziness/vertigo, warm/hot sensation, burning sensation, feeling of heaviness, pressure sensation, flushing, feeling of tightness, and numbness/paresthesia. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Promius Pharma, LLC. at 1-888-966-8766 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
Migraine Headache: Table 1 lists adverse reactions that occurred in 2 US placebo-controlled clinical trials in migraine subjects (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.
|a Includes injection site pain, stinging/burning, swelling, erythema, bruising, bleeding.|
|Adverse Reaction||Percent of Subjects Reporting|
Injection 6 mg
(n = 547)
(n = 370)
Feeling of heaviness
Feeling of tightness
Tight feeling in head
Tightness in chest
Pressure in chest
|Ear, nose, and throat
Discomfort: nasal cavity/sinuses
|Injection site reactiona||59||24|
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 a Study with ZEMBRACE SymTouch
The most common adverse reactions in a placebo-controlled trial with ZEMBRACE SymTouch were injection site reactions (including injection site bruising, erythema, hemorrhage, induration, irritation, pain, paresthesia, pruritis, swelling, and urticaria), occurring in 30% of ZEMBRACE SymTouch-treated patients compared to 13% of placebo-treated patients. Adverse reactions with ZEMRACE SymTouch are expected to be similar to those observed with sumatriptan injection.
6.2 Postmarketing Experience
The following adverse reactions have been identified during postapproval use of sumatriptan tablets, sumatriptan nasal spray, and sumatriptan injection. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
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 ZEMBRACE SymTouch 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 ZEMBRACE SymTouch injection in patients receiving MAO-A inhibitors is contraindicated [see Clinical Pharmacology (12.3)].
7.3 Other 5-HT1 Agonists
Because their vasospastic effects may be additive, coadministration of ZEMBRACE SymTouch injection and other 5-HT1 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 coadministration of triptans and SSRIs, SNRIs, TCAs, and MAO inhibitors [see Warnings and Precautions (5.7)].
8 USE IN SPECIFIC POPULATIONS
- Pregnancy: Based on animal data, may cause fetal harm. (8.1)
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 embryolethality, fetal abnormalities, and pup mortality. When administered by the intravenous route to pregnant rabbits, sumatriptan was embryolethal (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.
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.
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 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, 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.
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 ZEMBRACE SymTouch and any potential adverse effects on the breastfed infant from sumatriptan or from the underlying maternal condition.
Infant exposure to sumatriptan can be minimized by avoiding breastfeeding for 12 hours after treatment with ZEMBRACE SymTouch.
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 in pediatric patients have not been established. ZEMBRACE SymTouch injection is not recommended for use in patients younger than 18 years of age.
Two controlled clinical trials evaluated sumatriptan 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 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 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.
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 intranasal sumatriptan are not presently available.
8.5 Geriatric Use
Clinical trials of sumatriptan injection 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 ZEMBRACE SymTouch injection [see Warnings and Precautions (5.1)].
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 ZEMBRACE SymTouch 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.
ZEMBRACE SymTouch injection contains sumatriptan succinate, a selective 5-HT1B/1D receptor agonist. Sumatriptan succinate is chemically designated as 3-[2-(dimethylamino) ethyl]-N- methyl-indole-5-methanesulfonamide succinate (1:1), and it has the following structure:
The empirical formula is C14H21N3O2S•C4H6O4, representing a molecular weight of 413.5. Sumatriptan succinate is a white to off-white powder that is readily soluble in water and in saline.
ZEMBRACE SymTouch is a clear, colorless to pale yellow, sterile, nonpyrogenic solution for subcutaneous injection. Each 0.5 mL of ZEMBRACE SymTouch contains 4.2 mg of sumatriptan succinate equivalent to 3-mg of sumatriptan (base) and 4.15 mg of sodium chloride, USP in Water for Injection, USP.
The pH range of solution is approximately 4.2 to 5.3 and the osmolality of injection is approximately 291 mOsmol (275 to 315 mOsmol).
