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‘Zomig Rapimelt’ Rapid, reliable and convenient migraine treatment Clinical Product Summary ‘Zomig’ and ‘Zomig Rapimelt’ are trade marks of the AstraZeneca group of companies. Contents Foreword 2 Introduction 4 The ‘Zomig’ Range of Products 5 Pharmacokinetics 7 Clinical Efficacy 9 Fast onset of action High and sustained efficacy Relief of migraine-associated symptoms Resumption of daily activities Tolerability 15 Patient Preferences 16 Preference compared with conventional tablets Preference compared with other orally disintegrating tablets Post-marketing Experience 20 ‘Zomig Rapimelt’ Product Summary 22 1 Foreword Dr Andrew Dowson, The King’s Headache Services, King’s College Hospital, London, UK Primary goals in the acute treatment of migraine are to provide rapid, reliable and sustained relief from headache pain and migraineassociated symptoms, by administration of well-tolerated and patient-friendly medications.The emergence of the migraine-specific treatments known as 5-Hydroxytryptamine 1B and 1D (5-HT1B/1D) receptor agonists or ‘triptans’ in the early 1990s represented a major step towards realisation of these goals.Today, several triptans are available. Zolmitriptan (‘Zomig’†), a 2nd generation triptan, is available in 3 different formulations, so that it is now possible to make prescribing decisions on a case-by-case basis, in order to provide treatments based on patient expectations, preferences, migraine characteristics and lifestyles. Conventional tablets are the most frequently used formulation and are often preferred for the treatment of migraine. However, many patients suffer from nausea during a migraine attack and have difficulties swallowing conventional oral tablets. Fluid intake may exacerbate nausea and provoke vomiting. Migraine attacks occur unpredictably and can easily strike in situations where fluids to take with the medication are not readily available. Patients ideally require a treatment that enables any migraine to be promptly treated in any given situation. Zolmitriptan has been available as a conventional oral tablet since 1997 and is established as a fast, effective and well-tolerated therapy for the acute treatment of migraine. An orally disintegrating tablet (ODT) formulation of zolmitriptan that dissolves on the tongue, with no need for additional fluid intake, has also been developed.This formulation offers a convenient alternative for patients who cannot or prefer not to take conventional tablets. The fact that the orally disintegrating tablet can be taken without 2 liquids allows patients to take the medication early in the course of a migraine attack, which has been proven to improve response to treatment. Data presented in this clinical product summary show that the orally disintegrating formulation of zolmitriptan is bioequivalent to the conventional tablet. Placebo-controlled trials and postmarketing surveillance data confirm that orally disintegrating zolmitriptan provides fast-acting, highly effective and well-tolerated relief of migraine and its associated symptoms.Treatment satisfaction data show that patients generally consider orally disintegrating zolmitriptan to be a more convenient option than conventional tablets and that it facilitates the treatment of migraine whenever and wherever it strikes. Post-marketing studies also suggest that zolmitriptan orally disintegrating tablet is preferred to other available triptans. † Zomig Rapimelt is the registered trade mark in Australia, Austria, Denmark, Finland, Iceland, Ireland, Mexico, Norway, Portugal, Sweden and the UK. Elsewhere the product is identified as Zomig Rapimelt (Canada, Italy), ZomigOro (France), Ascotop Schmeltztabletten (Germany), Zomig-ZMT (USA), Zomig Flas (Spain), Zomig Oro (Switzerland), ZomigZip (Holland), Zomig Instant (Belgium), Zomig Instant (Luxembourg), Zomig OD (Brazil) and Zomigon Rapimelt (Greece). 3 Introduction Migraine is a common medical condition characterised by neurological, gastrointestinal and autonomic symptoms,[1] and is estimated to affect 10% to 15% of the worldwide population.[2] The chronic and debilitating nature of migraine, attacks of which occur unpredictably and unexpectedly, can impede patients’ ability to carry on with normal activities of daily living, thereby reducing quality of life[3,4] and having a negative socioeconomic influence.[5–7] Although the precise aetiology of migraine is not completely clear, the trigeminovascular system is thought to play a vital role in its pathogenesis.