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Mechanism Of Action
Sumatriptan is the active component of ZECUITY. 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 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 proinflammatory neuropeptide release.
Significant elevation in blood pressure, including hypertensive crisis, has been reported in patients treated with sumatriptan, 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
Following ZECUITY administration to the upper arm the maximum mean sumatriptan serum concentration (Cmax) was 22 ng/mL, the mean total area under the curve (AUC0_ inf) was 110 hr*ng/mL, and the median tmax was 1.1 hours. The mean Cmax and mean AUC0-inf measured after ZECUITY administration were approximately 37% and 45% of the values measured after administration of 100 mg Imitrex® tablets, respectively.
The effect of ZECUITY application to the upper arm versus thigh was assessed in 19 healthy subjects. The application sites are considered interchangeable as the relative bioavailability of sumatriptan following application of the ZECUITY TDS to these two sites was comparable.
Protein binding, determined by equilibrium dialysis over the concentration range of 10 to 1000 ng/mL, is between 14% and 21%. The effect of sumatriptan on the protein binding of other drugs has not been evaluated. The apparent volume of distribution of sumatriptan is 2.4 L/kg.
In vitro studies with human microsomes suggest that sumatriptan is metabolized by MAO, predominantly the A isoenzyme. No new metabolites were identified in comparison with the oral sumatriptan tablets. Most of a radiolabeled sumatriptan dose that is excreted in the urine is the major metabolite indole acetic acid (IAA) or the IAA glucuronide, both of which are inactive.
After a single ZECUITY dose in 9 subjects, 11% of the sumatriptan dose was excreted in the urine as unchanged sumatriptan and 69% as the indole acetic acid metabolite. After a single ZECUITY dose, the mean sumatriptan half-life was 3.1 hours.
Similar pharmacokinetic values were observed during a migraine attack compared to a migraine-free period following ZECUITY administration on the upper arm in 18 patients with a diagnosis of migraine.
External Heat Source
A heat effect study in 12 healthy adult subjects demonstrated similar pharmacokinetic values without and with the application of an external heat source (40°C heat wrap placed over top of the ZECUITY TDS for the 4 hour dosing period).
Age: The pharmacokinetics of sumatriptan after ZECUITY administration to the upper arm were compared for 8 healthy elderly subjects versus 8 paired gender and race matched healthy young adult subjects. No significant pharmacokinetic differences were observed. [see Use In Specific Populations].
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 ZECUITY in this population is contraindicated [see CONTRAINDICATIONS].
Race: The effect of race on sumatriptan pharmacokinetics after ZECUITY administration was assessed in an analysis of 8 pooled Phase 1 studies with 168 healthy subjects (50 non-Caucasian and 118 Caucasian). Cmax is about 8% lower and AUC0-4 hours is about 10% lower in non-Caucasian compared to Caucasian subjects, respectively. These differences are not expected to be clinically significant.
Gender: No effect of gender on sumatriptan pharmacokinetics was identified in a study in 17 healthy subjects (8 male and 9 female).
Drug Interaction Studies
Monoamine Oxidase-A Inhibitors: In a study 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. [see CONTRAINDICATIONS].
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.
In rats with a single subcutaneous dose (0.5 mg/kg/day) 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.
Acute Migraine Attack - Placebo Controlled Efficacy Study
The efficacy of ZECUITY in the acute treatment of migraine headaches with or without aura was demonstrated in a randomized, double-blind, controlled study (Study 1).
Patients in Study 1 were predominantly female (85%) and Caucasian (82%), with a mean age of 41 years. Patients were instructed to treat a migraine headache of moderate to severe pain with a single ZECUITY TDS or matching TDS with no sumatriptan in the drug reservoir. Additional medications were allowed as rescue therapy beginning 2 hours after the initial treatment.
The primary efficacy endpoint in Study 1 was the proportion of patients who had no headache pain at 2 hours post TDS activation. Absence of nausea, photophobia, and phonophobia at 2 hours post TDS activation were assessed as secondary endpoints. Headache pain relief, defined as a reduction in migrainerelated headache pain severity from moderate or severe pain to mild or no pain, was also assessed. As shown in Table 4, a significantly greater proportion of patients had no headache pain, had headache pain relief, no nausea, no phonophobia, or no photophobia at two hours after TDS activation in the ZECUITY treatment group than in the control group.
Table 4: Percentage of Patients with No Headache Pain,
With Headache Pain Relief, No Nausea, No Photophobia, and No Phonophobia Two
Hours After TDS Activation
|Two Hours After ZECUITY TDS Activation||ZECUITY
(n = 226)
(n = 228)
|No Headache Pain||18%||9%||0.0092|
|With Headache Pain Relief||53%||29%||< 0.0001|
|No Nausea||84%||63%||< 0.0001|
Analyses of the relationship between age, race, gender, or BMI and response showed no significant differences in response rates.
Last reviewed on RxList: 4/3/2014
This monograph has been modified to include the generic and brand name in many instances.
Additional Zecuity Information
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