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Sumatriptan binds with high affinity to human cloned 5-HT1B/1D receptors. Sumatriptan presumably exerts its therapeutic effects in the treatment of migraine headache through agonist effects at the 5-HT1B/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.
Blood Pressure: Significant elevation in blood pressure, including hypertensive crisis, has been reported in patients with and without a history of hypertension [see Warnings and Precautions (5.8)].
Peripheral (Small) Arteries: In healthy volunteers (N = 18), a trial evaluating the effects of sumatriptan on peripheral (small vessel) arterial reactivity failed to detect a clinically significant increase in peripheral resistance.
Heart Rate: Transient increases in blood pressure observed in some subjects in clinical trials carried out during sumatriptan’s development as a treatment for migraine were not accompanied by any clinically significant changes in heart rate.
After a single 3-mg dose, ZEMBRACE SymTouch was bioequivalent to IMITREX subcutaneous injection.
Absorption and Bioavailability: 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 auto-injector techniques. The Tmax or amount absorbed was not significantly altered by either the site or technique of injection.
Distribution: Protein binding, determined by equilibrium dialysis over the concentration range of 10 to 1,000 ng/mL, is low, approximately 14% to 21%. The effect of sumatriptan on the protein binding of other drugs has not been evaluated.
Following a 6-mg subcutaneous injection into the deltoid area of the arm in 9 males (mean age: 33 years, mean weight: 77 kg) the volume of distribution central compartment of sumatriptan was 50 ± 8 liters and the distribution half-life was 15 ± 2 minutes.
Metabolism: In vitro studies with human microsomes suggest that sumatriptan is metabolized by MAO, predominantly the A isoenzyme. Most of a radiolabeled dose of sumatriptan excreted in the urine is the major metabolite indole acetic acid (IAA) or the IAA glucuronide, both of which are inactive.
Elimination: After a single 6-mg subcutaneous dose, 22% ± 4% was excreted in the urine as unchanged sumatriptan and 38% ± 7% as the IAA metabolite.
Following a 6-mg subcutaneous injection into the deltoid area of the arm, the systemic clearance of sumatriptan was 1,194 ± 149 mL/min and the terminal half-life was 115 ± 19 minutes.
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 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 ZEMBRACE SymTouch injection in this population is contraindicated [see Contraindications (4)].
Race: The systemic clearance and Cmax of subcutaneous sumatriptan were similar in black (n = 34) and Caucasian (n = 38) healthy male subjects.
Drug Interaction Studies:
Monoamine Oxidase-A Inhibitors: In a trial of 14 healthy females, pretreatment with an MAO-A inhibitor decreased the clearance of sumatriptan, resulting in a 2-fold increase in the area under the sumatriptan plasma concentration-time curve (AUC), corresponding to a 40% increase in elimination half-life.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
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 high dose in rat was reduced from 360 mg/kg/day during Week 21). The highest dose tested in mice and rats was approximately 130 and 260 times, respectively, 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.
Impairment of Fertility
When sumatriptan (0, 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.
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 opacitiesand 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; however, the relative plasma exposure at the lowest dose tested was approximately 3 times the human exposure after a 6-mg subcutaneous dose.
14 CLINICAL STUDIES
Clinical Studies with Sumatriptan Injection
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.
|a Relief is defined as the reduction of moderate or severe pain to no or mild pain after dosing without use of rescue medication|
|Dose of Sumatriptan Injection||Percent Subjects With Relief a||Adverse Events Incidence (%)|
|at 10 Minutes||at 30 Minutes||at 1 Hour||at 2 Hours|
In 2 randomized, placebo-controlled clinical trials of sumatriptan injection 6 mg in 1,104 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.