[8] Upon inappropriate activation of the trigeminal nerve pathway, vasoactive neuropeptides are released, ultimately resulting in neurogenic inflammation, pain, nausea, phonophobia and photophobia. It is widely accepted that 5-HT1B and 5-HT1D receptors play an integral role in the generation of migraine attacks. Despite progress in the understanding of the underlying pathophysiology of migraine and the development of drugs, such as the triptans, that specifically target the disease process, migraine is still an under-diagnosed and under-treated condition.[9,10] ‘Zomig’ attacks migraine through both central and peripheral activity Zolmitriptan (‘Zomig’), first introduced in 1997, is a highly effective and selective 5-HT1B/1D receptor agonist that is able to inhibit activation of the trigeminovascular system both peripherally and centrally.[11–13] The N-desmethyl metabolite of zolmitriptan, 183C91, also has high affinity for 5-HT1B/1D receptors.The structural formula of zolmitriptan is shown in figure 1. O O NH H N N(CH3)2 Figure 1. Structural formula of zolmitriptan. 4 The ‘Zomig’ Range of Products Although triptans have been traditionally formulated as conventional oral tablets, this may not be the most suitable formulation for all patients or for every situation.The results of clinical trials and patient surveys have shown that highly effective pain relief with a rapid onset of action is a top priority for patients and physicians alike.[10,14] Although oral therapy has generally been considered the preferred route of administration, some patients dislike taking conventional tablets, others have difficulty swallowing tablets during an attack, and some find that swallowing tablets can induce and/or exacerbate nausea and vomiting. Furthermore, it is not always possible to access liquids quickly in the event of a migraine attack. A survey of patients with migraine in France, Germany, Italy, the UK and the USA found that only a minority of patients (36%) were very satisfied with the migraine therapy currently used and that many supplemented prescribed medication with alternative therapies.[10] Data also show that 34% of migraine patients do not feel in control of life,[5] 78% report limitations of daily routines and 45% worry about an attack while driving.[15] When patients were asked which form of migraine medication was preferred, 73% chose tablets that dissolve in the mouth and can be taken without liquid.[5] Conventional ‘Zomig’ tablets, first launched in 1997, are now available worldwide for the acute treatment of migraine attacks with or without aura, and are the cornerstone of oral therapy for many patients. Clinical trials have established that the conventional ‘Zomig’ tablet is reliably effective and well tolerated in the acute 5 ‘Zomig Rapimelt’ can be taken whenever and wherever a migraine attack strikes treatment of migraine, with an onset of effect reported as early as 30 minutes after dosing.[16,17] ‘Zomig’ is also widely available as an orally disintegrating tablet that dissolves rapidly on the tongue and can be taken discreetly as soon as a migraine headache starts with no need for additional fluid intake. This convenient Rapimelt formulation provides excellent relief for patients who, for whatever reason, prefer not to/cannot take conventional tablets.The convenience of ‘Zomig Rapimelt’ may also allow patients to take the medication earlier in the course of a migraine attack, when water or other liquids may not be available. Clinical research has shown that treating migraine early in the course of an attack results in a more effective response to therapy.[18] The ‘Zomig’ range of products is completed by the nasal spray formulation. ‘Zomig’ Nasal Spray offers even faster relief than the oral route of administration via an easy to use, one-dose, discreet device for intra-nasal delivery. In summary, ‘Zomig’ is available in a range of delivery options that suits different lifestyles and situations.These formulations have been carefully developed to satisfy the needs and preferences of a wide range of patients. Physicians can therefore match treatments to individual patients, and a thorough assessment of each patient’s expectations, needs and preferences should be performed before a prescribing decision is made. The following sections describe the ability of ‘Zomig Rapimelt’ to provide fast and consistently effective relief of migraine with excellent tolerability. Patient perceptions of the convenience and practicality of ‘Zomig Rapimelt’ are also discussed. 