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Sumavel DosePro

"Most of us get headaches from time to time. Some are mild. Others cause throbbing pain. They can last for minutes or days. There are many different types of headaches. How you treat yours depends on which kind you have.

Headaches migh"...

Sumavel DosePro

CLINICAL PHARMACOLOGY

Mechanism Of Action

Sumatriptan is the active component of Sumavel DosePro. Sumatriptan binds with high affinity to human cloned 5-HT1B/1D receptors. Sumatriptan 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 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 arteriovenous anastomoses) 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 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.

Pharmacokinetics

Absorption and Bioavailability

Sumavel DosePro is bioequivalent to sumatriptan needle-based injection via autoinjector at the thigh and abdomen administration sites. A sub-optimal dose may be delivered when administered to the arm and therefore, the arm is not recommended as a site of administration.

Pharmacokinetic parameters following a 6 mg subcutaneous dose of Sumavel DosePro into the thigh were determined in 32 subjects (males and females). The maximum serum concentration (Cmax) (mean ± standard deviation) was 71.9 ± 14.4 ng/mL; the time to peak concentration (Tmax) was 12 minutes after dosing (range, 4 to 20 minutes); and the terminal half-life was 103 ± 22 minutes.

Pharmacokinetic parameters following a 6 mg subcutaneous dose of Sumavel DosePro into the abdomen were determined in 35 subjects (males and females). The maximum serum concentration (Cmax) (mean ± standard deviation) was 78.6 ± 17.3 ng/mL; the time to peak concentration (Tmax) was 12 minutes after dosing (range, 6 to 20 minutes); and the terminal half-life was 102 ± 12 minutes.

Distribution

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.

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.

Special 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).

Renal Impairment: The effect of renal impairment on the pharmacokinetics of sumatriptan has not been examined.

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 Sumavel DosePro in this population is not recommended [see Use In Specific Populations].

Race: 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.

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; 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.

Clinical Studies

Migraine

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 4, 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 subjects obtaining adequate relief was decreased and the latency to that relief is greater with lower doses. In one well-controlled study, 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 3.

Table 3: Proportion of Subjects With Migraine Relief and Incidence of Adverse Events by Time and by Sumatriptan Dose

Dose of Sumatriptan Injection Percent Subjects with Reliefa Adverse Events 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 pain or mild pain after dosing without use of rescue medication.

In 2 randomized, placebo-controlled clinical trials of sumatriptan injection 6 mg in 1,104 subjects with moderate or severe migraine pain, 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 injection. Approximately 82% and 65% of subjects treated with sumatriptan 6 mg had headache relief and were pain free within 2 hours, respectively.

Table 4 shows the 1- and 2-hour efficacy results for sumatriptan injection 6 mg.

Table 4: Proportion of Subjects With Pain Relief and Relief of Migraine Symptoms After 1 and 2 Hours of Treatment

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

Subcutaneous sumatriptan also relieved photophobia, phonophobia (sound sensitivity), nausea, and vomiting associated with migraine attacks. 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 subject, or concomitant use of common migraine prophylactic drugs (e.g., beta-blockers).

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. 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 injection compared with those who received placebo (see Table 5).

Table 5: Proportion of Subjects With Cluster Headache Relief by Time

  Study 1 Study 2
Placebo
(n = 39)
Sumatriptan Injection 6 mg
(n = 39)
Placebo
(n = 88)
Sumatriptan Injection 6 mg
(n = 92)
Subjects 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
a P < 0.05.
(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 or placebo is presented in Figure 1.

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

Time to Relief of Cluster Headache from Time of Injection - Illustration

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 placebotreated headaches and 18 of the 131 headaches treated with sumatriptan injection).

Other data suggest that treatment with sumatriptan 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).

Last reviewed on RxList: 1/10/2014
This monograph has been modified to include the generic and brand name in many instances.

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