Needle-free subcutaneous sumatriptan (Sumavel DosePro): bioequivalence and ease of use.

BACKGROUND: Subcutaneous (s.c.) injection of sumatriptan is currently associated with needle aversion in some patients, and sharps disposal issues. OBJECTIVES: To investigate whether a needle-free system can deliver s.c. sumatriptan. If so, to examine whether needle-free administration is bioequivalent to a 26-gauge needle-based auto-injector. Lastly, to assess the needle-free system for clinical acceptability and ease of use during migraine attacks. METHODS: Two clinical trials. Study A: Pharmacokinetics and bioequivalence was studied in normal adult volunteers (n = 57 total), directly comparing needle-free (Sumavel DosePro) with needle-based (Imitrex STATdose System) administration of 6 mg s.c. sumatriptan. An incomplete, randomized, partial factorial, crossover design was used. Each subject received 2 administrations of each product, at 2 of the 3 anatomical sites (abdomen, thigh or arm). There were appropriate "washout" periods between each. Pharmacokinetic sampling was at standard time points, and tests for bioequivalence then followed. Study B: The term "ease of use" was used for clinical acceptability and utility of the needle-free system when it was assessed among 52 outpatients treating migraine attacks. Instructional materials were used as would be provided after ordinary prescription. The primary endpoint was successful use of the needle-free system to administer sumatriptan at the first attempt, including appropriate injection site selection. Second and subsequent uses of the needle-free system were also documented. RESULTS: For administration sites in the thigh and the abdomen, but not the arm, the needle-free and needle-based systems were bioequivalent (for all pharmacokinetic endpoints the mean ratios between the 2 devices were always between 90.1% and 115%). Among outpatients treating a migraine attack with the needle-free system, 51 of 52 on first attempt used the needle-free system successfully when treating a migraine attack. CONCLUSIONS: Sumavel DosePro needle-free delivery system is a new presentation of s.c. sumatriptan that delivers drug effectively, is bioequivalent to the existing needle auto-injector when used at the thigh or abdomen, and is easy to use.

Analysis of safety and tolerability data obtained from over 1,500 patients receiving topiramate for migraine prevention in controlled trials.

OBJECTIVE: Topiramate is an effective and generally well-tolerated migraine preventive therapy, as shown in three large, randomized, double-blind, placebo-controlled registration trials. Based upon efficacy/tolerability, topiramate 100 mg/day (50 mg BID) is the recommended target dose for most patients with migraine. To further assess the safety and tolerability of topiramate for migraine prevention, we analyzed safety data from 1,580 patients who participated in the three pivotal registration trials or an earlier pilot, randomized, double-blind, placebo-controlled trial. METHODS: The safety population consisted of all patients who took >or=1 dose of study medication during the double-blind phase (topiramate 50 mg/day [N = 235], 100 mg/day [N = 386], 200 mg/day [N = 514], or placebo [N = 445]). Safety assessments included adverse event (AE) reports, physical examination, and clinical laboratory tests. RESULTS: Paresthesia was the most common topiramate-associated AE (35%, 51%, and 49% of patients receiving topiramate 50 mg/day, 100 mg/day, or 200 mg/day, respectively [6% on placebo]). The most common topiramate-associated AE were generally mild or moderate in severity and occurred at consistently higher rates during the titration period, compared with the maintenance period of the double-blind phase. AEs leading to withdrawal from the recommended dose of topiramate 100 mg/day included paresthesia (8%), fatigue (5%), nausea (2%), and difficulty with concentration (2%). Serious AEs were infrequent, occurring in 2% of 1,135 topiramate-treated patients and 3% of 445 placebo-treated patients. Patients on topiramate experienced significant decreases in mean body weight compared with placebo. CONCLUSIONS: Topiramate is generally safe and reasonably well tolerated for the prevention of migraine in adults. The most common topiramate-associated AEs were mild or moderate in severity and occurred more frequently during titration to target doses.

The impact of topiramate on health-related quality of life indicators in chronic migraine.

