Sumatriptan: Package Insert and Label Information (Page 2 of 4)

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.

Cardiovascular

Hypotension, palpitations.

Neurological

Dystonia, tremor.

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 sumatriptan injection 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 sumatriptan injection in patients receiving MAO-A inhibitors is contraindicated [see Clinical Pharmacology ( 12.3)] .

7.3 Other 5-HT 1 Agonists

Because their vasospastic effects may be additive, co-administration of sumatriptan injection and other 5-HT 1 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 co-administration of triptans and SSRIs, or SNRIs, TCAs, and MAO inhibitors [see Warnings and Precautions ( 5.7)] .

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C.

There are no adequate and well-controlled trials of sumatriptan injection in pregnant women. In development 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. Sumatriptan 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 rats was 60 mg/kg/day, or approximately 100 times the single maximum recommended human dose (MRHD) of 6 mg administered subcutaneously on a mg/m 2 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/m 2 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/m 2 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/m 2 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/m 2 basis.

8.3 Nursing Mothers

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 sumatriptan injection.

8.4 Pediatric Use

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 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 patients 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 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 sumatriptan injection [see Warnings and Precautions ( 5.1)].

10 OVERDOSAGE

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)] ; 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.

11 DESCRIPTION

Sumatriptan injection 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:

Structural Formula
(click image for full-size original)

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 is a clear, colorless to pale yellow, sterile, nonpyrogenic solution for subcutaneous injection. Each 0.5 mL of sumatriptan injection 8 mg/mL solution contains 4 mg of sumatriptan (base) as the succinate salt and 3.8 mg of sodium chloride, USP in Water for Injection, USP. Each 0.5 mL of sumatriptan injection 12 mg/mL solution contains 6 mg of sumatriptan (base) as the succinate salt and 3.5 mg of sodium chloride, USP in Water for Injection, USP. The pH range of both solutions is approximately 4.2 to 5.3. The osmolality of both injections is 291 mOsmol.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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 [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 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 and Bioavailability

The bioavailability of sumatriptan via subcutaneous site injection to 18 healthy male patients 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.

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.

Specific Populations

Age
The pharmacokinetics of sumatriptan in the elderly (mean age: 72 years, 2 males and 4 females) and in patients with migraine (mean age: 38 years, 25 males and 155 females) were similar to that in healthy male patients (mean age: 30 years).

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 patients 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 [see Contraindications ( 4)] .

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

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.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

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/m 2 basis. There was no evidence in either species of an increase in tumors related to sumatriptan administration.

Mutagenesis

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 up to 60 mg/kg/day or approximately 100 times the single human dose of 6 mg on a mg/m 2 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.

13.2 Animal Toxicology and/or Pharmacology

Corneal Opacities

Dogs receiving oral sumatriptan developed corneal opacities and 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

14.1 Migraine

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.

Table 2. Proportion of Patients with Migraine Relief and Incidence of Adverse Reactions by Time and by Sumatriptan Dose in Study 1

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 Patients with Relief a Adverse Reactions Incidence (%)
at 10 Minutes at 30 Minutes at 1 Hour at 2 Hours
Placebo 1 mg 2 mg 3 mg 4 mg 6 mg 8 mg 5 10 7 17 13 10 23 15 40 23 47 37 63 57 24 43 57 57 50 73 80 21 40 43 60 57 70 83 55 63 63 77 80 83 93

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 injection 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.

Table 3. Proportion of Patients with Pain Relief and Relief of Migraine Symptoms after 1 and 2 Hours of Treatment in Studies 2 and 3

a 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
Placebo (n = 190) Sumatriptan Injection 6 mg (n = 384) Placebo (n = 180) Sumatriptan Injection 6 mg (n = 350)
Patients with pain relief (grade 0/1) Patients with no pain Patients without nausea Patients without photophobia Patients with little or no clinical disability b 18% 5% 48% 23% 34% 70% a 48% a 73% a 56% a 76% a 26% 13% 50% 25% 34% 70% a 49% a 73% a 58% a 76% a
2-Hour Data Study 2 Study 3
Placebo c Sumatriptan injection 6 mg d Placebo c Sumatriptan injection 6 mg d
Patients with pain relief (grade 0/1) Patients with no pain Patients without nausea Patients without photophobia Patients with little or no clinical disability b 31% 11% 56% 31% 42% 81% a 63% a 82% a 72% a 85% a 39% 19% 63% 35% 49% 82% a 65% a 81% a 71% a 84% a

Sumatriptan injection also relieved photophobia, phonophobia (sound sensitivity), nausea, and vomiting associated with migraine attacks. Similar efficacy was seen when patients self-administered sumatriptan injection using the sumatriptan injection autoinjector.

The efficacy of sumatriptan injection was unaffected by whether or not the migraine was associated with aura, duration of attack, gender or age of the patient, or concomitant use of common migraine prophylactic drugs (e.g., beta-blockers).

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