MIGREX

Sumatriptan injection, USP contains sumatriptan succinate, a selective 5-HT 1B/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 C 14 H 21 N 3 O 2 S•C 4 H 6 O 4, 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.

Sumatriptan injection, USP is a clear, colorless to pale yellow, sterile, nonpyrogenic solution for subcutaneous injection.

Each 0.5 mL of sumatriptan injection USP, 12 mg/mL solution contains 8.4 mg of sumatriptan succinate equivalent to 6 mg of sumatriptan and 3.5 mg of sodium chloride, USP in water for injection, USP.

The pH range of the solution is approximately 4.2 to 5.3.

The osmolality of the injection is 291 mOsmol. sumatriptan-image01.

Injection, USP is indicated in adults for the acute treatment of migraine, with or without aura, and 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 attack treated with Sumatriptan Injection reconsider the diagnosis before Sumatriptan Injection is administered to treat any subsequent attacks.

• Sumatriptan Injection is not indicated for the prevention of migraine attacks or cluster headache attacks.

• Acute treatment of migraine with or without aura in adults.

• Not indicated for the prophylactic therapy of migraine or cluster headache attacks.

Diabetes Menopausal woman

Male over 40 Hypersensitivity to sulphonamides Mild to moderate hepatic impairment Renal impairment Atypical migraine Basil migraine Hemiplegic migraine Ophthalmoplegic migraine Cerebrovascular pathology Patients at risk for coronary artery failure Elderly Subject at risk of seizure Subject at risk of cardiovascular disease Subject under 18 Smoking Extended treatment Repeated treatment.

Sumatriptan binds with high affinity to human cloned 5-HT 1B/1D receptors.

Sumatriptan presumably exerts its therapeutic effects in the treatment of migraine and cluster headaches through agonist effects at the 5-HT 1B/1D receptors on intracranial blood vessels and sensory nerves of the trigeminal system, which result in cranial vessel constriction and inhibition of pro-inflammatory neuropeptide release. 12.2 Pharmacodynamics Blood Pressure Significant elevation in blood pressure, including hypertensive crisis, has been reported in patients with and without a history of hypertension.

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.

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. 12.3 Pharmacokinetics Absorption 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 (C max ) of sumatriptan was (mean ± standard deviation) 74 ± 15 ng/mL and the time to peak concentration (T max ) was 12 minutes after injection (range: 5 to 20 minutes).

In this trial, the same dose injected subcutaneously in the thigh gave a C max of 61 ± 15 ng/mL by manual injection versus 52 ± 15 ng/mL by autoinjector techniques.

T max 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 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 sumatriptan injection in this population is contraindicated.

The systemic clearance and C max 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 subcutaneous sumatriptan, resulting in a 2-fold increase in the area under the sumatriptan plasma concentration-time curve (AUC), corresponding to a 40% increase in elimination half-life.

Sumatriptan is a selective agonist of the vascular receptors at 5-hydroxytryptamine-1 (5HT 1d) without effect on other 5HT receptor subtypes (5HT 2-5HT 7). 5HT 1d vascular receptors are located primarily in the cranial blood vessels and induce vasoconstriction.

Sumatriptan is responsible for selective vasoconstriction of carotid arterial circulation.

Carotid arterial circulation vasculizes extracranial and intracranial tissues such as meninges.

It is believed that dilation and/or edema formation at these vessels may be consistent with the mechanism of migraine in humans.

Furthermore, the results of studies in animals indicate that sumatriptan inhibits the activity of trijumal nerve.

Both these actions (cranial vasoconstriction and inhibition of human trijumal activity) may contribute to the anti-seminar activity of the human trijumal.

• Liver status (abnormality) (Very rare)
• Hyperhidrosis Urticaria Allergic dermatitis
• Pain (Common)
• Coldness (Common)
• Weakness (Common)
• Feeling heavy (Common)
• Heat sensation (Common)
• Fatigue (Common)
• Feeling heavy in the chest Anaphylactic reaction Hypersensitivity
• Traumatic pain caused Inflammatory pain caused Dysphagia Scotome Papillotation Visual acuity (decrease)
• Blindness Diplopia Nystagmus Vision disorder Vertigo (Common)
• Feeling heavy in the throat
• Sighted throat Anxiety Congestive puff (Common)
• Blood pressure (increase) (Common)
• Palpitation Myocardial infarction Tachycardia Arrhythmia Electrocardiogram anomaly
• Angor Hypotension Raynaud's syndrome Bradycardia Coronary Vasospasm Nausea (Common)
• Vomiting (Common)
• Ischemic colitis Diarrhoea Muscle pain (Common)
• Joint pain Neurosensory disorder (Common)
• Somnolence (Common)
• Redhead Paraesthesia Hypoesthesia Trembling Convulsions Dystonia
• Dyspnoea (Common)
• Sensation of chest oppression (Common).

Coronary vasospasm was observed after intravenous administration of sumatriptan 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 sumatriptan 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.

• 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-HT 1 ) agonist.

• Concurrent administration of a monoamine oxidase (MAO)-A inhibitor or recent (within 2 weeks) use of an MAO-A inhibitor.

• Hypersensitivity to sumatriptan (angioedema and anaphylaxis seen) .

• Severe hepatic impairment.

• History of coronary artery disease or coronary artery vasospasm.

• Wolff-Parkinson-White syndrome or other cardiac accessory conduction pathway disorders.

• History of stroke, transient ischemic attack, or hemiplegic or basilar migraine.

• Recent (within 24 hours) use of another 5-HT 1 agonist (e.g., another triptan) or of an ergotamine-containing medication.

• Concurrent or recent (past 2 weeks) use of monoamine oxidase-A inhibitor.

• Hypersensitivity to Sumatriptan Injection (angioedema and anaphylaxis seen).

• For subcutaneous use only.

• Acute treatment of migraine: single dose of to 6 mg.

• Acute treatment of cluster headache: single dose of 6 mg.

• Maximum dose in a 24-hour period: 12 mg, separate doses by at least 1 hour.

• Patients receiving doses other than 4 or 6 mg: Use the 6-mg single-dose vial 2.1 Dosing Information The maximum single recommended adult dose of Sumatriptan injection, USP 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. 2.3 Administration of Doses of Sumatriptan Other than 4 or 6 mg In patients receiving doses other than 4mg or 6 mg, use the 6-mg single-dose vial; Visually inspect the vial for particulate matter and discoloration before administration.

Do not use if particulates and discolorations are noted.

Sumtriptan injection, USP contains sumatriptan (base) as the succinate salt and is supplied as a clear, colorless to pale yellow, sterile, nonpyrogenic solution as follows: Sumtriptan injection, USP single-dose vial (6 mg/0.5 mL) in carton containing 5 vials (NDC 65145-118-05).

Store between 2° and 30°C (36° and 86°F).

Protect from light.

Retain in carton until time of use.

Discard unused portion.

Data from a prospective pregnancy exposure registry and epidemiological studies of pregnant women have not detected an increased frequency of birth defects or a consistent pattern of birth defects among women exposed to sumatriptan compared with the general population.

In 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.

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.

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 to September 2012.

Registry documented outcomes of 626 infants and foetuses 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 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.

Safety and effectiveness in pediatric patients have not been established. sumatriptan 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 aged 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 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 patients aged to 17 years 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.

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.

Clinical trials of sumatriptan injection did not include sufficient numbers of patients aged 65 years 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 sumatriptan injection.