BACKGROUND: Chronic migraine is a disabling primary chronic daily headache disorder that significantly impacts the daily activities of patients with this disorder. To our knowledge, this is the first report of a large, randomized, double-blind, placebo-controlled trial that assessed the impact of topiramate on the daily activities, emotional distress, headache-related disability, and global impression of change in patients with chronic migraine. OBJECTIVE: To assess whether topiramate 100 mg/day reduces migraine-related disability and limitations of daily activities in patients with chronic migraine. STUDY DESIGN/METHODS: Patients aged > or =18 years with chronic migraine were randomized 1 : 1 ratio to topiramate 100 mg/day or placebo. The double-blind period lasted 16 weeks. Three patient-reported outcome measures were administered: Migraine Disability Assessment, Migraine-Specific Quality of Life Questionnaire (Domains: Role Function Restrictive and Preventive and Emotional Function), and Subject's Global Impression of Change. Investigators completed a Physician's Global Impression of Change for each patient. Subject's Global Impression of Change and Physician's Global Impression of Change were completed one time, at the end of study, and measured on a 7-point scale (1 = very much improved to 7 = very much worse). The Migraine-Specific Quality of Life Questionnaire was analyzed using analysis of covariance (last observation carried forward) approach. Results were not adjusted for multiplicity. RESULTS: A total of 328 patients were randomized (topiramate, n = 165; placebo, n = 163), and 306 patients were included in the intent-to-treat population. Mean age was 38.2 years, and a majority of the patients were female (85.3%). Fifty-six percent of topiramate-treated patients vs 45% of placebo-treated patients reported >50% improvement from baseline in Migraine Disability Assessment scores (P = .074). The Migraine-Specific Quality of Life Questionnaire analysis demonstrated significant improvements at week 4 in all 3 domains, and at weeks 8 and 16 in both Role Function-Restrictive and Emotional Function domains (P < .05). Role Function-Preventive approached, but did not reach significance, at week 8 (P = .053). Seventy-five percent and 72% of topiramate-treated patients vs 61% and 59% of placebo-treated patients reported improvements on the Subject and Physician's Global Impression of Change scales (P = .025 and P = .037, respectively). CONCLUSION: Compared with placebo-treated patients, topiramate 100 mg/day appears to contribute to reductions in migraine-related limitations on daily activities and emotional distress beginning as early as week 4 and continuing up to week 16 after treatment. Physician's Global Impression of Change results are very similar with Subject's Global Impression of Change, indicating concordance between the physician's and the subject's assessment of improvement.

Analysis of pooled data from two pivotal controlled trials on the efficacy of topiramate in the prevention of migraine.

CONTEXT: A substantial proportion of the patient population with migraine headache should be considered for preventive treatment based on the frequency and disability associated with this disorder. Use of the anticonvulsant topiramate was previously examined in two large, double-blind, randomized, placebo-controlled clinical trials of a subset of patients who have 3 to 12 migraine episodes per month. OBJECTIVE: To better characterize the efficacy of topiramate for prevention of migraine, with or without aura, by pooling and analyzing data from the two large clinical trials. METHODS: The pooled intent-to-treat population included 937 patients receiving topiramate at one of three dosages (50 mg/d, 100 mg/d, 200 mg/d) or placebo. Outcome measures included change in mean monthly migraine frequency and categorical responder rate throughout the 26-week doubleblind phase. RESULTS: At daily doses of 100 and 200 mg, topiramate was associated with significant reductions in mean monthly migraine frequency throughout the double-blind phase compared with placebo (P<.001). Significantly more patients treated with these topiramate doses exhibited high-percentage reductions in monthly migraine frequency (>/=50% [P<.001], >/=75% [P<.001], 100% [P=.049]) versus placebo. The most common adverse events included anorexia, cognitive deficits, diarrhea, fatigue, nausea, and paresthesia. Topiramate (100 mg/d, 200 mg/d) was associated with significant and sustained reductions in mean monthly migraine frequency beginning as early as 1 week into therapy. CONCLUSION: Pooled efficacy data from two large, similarly designed, placebo-controlled migraine-prevention trials demonstrated that a statistically significant proportion of patients using topiramate met or exceeded two main outcome guidelines recommended by the International Headache Society (>/=50% and >/=75% reduction in frequency of monthly attacks). Based on efficacy and tolerability, topiramate at a dosage of 100 mg per day (50 mg twice daily) should be the target dosage for most patients with migraine.

