585918 review-article2015
TAN0010.1177/1756285615585918Therapeutic Advances in Neurological DisordersM. Vikelis et al.
Therapeutic Advances in Neurological Disorders
Review
The iontophoretic transdermal system formulation of sumatriptan as a new option in the acute treatment of migraine: a perspective
Ther Adv Neurol Disord 1–6 DOI: 10.1177/ 1756285615585918 © The Author(s), 2015. Reprints and permissions: http://www.sagepub.co.uk/ journalsPermissions.nav
Michail Vikelis, Konstantinos C. Spingos and Alan M. Rapoport
Abstract: An iontophoretic transdermal system (ITS) (skin patch) formulation of sumatriptan for the acute treatment of migraine attacks was approved by the US Food and Drug Administration in January 2013. This transdermal system bypasses the gastrointestinal tract, as it uses low electrical current to move sumatriptan transdermally into the subcutaneous tissue. Randomized, double-blind, controlled clinical trials have demonstrated minimal triptan-related side effects and superior efficacy versus placebo, comparable with other sumatriptan formulations. Sumatriptan ITS can be applied successfully during a mild or severe migraine attack. According to pharmacokinetic properties and clinical data, sumatriptan ITS may be a good choice for people with migraine and severe nausea, vomiting or gastroparesis, those with intolerable triptan-related adverse events and those not responding optimally to oral medications.
Keywords: gastrointestinal absorption, iontophoretic transdermal system, migraine, migraine treatment, patch, sumatriptan Introduction Migraine is one of the most common primary headache disorders, affecting around 12% of the general population in Western countries. Episodic attacks of headaches of moderate or severe intensity are its clinical hallmark. Six out of ten people with migraine have at least one severe attack per month, and more than one-third have up to three severe attacks per month. The headache pain in migraine is often throbbing and commonly accompanied by photophobia, osmophobia, phonophobia and aura in around 15% of patients [Silberstein, 1995; Stovner et al. 2007; Headache Classification Subcommittee of the International Headache Society, 2004; Menken et al. 2000]. Gastrointestinal (GI) symptoms, such as nausea, vomiting and gastroparesis, are common and disabling, challenging the effective management of migraine. Nausea is reported by nine out of 10 patients and it is estimated to be present during half of the attacks in half of the people with migraine [Stovner et al. 2007]. In addition, the presence of nausea and vomiting has been shown
to be related to the intensity of the migraine headache [Stovner et al. 2007] and to increase migraine symptom burden and medication-related impairment in everyday activities [Stovner et al. 2007]. The combination of recurrent, severe headache attacks accompanied by autonomic and GI symptoms, interictal anxiety and comorbid illnesses such as depression and anxiety lead to the overall disabling nature of migraine [Silberstein, 1995; Stovner et al. 2007; Headache Classification Subcommittee of the International Headache Society, 2004; Menken et al. 2000].
Correspondence to: Michail Vikelis, MD, MSc, PhD Glyfada Headache Center, 8 Lazaraki Str. Glyfada 16675, Greece [email protected] Konstantinos C. Spingos, MD, PhD Corfu Headache Clinic, Corfu, Greece Alan M. Rapoport, MD The David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
Acute treatment of migraine attacks is recommended in practically all patients with migraine. Triptans (selective serotonin receptor agonists) are effective evidence-based treatments for migraine in patients without contraindications. Triptans are the mainstay of treatment for acute migraine attacks in Western medicine. Seven triptans are available worldwide: sumatriptan, zolmitriptan, naratriptan, rizatriptan, eletriptan, frovatriptan and almotriptan, although some of
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Therapeutic Advances in Neurological Disorders them are not available in every country. Clinical trials have shown that the efficacy of triptans is better when they are used early after the onset of a migraine attack, before central sensitization is established [Burstein et al. 2005]; but in many cases, GI symptoms have been shown to decrease the use of oral medications in at least one-third of patients [Silberstein, 1995]. Consequently, many people with migraine may postpone or even avoid the timely use of oral medications and a parenteral formulation may be a better choice for these cases [Vikelis and Rapoport, 2011]. Triptan tablets are the most commonly used form of triptans for acute migraine treatment [Vikelis and Rapoport, 2012]. Currently available parenteral triptan formulations include subcutaneous injections, nasal sprays and suppositories [three injectable formulations of sumatriptan; two nasal sprays (sumatriptan and zolmitriptan); no suppository in the USA]. The perception of injections as invasive, uncomfortable and causing more adverse events (AEs) limits the use of this type of parenteral formulations [Rapoport et al. 2010]. In addition, sumatriptan injections are associated with a higher recurrence rate in comparison to oral and nasal formulations [Tepper and Millson, 2003]. Discomfort has also been associated with the use of suppositories [Vikelis and Rapoport, 2012]. Nasal sprays are regarded as a preferable route of delivery for patients with gastric stasis as they are absorbed by the nasal mucosal surfaces. However, a considerable percentage of each dose may actually be swallowed and subsequently absorbed in the small intestine. In that case, the rate of absorption as well as the speed of action of nasal sprays would be compromised [Fuseau et al. 2002; Uemura et al. 2005]. There are findings suggesting that the percentage of patients who prefer nasal sprays over other formulations increases with time after the first use, but most patients still prefer tablets [Rapoport et al. 2010; Dowson et al. 2007]. All of the above leads to the assumption that alternative parenteral options for the treatment of acute migraine would be welcomed by many people with migraine [Vikelis and Rapoport, 2011], as well as their treating doctors. Sumatriptan iontophoretic transdermal system (sumatriptan ITS) is a recently approved novel device that might help to avoid some of the limitations of other routes of administration of triptans [US FDA, 2013a]
