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Alsuma

"Nov. 13, 2012 -- Women who get migraines are more likely than those who don't to develop small areas of tissue changes in their brains, a new study shows. At the same time, these changes do not seem to affect the women's thinking or memory.

"...

Alsuma

Alsuma

CLINICAL PHARMACOLOGY

Mechanism of Action

Sumatriptan is the active component of ALSUMA. Sumatriptan is a selective agonist for the 5-HT1B and 5- HT1D receptors. Sumatriptan presumably exerts its antimigrainous effect through binding to vascular 5-HT1- type receptors, which have 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.

Pharmacodynamics

Blood Pressure: ALSUMA is contraindicated in patients with uncontrolled hypertension. [see CONTRAINDICATIONS] It should be administered with caution to patients with controlled hypertension. [see WARNINGS AND PRECAUTIONS]

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.

Pharmacokinetics

Absorption and Elimination

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 (Cmax) 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 study, 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.

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.

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 an MAO-A inhibitor decreased the clearance of sumatriptan, resulting in a two-fold increase in the area under the sumatriptan plasma concentration-time curve (AUC), corresponding to a 40% increase in elimination halflife.

Migraine Prophylactic Medications

There is no evidence that concomitant use of migraine prophylactic medications has any effect on the efficacy of sumatriptan. In 2 clinical trials in the United States, a retrospective analysis of 282 patients who had been using prophylactic drugs (verapamil, n = 63; amitriptyline, n = 57; propranolol, n = 94; for 45 other drugs, n = 123) were compared to those who had not used prophylaxis (n = 452). There were no differences in relief rates at 60 minutes postdose for sumatriptan injection, whether or not prophylactic medications were used.

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 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.

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 those in healthy male subjects (mean age, 30 years).

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

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 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.

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 3, onset of relief began as early as 10 minutes following a 6 mg sumatriptan 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 one well-controlled study in which placebo (n = 62) was compared to 6 different doses of sumatriptan injection (n = 30 each group) in a single-attack, parallel-group design, the dose response relationship was found to be as shown in Table 2.

Table 2: Dose-Response Relationship for Efficacy

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

In two US well-controlled clinical trials in 1,104 migraine patients with moderate or severe migraine pain, the onset of relief was rapid (less than 10 minutes) with a 6 mg subcutaneous dose of sumatriptan injection. 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 sumatriptan 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 3 shows the 1- and 2-hour efficacy results for subcutaneous sumatriptan 6 mg.

Table 3: Efficacy Data from US Clinical Efficacy Trials with Sumatriptan Injection in Patients with Migraine

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

Subcutaneous sumatriptan also relieved photophobia, phonophobia (sound sensitivity), nausea, and vomiting associated with migraine attacks.

The efficacy of subcutaneous sumatriptan 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., betablockers).

Cluster Headache

The efficacy of sumatriptan 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 sumatriptan injection compared to those who received placebo (see Table 4). 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.

Table 4: Efficacy Data from the Cluster Headache Efficacy Trials with Sumatriptan Injection

Patients with Pain Relief (no/mild) Study 1 Study 2
Placebo
(n=39)
Sumatriptan Succinate 6 mg
(n=39)
Placebo
(n=88)
Sumatriptan Succinate 6 mg
(n=92)
5 minutes post-injection 8% 21% 7% 23%*
10 minutes post-injection 10% 49%* 25% 49%*
15 minutes post-injection 26% 74%* 35% 75%*
* p < 0.05 (n = Number of headaches treated)

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.

Figure 1: Time to Relief from Time of Injection*

Time to Relief from Time of Injection - Illustration

*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 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 later-occurring headaches (i.e., those occurring after 2, but before 18 or 24 hours).

Last reviewed on RxList: 4/26/2013
This monograph has been modified to include the generic and brand name in many instances.

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