Sumatriptan succinate-injection

Drug interactions may change how your medications work or increase your risk for serious side effects. This document does not contain all possible drug interactions. Keep a list of all the products you use (including prescription/nonprescription drugs and herbal products) and share it with your doctor and pharmacist. Do not start, stop, or change the dosage of any medicines without your doctor's approval.Taking MAO inhibitors with this medication may cause a serious (possibly fatal) drug interaction. Avoid taking MAO inhibitors (isocarboxazid, linezolid, methylene blue, moclobemide, phenelzine, procarbazine, rasagiline, selegiline, tranylcypromine) during treatment with this medication. Most MAO inhibitors should also not be taken for two weeks before treatment with this medication. Ask your doctor when to start or stop taking this medication.The risk of serotonin syndrome/toxicity increases if you are also taking other drugs that increase serotonin. Examples include street drugs such as MDMA/"ecstasy" St. John's wort, certain antidepressants (including SSRIs such as fluoxetine/paroxetine, SNRIs such as duloxetine/venlafaxine), among others. The risk of serotonin syndrome/toxicity may be more likely when you start or increase the dose of these drugs.If you also take any ergotamine medication (e.g., dihydroergotamine or methysergide) or any other "triptan" drugs (e.g., zolmitriptan, rizatriptan), you will need to separate your sumatriptan dose from your dose of these other medications in order to lessen the chance of serious side effects. Ask your doctor how long you should wait between your doses of these drugs.Also report the use of drugs which might increase seizure risk (decrease seizure threshold) when combined with sumatriptan such as isoniazid (INH), phenothiazines (e.g., thioridazine), theophylline, or tricyclic antidepressants (e.g., amitriptyline) among others. Consult your doctor or pharmacist for details.

Take this medication only as needed when a migraine occurs, as directed by your doctor. This medication should not be taken on a regular schedule. Never increase your dose of this medication or take it more often than prescribed by your doctor.

Different brands of this medication have different storage needs. Check the product package for instructions on how to store your brand, or ask your pharmacist. Do not store in the bathroom. Do not discard the auto-injector. You may use it again with refills of the prefilled syringes. However, if you are using a one-time use auto-injector, discard the auto-injector after use. If you are unsure if your auto-injector can be re-used, ask your pharmacist. Keep all medicines away from children and pets.Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company.

Reviewed on 4/16/2014 References

IMITREX Injection contains sumatriptan succinate, a selective 5-HT 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.

IMITREX Injection is a clear, colorless to pale yellow, sterile, nonpyrogenic solution for subcutaneous injection. Each 0.5 mL of IMITREX 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 IMITREX 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.

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 and cluster headaches 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.

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].

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.

Pharmacokinetics

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 C 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 halflife 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 subjects with migraine (mean age: 38 years, 25 males and 155 females) were similar to that in healthy male subjects (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 subjects compared with healthy controls. The pharmacokinetics of subcutaneously administered sumatriptan in patients with severe hepatic impairment has not been studied. The use of IMITREX Injection in this population is contraindicated [see CONTRAINDICATIONS].

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 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.

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.

Clinical Studies

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 IMITREX Injection. Lower doses of IMITREX 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 IMITREX 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 IMITREX Dos e in Study 1

Dose of IMITREX Injection	Percent Patients with Reliefa				Adverse Reactions Incidence (%)
	at 10 Minutes	at 30 Minutes	at 1 Hour	at 2 Hours
Placebo	5	15	24	21	55
1 mg	10	40	43	40	63
2 mg	7	23	57	43	63
3 mg	17	47	57	60	77
4 mg	13	37	50	57	80
6 mg	10	63	73	70	83
8 mg	23	57	80	83	93
a Relief is defined as the reduction of moderate or severe pain to no or mild pain after dosing without use of rescue medication.

In 2 randomized, placebo-controlled clinical trials of IMITREX 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 IMITREX Injection. Approximately 82% and 65% of patients treated with IMITREX 6 mg had headache relief and were pain free within 2 hours, respectively.

Table 3 shows the 1- and 2-hour efficacy results for IMITREX 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

1-Hour Data	Study 2		Study 3
	Placebo (n =190)	IMITREX 6 mg (n=384)	Placebo (n=180)	IMITREX 6 mg (n = 350)
Patients with pain relief (grade 0/1)	18%	70%a	26%	70%a
Patients with no pain	5%	48%a	13%	49%a
Patients without nausea	48%	73%a	50%	73%a
Patients without photophobia	23%	56%a	25%	58%a
Patients with little or no clinical disabilityb	34%	76%a	34%	76%a
	Study 2		Study 3
		IMITREX		IMITREX
2-Hour Data	Placeboc	6 mgd	Placeboc	6 mgd
Patients with pain relief (grade 0/1)	31%	81%a	39%	82%a
Patients with no pain	11%	63%a	19%	65%a
Patients without nausea	56%	82%a	63%	81%a
Patients without photophobia	31%	72%a	35%	71%a
Patients with little or no clinical disabilityb	42%	85%a	49%	84%a
aP < 0.05 versus placebo. bA successful outcome in terms of clinical disability was defined prospectively as ability to work mildly impaired or ability to work and function normally. cIncludes patients that may have received an additional placebo injection 1 hour after the initial injection. dIncludes patients that may have received an additional 6 mg of IMITREX Injection 1 hour after the initial injection.