P<0.05 versus placebo.
b A successful outcome in terms of clinical disability was defined prospectively as ability to work mildly impaired or ability to work and function normally.
c Includes patients that may have received an additional placebo injection 1 hour after the initial Injection.
d Includes patients that may have received an additional 6 mg of sumatriptan injection 1 hour after the initial injection.
|1-Hour Data||Study 2||Study 3|
(n = 190)
(n = 384)
(n = 180)
(n = 350)
|Subjects with pain relief
|Subjects with no pain||5%||48%a||13%||49%a|
|Subjects without nausea||48%||73%a||50%||73%a|
|Subjects without photophobia||23%||56%a||25%||58%a|
|Subjects with little or no clinical disabilityb||34%||76%a||34%||76%a|
|2-Hour Data||Study 2||Study 3|
|Subjects with pain relief (grade 0/1)||31%||81%a||39%||82%a|
|Subjects with no pain||11%||63%a||19%||65%a|
|Subjects without nausea||56%||82%a||63%||81%a|
|Subjects without photophobia||31%||72%a||35%||71%a|
|Subjects with little or no clinical disabilityb||42%||85%a||49%||84%a|
Sumatriptan injection also relieved photophobia, phonophobia (sound sensitivity), nausea, and vomiting associated with migraine attacks.
The efficacy of sumatriptan injections was unaffected by whether or not the migraine was associated with aura, duration of attack, gender or age of the subject, or concomitant use of common migraine prophylactic drugs (e.g., beta-blockers).
Clinical Study with ZEMBRACE SymTouch
In a double-blind, randomized, placebo-controlled clinical trial of ZEMBRACE SymTouch, 230 patients with migraine with or without aura received either ZEMBRACE SymTouch (N=111) or placebo (N=119) for a single migraine attack. The patients had a mean age of 41 years (range 18 to 65 years); approximately 76% were White and 85% were female.
The study excluded patients with medication overuse headache, treatment with onabotulinumtoxin A within 180 days, and patients with a history of cluster headache.
The primary efficacy endpoint was the proportion of patients who were pain-free (defined as a reduction from pre-dose moderate [Grade 2] or severe [Grade 3] pain to none [Grade 0]) 2 hours after the first dose. Of the ZEMBRACE SymTouch-treated patients, 46% were pain free at 2 hours after treatment compared to 27% of the placebo-treated patients.
16 HOW SUPPLIED/STORAGE AND HANDLING
16.1 How Supplied
- ZEMBRACE SymTouch 3 mg/0.5 mL Injection contains sumatriptan as the succinate salt and is supplied as a clear, colorless to pale yellow, sterile, nonpyrogenic solution in a prefilled, ready-to-use, single dose, disposable auto-injector unit (NDC # 67857-809-37).
- Each carton contains 4 units (NDC # 67857-809-38) and a Patient Information and Instructions for Use leaflet.
16.2 Storage and Handling
Store between 20°C and 25°C (68°F and 77°F) Excursions permitted between 15°C and 30°C (59°F and 86°F).
Protect from light.
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 ZEMBRACE SymTouch injection may cause serious cardiovascular side effects such as myocardial infarction or stroke. Although serious cardiovascular events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, irregular heartbeat, significant rise in blood pressure, weakness, and slurring of speech and should ask for medical advice when observing any indicative sign or symptoms are observed. Apprise patiens of the importance of this follow-up [see Warnings and Precautions (5.1, 5.2, 5.4, 5.5, 5.8)].
Inform patients that anaphylactic reactions have occurred in patients receiving sumatriptan injection. Such reactions can be life threatening or fatal. In general, anaphylactic reactions to drugs are more likely to occur in individuals with a history of sensitivity to multiple allergens [see Contraindications (4) and Warnings and Precautions (5.9)].
Concomitant Use with Other Triptans or Ergot Medications
Inform patients that use of ZEMBRACE SymTouch injection 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)].
Caution patients about the risk of serotonin syndrome with the use of ZEMBRACE SymTouch injection 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)].
Advise patients to notify their healthcare provider if they become pregnant during treatment or plan to become pregant [see Use in Specific Population (8.1)].