Indications The US Food and Drug Administration (FDA) has approved sumatriptan ITS (Zecuity, Teva Pharmaceuticals Industry Ltd, Tel Aviv, Israel) for the acute treatment of migraine with and without aura in adults [US FDA, 2013b]. Dosage and administration Iontophoresis is the method that uses low electrical current to move ionized drugs across the skin into the underlying subcutaneous tissue and from there into the blood circulation. It is a noninvasive method of drug delivery. Sumatriptan ITS includes an iontophoretic device and a drug reservoir card, which contains two nonwoven pads and two different gel formulations in wells; one is the active sumatriptan succinate and the other is sodium salt. The generated current applied in the positive well (anode) drives sumatriptan across the skin into the subcutaneous tissue and finally it is passively absorbed from the blood vessels. Sumatriptan ITS is designed to deliver 6.5 mg of sumatriptan over 4 h [US FDA, 2013a; Vikelis et al. 2012]. The system is destroyed if cut. Sumatriptan ITS must be applied only on dry, intact and nonirritated skin surfaces. The upper arm and the thigh are the proper body sites to apply it. After properly opening the package, preparing the patch and applying it to the skin, an activation button has to be pushed by the patient so that a red light turns on to signal that the system is active. After completion of the 4 h therapy, the system stops delivering drug and the light signal turns off automatically [US FDA, 2013a]. Patients should use only one patch at a time and no more than two in a 24 h period. In the latter case, the second patch should not be applied earlier than 2 h after removal of the first one [US FDA, 2013a]. Clinical pharmacology Pharmacodynamics and mechanism of action Sumatriptan is a selective agonist of the serotonin (5-hydroxytryptamine or 5-HT) receptor subtypes 1B and 1D. These receptors are found in blood vessels as well as in the presynaptic site of sensory synapses and in the brain stem, respectively. Sumatriptan has a dual mechanism of action. The activation of 5-HT1B receptors results in constriction of the dilated meningeal blood vessels. The simultaneous activation of 5-HT1D
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M Vikelis, KC Spingos et al. receptors on perivascular nerve terminals inhibits the release of vasoactive neuropeptides (e.g. substance P, calsitonin gene related protein) blocking the proinflammatory cascade [Ferrari and Saxena, 1993]. Sumatriptan may also have a central mechanism of action regarding the trigeminal nucleus caudalis at the level of the pons, where 5-HT1D receptors on the terminals of incoming trigeminal sensory fibers can disrupt the neurotransmission of pain. The class of 5-HT agonists has been associated with elevation in arterial blood pressure, including hypertensive crises, in patients with or without a history of arterial hypertension. However, no clinically significant changes in heart rate have been reported. Blood pressure changes are not common and it is unlikely to present a significant clinical problem, unless uncontrolled arterial hypertension is already present [US FDA, 2013a]. Pharmacokinetics The pharmacokinetics of the sumatriptan ITS has been investigated. One study compared the pharmacokinetic profile of four prototype sumatriptan patches with the subcutaneous sumatriptan injection (6 mg) and an oral tablet (50 mg) [Siegel et al. 2007]. The study was conducted in eight healthy adults with a crossover design and showed that the relationship between the amount of sumatriptan delivered and the quantity of the electric potential used is linear. The findings support iontophoresis as an effective method for the controlled delivery of sumatriptan. Besides that, AEs included application site reactions but no triptan-related AEs were recorded. Another study recruited 25 healthy adults who received a single dose of two different sumatriptan iontophoretic patches (containing 120 mg or 104 mg of sumatriptan succinate) and three older formulations of sumatriptan (100 mg tablet, 6 mg subcutaneous injection and 20 mg nasal spray). This study had an open-label, randomized, crossover design. Both patches showed lower maximum serum concentration (Cmax) compared with the subcutaneous and oral formulations, higher Cmax compared with the nasal preparation, and more consistent Cmax compared with the nasal spray and the tablet [Pierce et al. 2009]. Differences in consistency of plasma concentrations may have an important role in the therapeutic response, as gastric motility is reduced and drug absorption is compromised during an acute migraine attack, or
between attacks [Aurora et al. 2007]. Probably, the absence of typical triptan-related AEs observed with the patches in this study are explained by the finding that the Cmax of the 6 mg subcutaneous sumatriptan injection was more than three times higher compared with the Cmax of the sumatriptan ITS. Of note, the commercially available sumatriptan ITS has been slightly modified after feedback from both patients and investigators. Modifications include a new battery and changes to the dome of the patch in order to depress when pushed and turn on a red light signaling that the patch is activated. According to the bioequivalence study that was performed, the ratios of mean values for the commercial patch versus the study patch of Cmax, AUC0-inf (area under the plasma concentration– time curve from time 0 extrapolated to infinity) and AUC0-last (area under the plasma concentration– time curve from time 0 to the last quantifiable post-dose concentration) were 88.8, 81.4 and 91.2, respectively. The 90% confidence intervals of the ratios are within the 80–125% boundary as required by the FDA for the confirmation of bioequivalence [Center for Drug Evaluation and Research, 2012]. Clinical evidence for efficacy, adverse reactions and tolerance A randomized, double-blind, placebo-controlled phase III