Imitrex Injection (Sumatriptan Succinate Injection) - Description and Clinical Pharmacology

DESCRIPTION

IMITREX (sumatriptan succinate) Injection is a selective 5-hydroxytryptamine₁ receptor subtype agonist. Sumatriptan succinate is chemically designated as 3-[2-(dimethylamino)ethyl]-N-methyl-indole-5-methanesulfonamide succinate (1:1).

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 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 the solution is approximately 4.2 to 5.3. The osmolality of the injection is 291 mOsmol.

CLINICAL PHARMACOLOGY

Mechanism of Action:    Sumatriptan has been demonstrated to be a selective agonist for a vascular 5-hydroxytryptamine₁ receptor subtype (probably a member of the 5-HT_1D family) with no significant affinity (as measured using standard radioligand binding assays) or pharmacological activity at 5-HT₂, 5-HT₃ receptor subtypes or at alpha₁-, alpha₂-, or beta-adrenergic; dopamine₁; dopamine₂; muscarinic; or benzodiazepine receptors.

The vascular 5-HT₁ receptor subtype to which sumatriptan binds selectively, and through which it presumably exerts its antimigrainous effect, has been shown to be present on cranial arteries in both dog and primate, on the human basilar artery, and in the vasculature of the isolated dura mater of humans. In these tissues, sumatriptan activates this receptor to cause vasoconstriction, an action in humans correlating with the relief of migraine and cluster headache. In the anesthetized dog, sumatriptan selectively reduces the carotid arterial blood flow with little or no effect on arterial blood pressure or total peripheral resistance. In the cat, sumatriptan selectively constricts the carotid arteriovenous anastomoses while having little effect on blood flow or resistance in cerebral or extracerebral tissues.

Corneal Opacities:    Dogs receiving oral sumatriptan developed corneal opacities and defects in the corneal epithelium. Corneal opacities were seen at the lowest dosage 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 exposure at the lowest dose tested was approximately 5 times the human exposure after a 100-mg oral dose or 3 times the human exposure after a 6-mg subcutaneous dose.

Melanin Binding:    In rats with a single subcutaneous dose (0.5 mg/kg) of radiolabeled sumatriptan, the elimination half-life of radioactivity from the eye was 15 days, suggesting that sumatriptan and its metabolites bind to the melanin of the eye. The clinical significance of this binding is unknown.

Pharmacokinetics:    Pharmacokinetic parameters following a 6-mg subcutaneous injection into the deltoid area of the arm in 9 males (mean age, 33 years; mean weight, 77 kg) were systemic clearance: 1,194 ± 149 mL/min (mean ± S.D.), distribution half-life: 15 ± 2 minutes, terminal half-life: 115 ± 19 minutes, and volume of distribution central compartment: 50 ± 8 liters. Of this dose, 22% ± 4% was excreted in the urine as unchanged sumatriptan and 38% ± 7% as the indole acetic acid metabolite.

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) 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 study, 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. The T_max or amount absorbed was not significantly altered by either the site or technique of injection.

The bioavailability of sumatriptan via subcutaneous site injection to 18 healthy male subjects was 97% ± 16% of that obtained following intravenous injection. 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.

Special Populations: Renal Impairment:    The effect of renal impairment on the pharmacokinetics of sumatriptan has not been examined, but little clinical effect would be expected as sumatriptan is largely metabolized to an inactive substance.

Hepatic Impairment:    The effect of hepatic disease on the pharmacokinetics of subcutaneously and orally administered sumatriptan has been evaluated. There were no statistically significant differences in the pharmacokinetics of subcutaneously administered sumatriptan in hepatically impaired patients compared to healthy controls. However, the liver plays an important role in the presystemic clearance of orally administered sumatriptan. Accordingly, the bioavailability of sumatriptan following oral administration may be markedly increased in patients with liver disease. In 1 small study of hepatically impaired patients (n = 8) matched for sex, age, and weight with healthy subjects, the hepatically impaired patients had an approximately 70% increase in AUC and C_max and a T_max 40 minutes earlier compared to the healthy subjects.

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 subjects (mean age, 30 years) (see PRECAUTIONS: Geriatric Use).

Race:    The systemic clearance and C_max of sumatriptan were similar in black (n = 34) and Caucasian (n = 38) healthy male subjects.

Drug Interactions: Monoamine Oxidase Inhibitors:    In vitro studies with human microsomes suggest that sumatriptan is metabolized by monoamine oxidase (MAO), predominantly the A isoenzyme. In a study of 14 healthy females, pretreatment with MAO-A inhibitor decreased the clearance of sumatriptan. Under the conditions of this experiment, the result was a 2-fold increase in the area under the sumatriptan plasma concentration × time curve (AUC), corresponding to a 40% increase in elimination half-life. No significant effect was seen with an MAO-B inhibitor.

PHARMACODYNAMICS:

TYPICAL PHYSIOLOGIC RESPONSES:

Blood Pressure:   (see WARNINGS)

Peripheral (small) Arteries:   In healthy volunteers (n = 18), a study 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 studies carried out during sumatriptan's development as a treatment for migraine were not accompanied by any clinically significant changes in heart rate.

Respiratory Rate:   Experience gained during the clinical development of sumatriptan as a treatment for migraine failed to detect an effect of the drug on respiratory rate.

CLINICAL STUDIES

Migraine:    In US 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 2 below, onset of relief began as early as 10 minutes following a 6-mg IMITREX Injection. Smaller doses of sumatriptan may also prove effective, although the proportion of patients obtaining adequate relief is decreased and the latency to that relief is greater.

In 1 well-controlled study where placebo (n = 62) was compared to 6 different doses of IMITREX Injection (n = 30 each group) in a single-attack, parallel-group design, the dose response relationship was found to be as shown in Table 1.

In 2 US well-controlled clinical trials in 1,104 migraine patients with moderate and severe migraine pain, the onset of relief was rapid (less than 10 minutes). Headache relief, as evidenced 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. Headache relief was achieved in approximately 82% of patients within 2 hours, and 65% of all patients were pain free within 2 hours.

Table 2 shows the 1- and 2-hour efficacy results.

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 an autoinjector.

The efficacy of IMITREX Injection is unaffected by whether or not migraine is 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. Patients age 21 to 65 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 to those who received placebo (see Table 3). One study evaluated a 12-mg dose; there was no statistically significant difference in outcome between patients randomized to the 6- and 12-mg doses.

The Kaplan-Meier (product limit) Survivorship Plot (Figure 1) provides an estimate of the cumulative probability of a patient with a cluster headache obtaining relief after being treated with either sumatriptan or placebo.

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 sumatriptan-treated headaches).

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