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 ZEMBRACE SymTouch injection may cause somnolence and dizziness; instruct patients to evaluate their ability to perform complex tasks during migraine attacks and after administration of ZEMBRACE SymTouch injection.
How to Use ZEMBRACE SymTouch
Provide patients instruction on the proper use of ZEMBRACE SymTouch injection if they are able to self-administer ZEMBRACE SymTouch injection in medically unsupervised conditions.
Inform patients that the needle in the ZEMBRACE SymTouch penetrates approximately ¼ of an inch (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.
ZEMBRACE and SymTouch are registered trademarks of Dr. Reddy’s Laboratories Limited
Manufactured for: Dr. Reddy’s Laboratories Limited
by Ajinomoto Althea Inc., San Diego, CA 92121
Distributed by: Promius Pharma, LLC, Princeton, NJ 08540
What is the most important information I should know about ZEMBRACE SymTouch?
ZEMBRACE SymTouch 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:
What is ZEMBRACE SymTouch?
ZEMBRACE SymTouch is a prescription medicine used to treat acute migraine headaches with or without aura in adults who have been diagnosed with migraine.
ZEMBRACE SymTouch 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.
ZEMBRACE SymTouch is not used to prevent or decrease the number of migraine you have. It is not known if ZEMBRACE SymTouch is safe and effective in children under 18 years of age.
Who should not take ZEMBRACE SymTouch?
Do not take ZEMBRACE SymTouch if you have:
Ask your healthcare provider if you are not sure if your medicine is listed above.
What should I tell my healthcare provider before taking ZEMBRACE SymTouch?
Before taking ZEMBRACE SymTouch, tell your healthcare provider about all of your medical conditions, including if you:
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.
Using ZEMBRACE SymTouch with certain other medicines can affect each other, causing serious side effects.
Especially tell your healthcare provider if you take anti-depressant medicines called:
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 ZEMBRACE SymTouch?
What should I avoid while taking ZEMBRACE SymTouch?
ZEMBRACE SymTouch 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 ZEMBRACE SymTouch?
See “What is the most important information I should know about Zembrace SymTouch?” ZEMBRACE SymTouch may cause serious side effects, including:
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 ZEMBRACE SymTouch. 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 ZEMBRACE SymTouch?
Keep ZEMBRACE SymTouch and all medicines out of the reach of children.
General information about the safe and effective use of ZEMBRACE SymTouch.
Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflets. Do not use ZEMBRACE SymTouch for a condition for which it was not prescribed. Do not give ZEMBRACE SymTouch to other people, even if they have the same symptoms you have. It may harm them.
This Patient Information leaflet summarizes the most important information about ZEMBRACE SymTouch. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about ZEMBRACE SymTouch that is written for healthcare professionals.
For more information, go to www.drreddys.com or call 1-888-966-8766.
What are the ingredients in ZEMBRACE SymTouch Injection?
Active ingredient: sumatriptan succinate
Inactive ingredients: sodium chloride, water for injection
ZEMBRACE and SymTouch are registered trademarks of Dr. Reddy’s Laboratories Limited
Manufactured for: Dr. Reddy’s Laboratories Limited; by Ajinomoto Althea, Inc., San Diego, CA 92121
Distributed by: Promius Pharma, LLC., Princeton, NJ 08540
|This Patient Information has been approved by the U.S. Food and Drug Administration.||Revised: Jun 2019|
Instructions for Use
ZEMBRACE™ SymTouch™ (Zem-brace Sim-Touch)
| Read this Instructions for Use before you start to use the ZEMBRACE™ SymTouch™. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or treatment. You and your healthcare provider should talk about ZEMBRACE SymTouch when you start taking it and at regular checkups.
The ZEMBRACE SymTouch Autoinjector is a single-use, pre-filled injection device with the exact dose you need.
The device should be used only 1 time and then discarded.
Keep out of reach of children.