trial of sumatriptan ITS for the acute treatment of migraine recruited 530 adults [Goldstein et al. 2009]. The diagnosis of migraine was made according to the criteria of International Classification of Headache Disorders II. Subjects were treated by application of either sumatriptan ITS or placebo patch for one migraine attack of moderate to severe intensity. The percentage of patients achieving complete freedom from pain at 2 h after patch activation was achieved by 18% in the sumatriptan ITS group and 9% in the placebo group [number needed to treat (NNT) =11.1; p = 0.0092]. In addition, significantly more patients receiving the active substance achieved the secondary endpoints, including freedom from photophobia at 2 h after patch activation (51% versus 36%; NNT = 6.66; p = 0.0028), phonophobia (55% versus 39%; NNT = 6.25; p = 0.0002) and nausea (84% versus 63%; NNT = 4.8; p < 0.0001), no use of rescue medication (60% versus 40%; NNT = 5; p < 0.0001), relief from headache at 2 h (53% versus 29%; NNT = 4.2; p < 0.0001), relief from headache at 1 h (29% versus 19%; NNT = 10; p = 0.0135),
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Therapeutic Advances in Neurological Disorders freedom from nausea at 1 h (71% versus 58%; NNT = 7.7; p = 0.0251) and sustained headache relief within 2–24 h after patch activation (34% versus 21%; NNT = 7.7; p = 0.0015). The NNTs for headache relief at 1 and 2 h were consistent with the literature NNTs for 100 mg oral sumatriptan (6.8 and 3.5, respectively) [Derry et al. 2012a], and for 20 mg intranasal sumatriptan (4.9 and 3.5, respectively) [Derry et al. 2012b]. The most difficult single endpoint to reach in an acute migraine trial is pain freedom at 2 h. It is the endpoint suggested by the International Headache Society. This is a design that would result in a higher NNT compared with NNTs for other formulations studied by easier to reach endpoints. NNT for pain freedom at 2 h was 11.1, compared with NNTs of 4.7, 6.1 and 2.3 reported for 100 mg oral sumatriptan, 50 mg oral sumatriptan and 6 mg subcutaneous sumatriptan, respectively [Derry et al. 2012a, 2012c]. More recently, a phase III randomized, doubleblind, placebo-controlled trial evaluated the efficacy and tolerability of sumatriptan ITS for the acute treatment of a single moderate to severe migraine attack in 469 patients (18–66 years old) [Goldstein and Smith, 2012]. The proportion of patients who were pain free at 2 h after patch activation (the primary endpoint) was reached by a significantly larger proportion of patients treated with sumatriptan ITS compared with placebo (18% versus 9%; p = 0.0092). Significant favorable results were also reported for secondary endpoints, including freedom from nausea (71% versus 58%; p = 0.0251), photophobia (51% versus 36%; p = 0.0028), and phonophobia (55% versus 39%; p = 0.0002). The actively treated patients experienced rapid and sustained headache pain relief (at 2 h: 52.9% versus 28.6%, p < 0.0001), and used less rescue medication (by the 24 h time point: 60% versus 40%; p < 0.0001). Treatment-emergent AEs (mostly transient mild to moderate application-site reactions) were frequent in both groups, reported by 50% of patients receiving active treatment as well as 44% of those receiving placebo. An open-label extension of the latter study assessed the long-term tolerability and efficacy of sumatriptan ITS [Smith and Goldstein, 2012]. One hundred and eighty-three patients opted to use sumatriptan ITS to treat their moderate or severe migraine headaches for up to 12 months. In total, 2089 patches were used. The most common
AEs involved the patch application site (45%). The most common nonapplication site AEs included nausea (3.3%), upper respiratory tract infection (3.3%) and nasopharyngitis (2.2%). The incidence of triptan-associated AEs was 1.6%. At 2 h after patch activation, freedom from headache pain, headache pain relief, freedom from nausea, freedom from phonophobia, freedom from photophobia and freedom from migraine were reported by 23.8%, 58.2%, 78.9%, 60.1%, 53.4% and 20.7% of all patients, respectively. There was no evidence of waning tolerability or efficacy. Patient comfort The ease of assembly and application of a single use of the sumatriptan ITS during a migraine attack has been validated in a single-center, openlabel study [Meadows and Pierce, 2014]. Fortyeight subjects (20–64 years old) were equally divided into three groups: people with migraine trained to use sumatriptan ITS, people with migraine not trained to use sumatriptan ITS, and healthcare practitioners not trained to use sumatriptan ITS. The participants rated usability on a scale of 1–7 (1 being difficult, 7 being easy). Across the three groups, the mean score was 6.1 for ease of assembly and 6.8 for ease of application, indicating that patients can readily assemble and use sumatriptan ITS during a migraine attack. Specific populations Pregnancy. Sumatriptan ITS is a Pregnancy Category C medication, hence it should be used with caution to balance potential benefits with potential risks to the fetus [US FDA, 2013a]. Lactation. It is not known whether sumatriptan is excreted in human milk following transdermal administration. Given the potential for serious adverse reactions in nursing infants from exposure to sumatriptan, a decision should be made between discontinuing either nursing or medication [US FDA, 2013a]. Notably, sumatriptan tablets may be used by nursing mothers in the USA but it is recommended that infant exposure may be reduced by avoiding breast feeding for 12 h after administration. Children. Safety and effectiveness in pediatric patients has not been established. Older people. It is not known whether older patients (>65) respond differently than younger