Sumatriptan 6 mg subcutaneous as an effective migraine treatment in patients with cutaneous allodynia who historically fail to respond to oral triptans.

The objective of the study was to assess the efficacy of 6 mg subcutaneous (s.c.) sumatriptan to treat migraine and the relationship between response of migraine and cutaneous allodynia in a population of migraine patients who historically failed to respond to oral triptan medications. This was an open-label study consisting of patients with migraines who historically failed to respond to oral triptan medications. Forty-three patients were asked to treat three migraine attacks with 6 mg s.c. sumatriptan. The primary efficacy endpoint was the percentage of patients achieving relief of headache at 2 h. Ninety-one percent of the patients responded to a single dose of s.c. sumatriptan 6 mg. Fifty percent of all patients were pain-free by 2 h and over 30% had a 24-h sustained pain-free response. When administered within 90 min from the onset of migraine (i.e., during the developing phase of cutaneous allodynia), s.c. 6 mg sumatriptan proved to be effective despite the occurrence of allodynia in a group of patients, who historically had failed to respond to oral triptan medications. These findings suggest that the window of opportunity to treat allodynic patients with injectable triptans may be longer (up to 2 h) than with oral triptans (up to 1 h).

Characterization and prediction of emergency department use in chronic daily headache patients.

OBJECTIVE: To examine the characteristics of chronic daily headache sufferers who use emergency departments (EDs) and identify factors predictive of ED visits. BACKGROUND: Several large clinical trials have found that a sizable subset of headache patients uses EDs frequently, although such visits should be preventable. METHODS: Participants in two large clinical trials provided baseline data on ED use, hospitalizations, disability, daily activities, and quality of life. RESULTS: Of the 785 patients included, 182 (23.2%) reported at least 1 ED visit over the past year. Most of these patients (82.9%) reported one to six visits; however, 4.4% reported>/=21 visits (mean 5.0; SD 8.5). The percentage of patients with overnight hospitalizations during the previous year was significantly greater in the ED user group than non-ED user group (17.6% vs 1.7%; P<.001), as was the number of visits to healthcare practitioners (median 24.3 vs 11.8; P<.001). Compared with non-ED users, a higher percentage of ED users reported severe disability on the Migraine Disability Assessment Scale (MIDAS) (85.7% vs 69.3%, P<.001) and indicated that their headache more negatively impacted mood and daily activities (all P<.05). ED users also had significantly higher depression scores and lower scores on all domains of the Short Form--36 (SF--36) (all P<.05). In a logistic regression model, patient age, neurologist visit, severe (vs not severe) rating on the MIDAS, Role Physical (SF--36), and prior overnight hospitalization were significant predictors of ED use (max--rescaled R(2)=21.0%). CONCLUSIONS: Patients seeking ED treatment for chronic daily headache are more severely affected and have more unmet medical needs than those who do not use the ED. Management strategies that help prevent frequent ED use might be possible.

Divalproex sodium extended-release for the prophylaxis of migraine headache.

The Diamond Headache Clinic first began using valproic acid in 1984. Subsequently, a variety of open-label and then placebo-controlled trials were carried out with valproic acid, followed by an enteric-coated formulation known as divalproex sodium delayed-release. These trials demonstrated a consistent pattern of efficacy and the delayed-release form improved tolerability while offering a twice-daily dosing schedule. This led to the development of an extended-release formulation. This formulation further improved tolerability and led to a once-daily dosing. The pivotal trial conducted in patients with migraine with the extended-release formulation demonstrated efficacy similar to that seen with the delayed-release form.