Do not use after the expiration date has passed.
Do not store or expose to high temperatures.
Do not freeze.
Do not remove the Red Cap until you are ready to inject.
Do not use if dropped after removing the Red Cap.
Do not put or press thumb, fingers or hand over the Yellow Needle Guard.
Step 1 – Inspect Autoinjector and Gather Supplies
1A- Remove Autoinjector from the carton.
1B – Check the Expiration Date on the Autoinjector
Do not use if the expiration date has passed.
1C – Inspect the medicine through the Medicine Viewing Window
Inspect the appearance of ZEMBRACE SymTouch Autoinjector medicine through the medicine window. It must be a clear, colorless to pale yellow solution.
Do not inject the medicine if the solution looks discolored or cloudy or contains lumps, flakes, or particles.
1D – Gather the following supplies
Step 2 – Choose and Prepare Your Injection Site
2A - Choose your injection site
The recommended injection sites are the sides of the thighs and the arms.
Caution: Do not inject where your skin is scarred, bruised, tender, red or near any open wound.
2B – Clean the injection site with an alcohol swab
Do not touch injection site area after cleaning.
2C - Remove the Red Cap
Hold the body of the Autoinjector in one hand and pull the Red Cap straight off.
Warning: Do not put or press thumb, fingers or hand over the Yellow Needle Guard, doing so may result in a needle stick injury.
Step 3 – Inject the Medicine
3A – Place Autoinjector straight on your injection site
Place the Autoinjector straight on your injection site (90 degrees) with the Yellow Needle Guard end gently pressed against your skin.
3B - Perform Injection
Press and hold the Autoinjector down against your skin. You will hear the first “Click 1” as the injection starts. Continue to hold the device down until you hear the second “Click 2.”
Wait 5 seconds before you remove the Autoinjector!
After “Click 2,” continue to hold down and slowly count to 5 to make sure you receive your full dose.
Important: To receive your full dose, always hold the Autoinjector down on your injection site for additional time after you hear the second click. This allows all of the medicine to be delivered.
3C - Remove Autoinjector from skin
Remove the Autoinjector by lifting it straight away from your skin. The Yellow Needle Guard will drop down and lock over the needle.
Step 4 – Confirm Injection and Dispose the Autoinjector
4A - Confirm Red Color in Medicine Viewing Window
Look to confirm that the Red Plunger Rod has filled the Medicine Viewing Window. This means you received the full dose.
Caution: Call your healthcare provider if the Red Plunger Rod has not filled the Medicine Viewing Window. This may mean that only a partial dose was delivered.
Do not try to reuse the Autoinjector.
4B Disposal of the Autoinjector
Put your used Autoinjector, caps, needles, and sharps in an FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) loose needles and syringes in your household trash. Do not recycle your used sharps disposal container.
If you do not have a FDA-cleared sharps disposal container, you may use a household container that is: made of a heavy-duty plastic; can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out; upright and stable during use; leak-resistant; and properly labeled to warn of hazardous waste inside the container.
When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA’s website at: http://www.fda.gov/safesharpsdisposal.
Do not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container.
If needed, make sure you get a refill of your Autoinjector.
4C - Treat Injection Site
Treat the injection site with a cotton ball, gauze pad or bandage, as needed.
Do not rub the injection site.
ZEMBRACE SymTouch are registered trademarks of Dr. Reddy’s Laboratories, Ltd.
This Instructions for Use has been approved by the U.S. Food and Drug Administration. Mar 2017
PRINCIPAL DISPLAY PANEL - NDC: 67857-809-37 - Autoinjector Label
PRINCIPAL DISPLAY PANEL - NDC: 67857-809-38 - 4-count Carton Label (Partition)
PRINCIPAL DISPLAY PANEL - NDC: 67857-809-38 - 4-count Carton Label (Interior)
PRINCIPAL DISPLAY PANEL - NDC: 67857-809-38 - 4-ct Carton Label (Exterior)