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M Vikelis, KC Spingos et al. subjects to sumatriptan ITS since clinical studies have not included sufficient numbers of this specific population [US FDA, 2013a]. Cardiac risk. A cardiovascular evaluation is recommended for older patients with known cardiovascular risk factors [US FDA, 2013a]. Conclusion Sumatriptan ITS (Zecuity patch) produces a reasonably quick, consistent and well tolerated antimigraine action without triptan-related AEs. Based on the findings and interpretations above, including information from a review [Vikelis et al. 2012], people with migraine and gastroparesis resulting in delayed, partial or inconsistent response to oral formulations do well with ITS sumatriptan. Other reasons to consider the patch are vomiting or severe nausea which often lead to postponing or avoiding oral therapy; insufficient absorption in the GI tract; concerns about the possibility of vomiting after drinking water during a migraine attack; delay in using any type of medication for any reason; apprehension about using sumatriptan injections due to triptan-related AEs, discomfort or difficulty in using the apparatus. We expect that patients with these issues will find the sumatriptan patch useful. Conflict of interest statement Michail Vikelis has consulted for, advised, or spoken for Allergan, AstraZeneca Hellas, Janssen-Cilag Hellas, Nexus Medicals and Novis Pharmaceuticals Hellas. Konstantinos C. Spingos has spoken for Janssen-Cilag Hellas and Novartis Hellas S.A.C.I. Alan M. Rapoport has consulted or spoken for Allergan, Depomed, Doctor, Reddy’s, Impax, MAP, Merck, NuPathe, Transcept, and Winston. Funding No writing assistance or other support was utilized in the production of this manuscript. This research received no specific grant from any funding agency in the public, commercial, or notfor-profit sectors. References Aurora, S., Kori, S., Barrodale, P., Nelsen, A. and McDonald, S. (2007) Gastric stasis occurs in spontaneous, visually induced, and interictal migraine. Headache 47: 1443–1446. Burstein, R., Levy, D. and Jakubowski, M. (2005) Effects of sensitization of trigeminovascular neurons
to triptan therapy during migraine. Rev Neurol (Paris) 161: 658–660. Center for Drug Evaluation and Research (2012) Clinical Pharmacology and Biopharmaceutics Review(s). Available at: http://www.accessdata.fda.gov/ drugsatfda_docs/nda/2013/202278Orig1s000ClinPha rmR.pdf (accessed 12 February 2015). Derry, C., Derry, S. and Moore, R. (2012a) Sumatriptan (oral route of administration) for acute migraine attacks in adults. Cochrane Database Syst Rev 15(2): CD008615. Derry, C., Derry, S. and Moore, R. (2012b) Sumatriptan (intranasal route of administration) for acute migraine attacks in adults. Cochrane Database Syst Rev 15(2): CD009663. Derry, C., Derry, S. and Moore, R. (2012c) Sumatriptan (subcutaneous route of administration) for acute migraine attacks in adults. Cochrane Database Syst Rev 15(2): CD009665. Dowson, A., Bundy, M., Salt, R. and Kilminster, S. (2007) Patient preference for triptan formulations: a prospective study with zolmitriptan. Headache 47: 1144–1151. Ferrari, M. and Saxena, P. (1993) On serotonin and migraine: a clinical and pharmacological review. Cephalalgia 13: 151–165. Fuseau, E., Petricoul, O., Moore, K., Barrow, A. and Ibbotson, T. (2002) Clinical pharmacokinetics of intranasal sumatriptan. Clin Pharmacokinet 41: 801–11. Goldstein, J., Pugach, N. and Smith, T. (2009) Acute anti-migraine efficacy and tolerability of Zelrix, a novel iontophoretic transdermal patch of sumatriptan. Cephalalgia 29(Suppl. 1): 20. Goldstein, J. and Smith, T. (2012) A sumatriptan iontophoretic transdermal system for the acute treatment of migraine. Headache 52: 1402–1410. Headache Classification Subcommittee of the International Headache Society (2004) The international classification of headache disorders: 2nd edition. Cephalalgia 24(Suppl. 1): 9–160. Meadows, K. and Pierce, M. (2014) Sumatriptan transdermal system can be correctly assembled and applied during migraine attacks. Headache 54: 850–860. Menken, M., Munsat, T. and Toole, J. (2000) The global burden of disease study: implications for neurology. Arch Neurol 27: 418–420. Pierce, M., Marbury, T., O’Neill, C., Siegel, S., Du, W. and Sebree, T. (2009) Zelrix: a novel transdermal formulation of sumatriptan. Headache 49: 817–825.
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Therapeutic Advances in Neurological Disorders Rapoport, A., Freitag, F. and Pearlman, S. (2010) Innovative delivery systems for migraine: the clinical utility of a transdermal patch for the acute treatment of migraine. CNS Drugs 24: 929–940.
Bioequivalence and rapid absorption of zolmitriptan nasal spray compared with oral tablets in healthy Japanese subjects. Clin Drug Investig 25: 199–208.
Siegel, S., O’Neill, C., Dube, L., Kaldeway, P., Morris, R., Jackson, D. et al. (2007) A unique iontophoretic patch for optimal transdermal delivery of sumatriptan. Pharm Res 24: 1919–1926.
US FDA (2013a) Zecuity™. Full prescribing information. US Food and Drug Administration. Available at: http://www.accessdata.fda.gov/ drugsatfda_docs/label/2013/202278s000lbl.pdf (accessed 12 February 2015).
Silberstein, S. (1995) Migraine symptoms: results of a survey of self-reported migraineurs, Headache 35: 387–396. Smith, T. and Goldstein, J. (2012) Twelve-month tolerability and efficacy study of sumatriptan ITS, the Sumatriptan Iontophoretic Transdermal System. Headache 52: 612–624. Stovner, L., Hagen, K., Jensen, R., Katsarava, Z., Lipton, R., Scher, A. et al. (2007) The global burden of headache: a documentation of headache prevalence and disability worldwide. Cephalalgia 27: 193–210.
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Tepper, S. and Millson, D. (2003) Safety profile of the triptans. Expert Opin Drug Saf 2: 123–132. Uemura, N., Onishi, T., Mitaniyama, A., Kaneko, T., Ninomiya, K., Nakamura, K. et al. (2005)
US FDA (2013b) NDA approval. US Food and Drug Administration. Available at: http://www.accessdata. fda.gov/drugsatfda_docs/appletter/2013/202278Orig1s 000ltr.pdf (accessed 12 February 2015). Vikelis, M., Mitsikostas, D. and Rapoport, A. (2012) Sumatriptan iontophoretic patch (SUMATRIPTAN ITS): review of pharmacology, clinical efficacy and safety in the acute treatment of migraine. Neuropsychiatr Dis Treat 8: 429–434. Vikelis, M. and Rapoport, A. (2011) New drug delivery options for migraine. Expert Rev Neurother 11: 771–773. Vikelis, M. and Rapoport, A. (2012) Overview of oral triptans. In: Diener, H. and Dodick, D. (eds). Triptans for Migraine. London: Future Medicine E-Books.
