Sumatriptan Succinate - Scientific Information
|Manufacture:||Fresenius Kabi USA, LLC|
|Condition:||Cluster Headaches, Headache, Migraine, Migraine Headache (Migraine)|
|Form:||Liquid solution, Subcutaneous (SC)|
|Ingredients:||Sumatriptan Succinate, Sodium Chloride, Water for Injection|
Sumatriptan succinate injection contains sumatriptan succinate, a selective 5-HT1B/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:
Sumatriptan succinate is a white to off-white powder that is readily soluble in water and in saline.
Sumatriptan succinate injection is a clear, colorless to pale yellow, sterile, nonpyrogenic solution for subcutaneous injection. Each 0.5 mL of sumatriptan succinate injection 12 mg/mL solution contains 6 mg of sumatriptan (base) as the succinate salt and 3.5 mg of sodium chloride in water for injection. The pH range of the solution is approximately 4.2 to 5.3. The osmolality of the injection is 291 mOsmol.
Mechanism of Action
Sumatriptan binds with high affinity to human cloned 5-HT1B/1D receptors. Sumatriptan succinate presumably exerts its therapeutic effects in the treatment of migraine headache by binding to 5 HT1B/1D receptors located on intracranial blood vessels and sensory nerves of the trigeminal system.
Current theories proposed to explain the etiology of migraine headache suggest that symptoms are due to local cranial vasodilatation and/or to the release of sensory neuropeptides (including substance P and calcitonin gene-related peptide) through nerve endings in the trigeminal system. The therapeutic activity of sumatriptan succinate for the treatment of migraine and cluster headaches is thought to be due to the agonist effects at the 5-HT1B/1D receptors on intracranial blood vessels (including the arterio-venous anastomoses) and sensory nerves of the trigeminal system, which result in cranial vessel constriction and inhibition of pro-inflammatory neuropeptide release.
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.
Transient increases in blood pressure observed in some subjects 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.
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 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.
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.
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 renal impairment on the pharmacokinetics of sumatriptan has not been examined.
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 succinate injection in this population is contraindicated [see Contraindications].
The systemic clearance and Cmax of 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 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.
Carcinogenesis, Mutagenesis, Impairment of Fertility
In carcinogenicity studies, rats and mice were given sumatriptan by oral gavage. Mice were dosed for 78 weeks and rats were dosed for 104 weeks. Average exposures achieved in mice receiving the highest dose were approximately 110 times the exposure attained in humans after the maximum recommended single dose of 6 mg. The highest dose to rats was approximately 260 times the maximum single dose of 6 mg on a mg/m2 basis. There was no evidence of an increase in tumors in either species related to sumatriptan administration.
Sumatriptan was not mutagenic in the presence or absence of metabolic activation when tested in 2 gene mutation assays (the Ames test and the in vitro mammalian Chinese hamster V79/HGPRT assay). It was not clastogenic in 2 cytogenetics assays (the in vitro human lymphocyte assay and the in vivo rat micronucleus assay).
Impairment of Fertility
A fertility study (Segment I) by the subcutaneous route, during which male and female rats were dosed daily with sumatriptan prior to and throughout the mating period, has shown no evidence of impaired fertility at doses equivalent to approximately 100 times the maximum recommended single human dose of 6 mg on a mg/m2 basis. However, following oral administration, a treatment-related decrease in fertility, secondary to a decrease in mating, was seen for rats treated with 50 and 500 mg/kg/day. The no-effect dose for this finding was approximately 8 times the maximum recommended single human dose of 6 mg on a mg/m2 basis. It is not clear whether the problem is associated with the treatment of males or females or both.
Animal Toxicology and/or Pharmacology
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.
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.
In controlled clinical trials enrolling more than 1,000 subjects during migraine attacks who were experiencing moderate or severe pain and 1 or more of the symptoms enumerated in Table 2, onset of relief began as early as 10 minutes following a 6 mg sumatriptan succinate injection. Lower doses of sumatriptan succinate injection may also prove effective, although the proportion of subjects obtaining adequate relief was decreased and the latency to that relief is greater with lower doses.
In Study 1, 6 different doses of sumatriptan succinate 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 1.
|Dose of Sumatriptan Injection||Percent Subjects with Reliefa||Advers e Events Incidence(%)|
|at 10 Minutes||at 30 Minutes||at 1 Hour||at 2 Hours|
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 sumatriptan succinate injection 6 mg in 1,104 subjects 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 subjects within 1 hour of a single 6 mg subcutaneous dose of sumatriptan succinate injection. Approximately 82% and 65% of subjects treated with sumatriptan succinate 6 mg had headache relief and were pain free within 2 hours, respectively.
Table 2 shows the 1- and 2-hour efficacy results for sumatriptan succinate injection 6 mg in Studies 2 and 3.
|1-Hour Data||Study 2||Study 3|
(n = 384)
6 mg (n = 350)
|Subjects with pain relief||18%||70%a||26%||70%a|
|Subjects with no pain||48%||73%a||50%||73%a|
|Subjects without nausea||23%||56%a||25%||58%a|
|Subjects without photophobia||34%||79%a||34%||76%a|
|Subjects with little or no clinical disabilityb|
|2-Hour Data||Study 2||Study 3|
Succinate 6 mgd
|Subjects with pain relief||31%||81%a||39%||82%a|
|Subjects with no pain||56%||82%a||63%||81%a|
|Subjects without nausea||31%||72%a||35%||71%a|
|Subjects without photophobia||42%||85%a||49%||84%a|
|Subjects with little or no
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 subjects that may have received an additional placebo injection 1 hour after the initial injection.
d Includes subjects that may have received an additional 6 mg of sumatriptan succinate injection 1 hour after the initial injection.
Sumatriptan succinate injection also relieved photophobia, phonophobia (sound sensitivity), nausea, and vomiting associated with migraine attacks.
The efficacy of sumatriptan succinate injection was unaffected by whether or not the migraine was associated with aura, duration of attack, gender or age of the subject, or concomitant use of common migraine prophylactic drugs (e.g., beta-blockers).
The efficacy of sumatriptan succinate 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). Subjects aged 21 to 65 years 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 subjects receiving 6 mg of sumatriptan succinate injection compared with those who received placebo (see Table 3).
|Study 4||Study 5|
|Placebo (n = 39)||Sumatriptan uccinate 6 mg (n = 39)||Placebo (n = 88)||Sumatriptan Succinate 6 mg (n = 92)|
|Subjects with pain relief (no/mild)||8%||21%||7%||23%a|
|5 Minutes post-injection||10%||49%a||25%||49%a|
|10 Minutes post-injection||26%||74%a||35%||75%a|
|15 Minutes post-injection|
(n = Number of headaches treated.)
An estimate of the cumulative probability of a subject with a cluster headache obtaining relief after being treated with either sumatriptan succinate injection or placebo is presented in Figure 1.
Figure 1. Time to Relief of Cluster Headache from Time of Injectiona
a The figure uses Kaplan-Meier (product limit) Survivorship Plot. Subjects taking rescue medication were censored at 15 minutes.
The plot was constructed with data from subjects 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 sumatriptan succinate injection).
Other data suggest that treatment with sumatriptan succinate 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).