IMITREX Injection also relieved photophobia, phonophobia (sound sensitivity), nausea, and vomiting associated with migraine attacks. Similar efficacy was seen when patients self-administered IMITREX Injection using the IMITREX STAT dose Pen.

The efficacy of IMITREX 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).

Cluster Headache

The efficacy of IMITREX Injection in the acute treatment of cluster headache was demonstrated in 2 randomized, double-blind, placebo-controlled, 2-period crossover trials (Studies 4 and 5). Patients 21 to 65 years of age were enrolled and were instructed to treat a moderate to very severe headache within 10 minutes of onset. Headache relief was defined as a reduction in headache severity to mild or no pain. In both trials, the proportion of individuals gaining relief at 10 or 15 minutes was significantly greater among patients receiving 6 mg of IMITREX Injection compared with those who received placebo (see Table 4).

Table 4: Proportion of Patients with Clus ter Headache Relief by Time in Studies 4 and 5

	Study 4		Study 5
	Placebo (n = 39)	IMITREX 6 mg (n = 39)	Placebo (n = 88)	IMITREX 6 mg (n = 92)
Patients with pain relief (no/mild)
5 Minutes post-injection	8%	21%	7%	23%a
10 Minutes post-injection	10%	49%a	25%	49%a
15 Minutes post-injection	26%	74%a	35%	75%a
aP < 0.05. (n = Number of headaches treated.)

An estimate of the cumulative probability of a patient with a cluster headache obtaining relief after being treated with either IMITREX Injection or placebo is presented in Figure 1.

Figure 1: Time to Relief of Cluster Headache from Time of Injectiona

aThe figure uses Kaplan-Meier (product limit) Survivorship Plot. Patients taking rescue medication were censored at 15 minutes.

The plot was constructed with data from patients who either experienced relief or did not require (request) rescue medication within a period of 2 hours following treatment. As a consequence, the data in the plot are derived from only a subset of the 258 headaches treated (rescue medication was required in 52 of the 127 placebo-treated headaches and 18 of the 131 headaches treated with IMITREX Injection).

Other data suggest that treatment with IMITREX Injection is not associated with an increase in early recurrence of headache and has little effect on the incidence of later-occurring headaches (i.e., those occurring after 2, but before 18 or 24 hours).

You should not use this medication if you are allergic to sumatriptan, or if you have:

• coronary heart disease, angina (chest pain), blood circulation problems, lack of blood supply to the heart;
• a history of heart disease, heart attack, or stroke, including "mini-stroke";
• severe or uncontrolled high blood pressure;
• severe liver disease;
• ischemic bowel disease; or
• a headache that seems different from your usual migraine headaches.

Do not use sumatriptan if you have used an MAO inhibitor such as furazolidone (Furoxone), isocarboxazid (Marplan), phenelzine (Nardil), rasagiline (Azilect), selegiline (Eldepryl, Emsam, Zelapar), or tranylcypromine (Parnate) in the last 14 days.

To make sure you can safely use sumatriptan, tell your doctor if you have any of these other conditions:

• liver disease;
• kidney disease;
• epilepsy or other seizure disorder;
• high blood pressure, a heart rhythm disorder; or
• coronary heart disease (or risk factors such as diabetes, menopause, smoking, being overweight, having high cholesterol, having a family history of coronary artery disease, being older than 40 and a man, or being a woman who has had a hysterectomy).

FDA pregnancy category C. It is not known whether sumatriptan will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medication.

Your name may need to be listed on a sumatriptan pregnancy registry when you start using this medication.

Sumatriptan can pass into breast milk and may harm a nursing baby. Do not breast-feed within 12 hours after using a sumatriptan injection. If you use a breast pump during this time, throw out any milk you collect. Do not feed it to your baby.

This medicine should not be given to anyone under 18 or over 65 years of age.

Since sumatriptan is used as needed, it does not have a daily dosing schedule. Call your doctor promptly if your symptoms do not improve after using sumatriptan.

After using a sumatriptan injection, you must wait one (1) hour before using a second injection. Do not use more than two (2) injections in 24 hours.