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TAN0010.1177/1756285615585918Therapeutic Advances in Neurological DisordersM. Vikelis et al.
Therapeutic Advances in Neurological Disorders
Review
The iontophoretic transdermal system formulation of sumatriptan as a new option in the acute treatment of migraine: a perspective
Ther Adv Neurol Disord 1–6 DOI: 10.1177/ 1756285615585918 © The Author(s), 2015. Reprints and permissions: http://www.sagepub.co.uk/ journalsPermissions.nav
Michail Vikelis, Konstantinos C. Spingos and Alan M. Rapoport
Abstract: An iontophoretic transdermal system (ITS) (skin patch) formulation of sumatriptan for the acute treatment of migraine attacks was approved by the US Food and Drug Administration in January 2013. This transdermal system bypasses the gastrointestinal tract, as it uses low electrical current to move sumatriptan transdermally into the subcutaneous tissue. Randomized, double-blind, controlled clinical trials have demonstrated minimal triptan-related side effects and superior efficacy versus placebo, comparable with other sumatriptan formulations. Sumatriptan ITS can be applied successfully during a mild or severe migraine attack. According to pharmacokinetic properties and clinical data, sumatriptan ITS may be a good choice for people with migraine and severe nausea, vomiting or gastroparesis, those with intolerable triptan-related adverse events and those not responding optimally to oral medications.
Keywords: gastrointestinal absorption, iontophoretic transdermal system, migraine, migraine treatment, patch, sumatriptan Introduction Migraine is one of the most common primary headache disorders, affecting around 12% of the general population in Western countries. Episodic attacks of headaches of moderate or severe intensity are its clinical hallmark. Six out of ten people with migraine have at least one severe attack per month, and more than one-third have up to three severe attacks per month. The headache pain in migraine is often throbbing and commonly accompanied by photophobia, osmophobia, phonophobia and aura in around 15% of patients [Silberstein, 1995; Stovner et al. 2007; Headache Classification Subcommittee of the International Headache Society, 2004; Menken et al. 2000]. Gastrointestinal (GI) symptoms, such as nausea, vomiting and gastroparesis, are common and disabling, challenging the effective management of migraine. Nausea is reported by nine out of 10 patients and it is estimated to be present during half of the attacks in half of the people with migraine [Stovner et al. 2007]. In addition, the presence of nausea and vomiting has been shown
to be related to the intensity of the migraine headache [Stovner et al. 2007] and to increase migraine symptom burden and medication-related impairment in everyday activities [Stovner et al. 2007]. The combination of recurrent, severe headache attacks accompanied by autonomic and GI symptoms, interictal anxiety and comorbid illnesses such as depression and anxiety lead to the overall disabling nature of migraine [Silberstein, 1995; Stovner et al. 2007; Headache Classification Subcommittee of the International Headache Society, 2004; Menken et al. 2000].
Correspondence to: Michail Vikelis, MD, MSc, PhD Glyfada Headache Center, 8 Lazaraki Str. Glyfada 16675, Greece [email protected] Konstantinos C. Spingos, MD, PhD Corfu Headache Clinic, Corfu, Greece Alan M. Rapoport, MD The David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
Acute treatment of migraine attacks is recommended in practically all patients with migraine. Triptans (selective serotonin receptor agonists) are effective evidence-based treatments for migraine in patients without contraindications. Triptans are the mainstay of treatment for acute migraine attacks in Western medicine. Seven triptans are available worldwide: sumatriptan, zolmitriptan, naratriptan, rizatriptan, eletriptan, frovatriptan and almotriptan, although some of
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Therapeutic Advances in Neurological Disorders them are not available in every country. Clinical trials have shown that the efficacy of triptans is better when they are used early after the onset of a migraine attack, before central sensitization is established [Burstein et al. 2005]; but in many cases, GI symptoms have been shown to decrease the use of oral medications in at least one-third of patients [Silberstein, 1995]. Consequently, many people with migraine may postpone or even avoid the timely use of oral medications and a parenteral formulation may be a better choice for these cases [Vikelis and Rapoport, 2011]. Triptan tablets are the most commonly used form of triptans for acute migraine treatment [Vikelis and Rapoport, 2012]. Currently available parenteral triptan formulations include subcutaneous injections, nasal sprays and suppositories [three injectable formulations of sumatriptan; two nasal sprays (sumatriptan and zolmitriptan); no suppository in the USA]. The perception of injections as invasive, uncomfortable and causing more adverse events (AEs) limits the use of this type of parenteral formulations [Rapoport et al. 2010]. In addition, sumatriptan injections are associated with a higher recurrence rate in comparison to oral and nasal formulations [Tepper and Millson, 2003]. Discomfort has also been associated with the use of suppositories [Vikelis and Rapoport, 2012]. Nasal sprays are regarded as a preferable route of delivery for patients with gastric stasis as they are absorbed by the nasal mucosal surfaces. However, a considerable percentage of each dose may actually be swallowed and subsequently absorbed in the small intestine. In that case, the rate of absorption as well as the speed of action of nasal sprays would be compromised [Fuseau et al. 2002; Uemura et al. 2005]. There are findings suggesting that the percentage of patients who prefer nasal sprays over other formulations increases with time after the first use, but most patients still prefer tablets [Rapoport et al. 2010; Dowson et al. 2007]. All of the above leads to the assumption that alternative parenteral options for the treatment of acute migraine would be welcomed by many people with migraine [Vikelis and Rapoport, 2011], as well as their treating doctors. Sumatriptan iontophoretic transdermal system (sumatriptan ITS) is a recently approved novel device that might help to avoid some of the limitations of other routes of administration of triptans [US FDA, 2013a]
Indications The US Food and Drug Administration (FDA) has approved sumatriptan ITS (Zecuity, Teva Pharmaceuticals Industry Ltd, Tel Aviv, Israel) for the acute treatment of migraine with and without aura in adults [US FDA, 2013b]. Dosage and administration Iontophoresis is the method that uses low electrical current to move ionized drugs across the skin into the underlying subcutaneous tissue and from there into the blood circulation. It is a noninvasive method of drug delivery. Sumatriptan ITS includes an iontophoretic device and a drug reservoir card, which contains two nonwoven pads and two different gel formulations in wells; one is the active sumatriptan succinate and the other is sodium salt. The generated current applied in the positive well (anode) drives sumatriptan across the skin into the subcutaneous tissue and finally it is passively absorbed from the blood vessels. Sumatriptan ITS is designed to deliver 6.5 mg of sumatriptan over 4 h [US FDA, 2013a; Vikelis et al. 2012]. The system is destroyed if cut. Sumatriptan ITS must be applied only on dry, intact and nonirritated skin surfaces. The upper arm and the thigh are the proper body sites to apply it. After properly opening the package, preparing the patch and applying it to the skin, an activation button has to be pushed by the patient so that a red light turns on to signal that the system is active. After completion of the 4 h therapy, the system stops delivering drug and the light signal turns off automatically [US FDA, 2013a]. Patients should use only one patch at a time and no more than two in a 24 h period. In the latter case, the second patch should not be applied earlier than 2 h after removal of the first one [US FDA, 2013a]. Clinical pharmacology Pharmacodynamics and mechanism of action Sumatriptan is a selective agonist of the serotonin (5-hydroxytryptamine or 5-HT) receptor subtypes 1B and 1D. These receptors are found in blood vessels as well as in the presynaptic site of sensory synapses and in the brain stem, respectively. Sumatriptan has a dual mechanism of action. The activation of 5-HT1B receptors results in constriction of the dilated meningeal blood vessels. The simultaneous activation of 5-HT1D
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M Vikelis, KC Spingos et al. receptors on perivascular nerve terminals inhibits the release of vasoactive neuropeptides (e.g. substance P, calsitonin gene related protein) blocking the proinflammatory cascade [Ferrari and Saxena, 1993]. Sumatriptan may also have a central mechanism of action regarding the trigeminal nucleus caudalis at the level of the pons, where 5-HT1D receptors on the terminals of incoming trigeminal sensory fibers can disrupt the neurotransmission of pain. The class of 5-HT agonists has been associated with elevation in arterial blood pressure, including hypertensive crises, in patients with or without a history of arterial hypertension. However, no clinically significant changes in heart rate have been reported. Blood pressure changes are not common and it is unlikely to present a significant clinical problem, unless uncontrolled arterial hypertension is already present [US FDA, 2013a]. Pharmacokinetics The pharmacokinetics of the sumatriptan ITS has been investigated. One study compared the pharmacokinetic profile of four prototype sumatriptan patches with the subcutaneous sumatriptan injection (6 mg) and an oral tablet (50 mg) [Siegel et al. 2007]. The study was conducted in eight healthy adults with a crossover design and showed that the relationship between the amount of sumatriptan delivered and the quantity of the electric potential used is linear. The findings support iontophoresis as an effective method for the controlled delivery of sumatriptan. Besides that, AEs included application site reactions but no triptan-related AEs were recorded. Another study recruited 25 healthy adults who received a single dose of two different sumatriptan iontophoretic patches (containing 120 mg or 104 mg of sumatriptan succinate) and three older formulations of sumatriptan (100 mg tablet, 6 mg subcutaneous injection and 20 mg nasal spray). This study had an open-label, randomized, crossover design. Both patches showed lower maximum serum concentration (Cmax) compared with the subcutaneous and oral formulations, higher Cmax compared with the nasal preparation, and more consistent Cmax compared with the nasal spray and the tablet [Pierce et al. 2009]. Differences in consistency of plasma concentrations may have an important role in the therapeutic response, as gastric motility is reduced and drug absorption is compromised during an acute migraine attack, or
between attacks [Aurora et al. 2007]. Probably, the absence of typical triptan-related AEs observed with the patches in this study are explained by the finding that the Cmax of the 6 mg subcutaneous sumatriptan injection was more than three times higher compared with the Cmax of the sumatriptan ITS. Of note, the commercially available sumatriptan ITS has been slightly modified after feedback from both patients and investigators. Modifications include a new battery and changes to the dome of the patch in order to depress when pushed and turn on a red light signaling that the patch is activated. According to the bioequivalence study that was performed, the ratios of mean values for the commercial patch versus the study patch of Cmax, AUC0-inf (area under the plasma concentration– time curve from time 0 extrapolated to infinity) and AUC0-last (area under the plasma concentration– time curve from time 0 to the last quantifiable post-dose concentration) were 88.8, 81.4 and 91.2, respectively. The 90% confidence intervals of the ratios are within the 80–125% boundary as required by the FDA for the confirmation of bioequivalence [Center for Drug Evaluation and Research, 2012]. Clinical evidence for efficacy, adverse reactions and tolerance A randomized, double-blind, placebo-controlled phase III trial of sumatriptan ITS for the acute treatment of migraine recruited 530 adults [Goldstein et al. 2009]. The diagnosis of migraine was made according to the criteria of International Classification of Headache Disorders II. Subjects were treated by application of either sumatriptan ITS or placebo patch for one migraine attack of moderate to severe intensity. The percentage of patients achieving complete freedom from pain at 2 h after patch activation was achieved by 18% in the sumatriptan ITS group and 9% in the placebo group [number needed to treat (NNT) =11.1; p = 0.0092]. In addition, significantly more patients receiving the active substance achieved the secondary endpoints, including freedom from photophobia at 2 h after patch activation (51% versus 36%; NNT = 6.66; p = 0.0028), phonophobia (55% versus 39%; NNT = 6.25; p = 0.0002) and nausea (84% versus 63%; NNT = 4.8; p < 0.0001), no use of rescue medication (60% versus 40%; NNT = 5; p < 0.0001), relief from headache at 2 h (53% versus 29%; NNT = 4.2; p < 0.0001), relief from headache at 1 h (29% versus 19%; NNT = 10; p = 0.0135),
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Therapeutic Advances in Neurological Disorders freedom from nausea at 1 h (71% versus 58%; NNT = 7.7; p = 0.0251) and sustained headache relief within 2–24 h after patch activation (34% versus 21%; NNT = 7.7; p = 0.0015). The NNTs for headache relief at 1 and 2 h were consistent with the literature NNTs for 100 mg oral sumatriptan (6.8 and 3.5, respectively) [Derry et al. 2012a], and for 20 mg intranasal sumatriptan (4.9 and 3.5, respectively) [Derry et al. 2012b]. The most difficult single endpoint to reach in an acute migraine trial is pain freedom at 2 h. It is the endpoint suggested by the International Headache Society. This is a design that would result in a higher NNT compared with NNTs for other formulations studied by easier to reach endpoints. NNT for pain freedom at 2 h was 11.1, compared with NNTs of 4.7, 6.1 and 2.3 reported for 100 mg oral sumatriptan, 50 mg oral sumatriptan and 6 mg subcutaneous sumatriptan, respectively [Derry et al. 2012a, 2012c]. More recently, a phase III randomized, doubleblind, placebo-controlled trial evaluated the efficacy and tolerability of sumatriptan ITS for the acute treatment of a single moderate to severe migraine attack in 469 patients (18–66 years old) [Goldstein and Smith, 2012]. The proportion of patients who were pain free at 2 h after patch activation (the primary endpoint) was reached by a significantly larger proportion of patients treated with sumatriptan ITS compared with placebo (18% versus 9%; p = 0.0092). Significant favorable results were also reported for secondary endpoints, including freedom from nausea (71% versus 58%; p = 0.0251), photophobia (51% versus 36%; p = 0.0028), and phonophobia (55% versus 39%; p = 0.0002). The actively treated patients experienced rapid and sustained headache pain relief (at 2 h: 52.9% versus 28.6%, p < 0.0001), and used less rescue medication (by the 24 h time point: 60% versus 40%; p < 0.0001). Treatment-emergent AEs (mostly transient mild to moderate application-site reactions) were frequent in both groups, reported by 50% of patients receiving active treatment as well as 44% of those receiving placebo. An open-label extension of the latter study assessed the long-term tolerability and efficacy of sumatriptan ITS [Smith and Goldstein, 2012]. One hundred and eighty-three patients opted to use sumatriptan ITS to treat their moderate or severe migraine headaches for up to 12 months. In total, 2089 patches were used. The most common
AEs involved the patch application site (45%). The most common nonapplication site AEs included nausea (3.3%), upper respiratory tract infection (3.3%) and nasopharyngitis (2.2%). The incidence of triptan-associated AEs was 1.6%. At 2 h after patch activation, freedom from headache pain, headache pain relief, freedom from nausea, freedom from phonophobia, freedom from photophobia and freedom from migraine were reported by 23.8%, 58.2%, 78.9%, 60.1%, 53.4% and 20.7% of all patients, respectively. There was no evidence of waning tolerability or efficacy. Patient comfort The ease of assembly and application of a single use of the sumatriptan ITS during a migraine attack has been validated in a single-center, openlabel study [Meadows and Pierce, 2014]. Fortyeight subjects (20–64 years old) were equally divided into three groups: people with migraine trained to use sumatriptan ITS, people with migraine not trained to use sumatriptan ITS, and healthcare practitioners not trained to use sumatriptan ITS. The participants rated usability on a scale of 1–7 (1 being difficult, 7 being easy). Across the three groups, the mean score was 6.1 for ease of assembly and 6.8 for ease of application, indicating that patients can readily assemble and use sumatriptan ITS during a migraine attack. Specific populations Pregnancy. Sumatriptan ITS is a Pregnancy Category C medication, hence it should be used with caution to balance potential benefits with potential risks to the fetus [US FDA, 2013a]. Lactation. It is not known whether sumatriptan is excreted in human milk following transdermal administration. Given the potential for serious adverse reactions in nursing infants from exposure to sumatriptan, a decision should be made between discontinuing either nursing or medication [US FDA, 2013a]. Notably, sumatriptan tablets may be used by nursing mothers in the USA but it is recommended that infant exposure may be reduced by avoiding breast feeding for 12 h after administration. Children. Safety and effectiveness in pediatric patients has not been established. Older people. It is not known whether older patients (>65) respond differently than younger
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M Vikelis, KC Spingos et al. subjects to sumatriptan ITS since clinical studies have not included sufficient numbers of this specific population [US FDA, 2013a]. Cardiac risk. A cardiovascular evaluation is recommended for older patients with known cardiovascular risk factors [US FDA, 2013a]. Conclusion Sumatriptan ITS (Zecuity patch) produces a reasonably quick, consistent and well tolerated antimigraine action without triptan-related AEs. Based on the findings and interpretations above, including information from a review [Vikelis et al. 2012], people with migraine and gastroparesis resulting in delayed, partial or inconsistent response to oral formulations do well with ITS sumatriptan. Other reasons to consider the patch are vomiting or severe nausea which often lead to postponing or avoiding oral therapy; insufficient absorption in the GI tract; concerns about the possibility of vomiting after drinking water during a migraine attack; delay in using any type of medication for any reason; apprehension about using sumatriptan injections due to triptan-related AEs, discomfort or difficulty in using the apparatus. We expect that patients with these issues will find the sumatriptan patch useful. Conflict of interest statement Michail Vikelis has consulted for, advised, or spoken for Allergan, AstraZeneca Hellas, Janssen-Cilag Hellas, Nexus Medicals and Novis Pharmaceuticals Hellas. Konstantinos C. Spingos has spoken for Janssen-Cilag Hellas and Novartis Hellas S.A.C.I. Alan M. Rapoport has consulted or spoken for Allergan, Depomed, Doctor, Reddy’s, Impax, MAP, Merck, NuPathe, Transcept, and Winston. Funding No writing assistance or other support was utilized in the production of this manuscript. This research received no specific grant from any funding agency in the public, commercial, or notfor-profit sectors. References Aurora, S., Kori, S., Barrodale, P., Nelsen, A. and McDonald, S. (2007) Gastric stasis occurs in spontaneous, visually induced, and interictal migraine. Headache 47: 1443–1446. Burstein, R., Levy, D. and Jakubowski, M. (2005) Effects of sensitization of trigeminovascular neurons
to triptan therapy during migraine. Rev Neurol (Paris) 161: 658–660. Center for Drug Evaluation and Research (2012) Clinical Pharmacology and Biopharmaceutics Review(s). Available at: http://www.accessdata.fda.gov/ drugsatfda_docs/nda/2013/202278Orig1s000ClinPha rmR.pdf (accessed 12 February 2015). Derry, C., Derry, S. and Moore, R. (2012a) Sumatriptan (oral route of administration) for acute migraine attacks in adults. Cochrane Database Syst Rev 15(2): CD008615. Derry, C., Derry, S. and Moore, R. (2012b) Sumatriptan (intranasal route of administration) for acute migraine attacks in adults. Cochrane Database Syst Rev 15(2): CD009663. Derry, C., Derry, S. and Moore, R. (2012c) Sumatriptan (subcutaneous route of administration) for acute migraine attacks in adults. Cochrane Database Syst Rev 15(2): CD009665. Dowson, A., Bundy, M., Salt, R. and Kilminster, S. (2007) Patient preference for triptan formulations: a prospective study with zolmitriptan. Headache 47: 1144–1151. Ferrari, M. and Saxena, P. (1993) On serotonin and migraine: a clinical and pharmacological review. Cephalalgia 13: 151–165. Fuseau, E., Petricoul, O., Moore, K., Barrow, A. and Ibbotson, T. (2002) Clinical pharmacokinetics of intranasal sumatriptan. Clin Pharmacokinet 41: 801–11. Goldstein, J., Pugach, N. and Smith, T. (2009) Acute anti-migraine efficacy and tolerability of Zelrix, a novel iontophoretic transdermal patch of sumatriptan. Cephalalgia 29(Suppl. 1): 20. Goldstein, J. and Smith, T. (2012) A sumatriptan iontophoretic transdermal system for the acute treatment of migraine. Headache 52: 1402–1410. Headache Classification Subcommittee of the International Headache Society (2004) The international classification of headache disorders: 2nd edition. Cephalalgia 24(Suppl. 1): 9–160. Meadows, K. and Pierce, M. (2014) Sumatriptan transdermal system can be correctly assembled and applied during migraine attacks. Headache 54: 850–860. Menken, M., Munsat, T. and Toole, J. (2000) The global burden of disease study: implications for neurology. Arch Neurol 27: 418–420. Pierce, M., Marbury, T., O’Neill, C., Siegel, S., Du, W. and Sebree, T. (2009) Zelrix: a novel transdermal formulation of sumatriptan. Headache 49: 817–825.
http://tan.sagepub.com 5
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Therapeutic Advances in Neurological Disorders Rapoport, A., Freitag, F. and Pearlman, S. (2010) Innovative delivery systems for migraine: the clinical utility of a transdermal patch for the acute treatment of migraine. CNS Drugs 24: 929–940.
Bioequivalence and rapid absorption of zolmitriptan nasal spray compared with oral tablets in healthy Japanese subjects. Clin Drug Investig 25: 199–208.
Siegel, S., O’Neill, C., Dube, L., Kaldeway, P., Morris, R., Jackson, D. et al. (2007) A unique iontophoretic patch for optimal transdermal delivery of sumatriptan. Pharm Res 24: 1919–1926.
US FDA (2013a) Zecuity™. Full prescribing information. US Food and Drug Administration. Available at: http://www.accessdata.fda.gov/ drugsatfda_docs/label/2013/202278s000lbl.pdf (accessed 12 February 2015).
Silberstein, S. (1995) Migraine symptoms: results of a survey of self-reported migraineurs, Headache 35: 387–396. Smith, T. and Goldstein, J. (2012) Twelve-month tolerability and efficacy study of sumatriptan ITS, the Sumatriptan Iontophoretic Transdermal System. Headache 52: 612–624. Stovner, L., Hagen, K., Jensen, R., Katsarava, Z., Lipton, R., Scher, A. et al. (2007) The global burden of headache: a documentation of headache prevalence and disability worldwide. Cephalalgia 27: 193–210.
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Tepper, S. and Millson, D. (2003) Safety profile of the triptans. Expert Opin Drug Saf 2: 123–132. Uemura, N., Onishi, T., Mitaniyama, A., Kaneko, T., Ninomiya, K., Nakamura, K. et al. (2005)
US FDA (2013b) NDA approval. US Food and Drug Administration. Available at: http://www.accessdata. fda.gov/drugsatfda_docs/appletter/2013/202278Orig1s 000ltr.pdf (accessed 12 February 2015). Vikelis, M., Mitsikostas, D. and Rapoport, A. (2012) Sumatriptan iontophoretic patch (SUMATRIPTAN ITS): review of pharmacology, clinical efficacy and safety in the acute treatment of migraine. Neuropsychiatr Dis Treat 8: 429–434. Vikelis, M. and Rapoport, A. (2011) New drug delivery options for migraine. Expert Rev Neurother 11: 771–773. Vikelis, M. and Rapoport, A. (2012) Overview of oral triptans. In: Diener, H. and Dodick, D. (eds). Triptans for Migraine. London: Future Medicine E-Books.
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