6 Pharmacokinetics The pharmacokinetic profile of ‘Zomig Rapimelt’ can by summarised by: • • Bioequivalence to the conventional oral tablet • Elimination kinetics similar to those of the conventional oral tablet Rapid detection of the parent drug in the plasma, appearing at similar rates to the conventional oral tablet All of the above factors predict that, like the conventional oral tablet, ‘Zomig Rapimelt’ will be associated with rapid, long-lasting and reliable efficacy, paralleled by excellent tolerability. After being placed on the tongue,‘Zomig Rapimelt’ dissolves in seconds. The drug is rapidly dispersed and absorbed via the gastrointestinal route, with appearance of zolmitriptan in the plasma within 30 minutes of dosing.[19] The resultant zolmitriptan plasma concentration-time curve is similar to that observed after administration of a conventional ‘Zomig’ tablet (figure 2). Bioequivalence of ‘Zomig Rapimelt’ and the conventional tablet has been confirmed for both parent compound and the active N-desmethyl metabolite.[19] A slightly delayed time to zolmitriptan maximum plasma concentration (tmax) has been noted with ‘Zomig Rapimelt’ (3 hours vs 1.5 hours; table I). However, as can be seen from figure 2, there is a plateau of plasma concentrations between the 2nd and 5th hours post-dose, suggesting that the precise time of tmax within this time frame is of no clinical importance. Similar onset of action can be expected for ‘Zomig Rapimelt’ and ‘Zomig’ conventional tablet, since the plasma concentrations of zolmitriptan for each formulation are similar during the first 45 minutes after dosing (figure 2). 7 'Zomig' oral tablet 5 mg (2 x 2.5 mg) 'Zomig Rapimelt' 5 mg (2 x 2.5 mg) 10 Plasma concentration (ng/mL) ‘Zomig Rapimelt’ is bioequivalent to and offers all the benefits of the ‘Zomig’ conventional tablet 1 0.1 3 0 6 9 12 15 Nominal time (h) Figure 2. Geometric mean plasma concentrations of zolmitriptan following dosing with ‘Zomig Rapimelt’ (2 x 2.5 mg) compared with the conventional oral tablet (2 x 2.5 mg) in healthy volunteers.[19] In order for two formulations of a drug to have similar clinical characteristics they must be bioequivalent.Accordingly, the bioequivalence of ‘Zomig Rapimelt’ to conventional ‘Zomig’ tablets shows that ‘Zomig Rapimelt’ is well equipped to provide the rapid, long-lasting, reliable and well-tolerated relief from migraine pain that has become the hallmark of the conventional ‘Zomig’ tablet. Table I. Pharmacokinetic parameters of zolmitriptan and 183C91 after 3 single 5 mg (2 x 2.5 mg doses) doses of ‘Zomig Rapimelt’ or the conventional oral tablet in healthy volunteers[19] AUC (ng•h/ml) Cmax (ng/ml) tmax (hours) t1/2 (hours) Geometric CV mean Geometric CV mean Median Range Mean SD ‘Zomig Rapimelt’ Zolmitriptan (n=18) 51.1 51.9 8.8 43.6 3.0 0.6–5.0 2.9 0.4 183C91 (n=18) 36.5 18.1 5.8 20.2 3.0 1.0–6.0 3.0 0.5 Conventional tablet Zolmitriptan (n=18) 51.4 45.9 9.7 32.7 1.5 0.5–3.0 3.1 0.5 183C91 (n=18) 35.3 14.7 5.6 20.9 3.0 0.7–5.0 3.3 0.7 Abbreviations: AUC = area under the plasma concentration–time curve; Cmax = maximum plasma concentration; CV = coefficient of variation; n = number of volunteers assessed; SD = standard deviation; t1/2 = elimination half-life; tmax = time to maximum plasma concentration. 8 Clinical Efficacy Predictions regarding the efficacy of ‘Zomig Rapimelt’ for the acute treatment of migraine on the basis of its pharmacokinetic profile have been demonstrated in controlled clinical trials. Features of the efficacy of ‘Zomig Rapimelt’ in the acute treatment of migraine include: • • • a fast (30-minute) onset of action early and high pain-free status high, sustained pain relief. Three randomised, multicentre, double-blind, placebo-controlled trials involving patients with an established diagnosis of migraine have recently been performed. Active treatment was ‘Zomig Rapimelt’ 2.5 mg in studies A[20] and B[21] and ‘Zomig Rapimelt’ 5 mg in study C.[22] Study B differed slightly to studies A and C, in that patients were instructed to treat an attack as soon as possible, regardless of headache pain intensity, whereas in the other 2 studies, only attacks with moderate or severe pain were treated. Intention-to-treat populations consisted of 470 patients who treated a single migraine headache in study A, and 565 and 670 patients who treated up to 2 migraine attacks in studies B and C, respectively. In study B, 32.4% of attacks were of mild intensity at baseline. 9 ‘Zomig Rapimelt’ starts to work within 30 minutes ‘Zomig Rapimelt’ abolishes migraine headache within 1 hour 10 Fast onset of action Headache response, defined as a reduction in the intensity of pain from severe or moderate at baseline to mild or none, has been achieved as early as 30 minutes after dosing in higher proportions of patients treated with ‘Zomig Rapimelt’ relative to patients treated with placebo (figures 3 and 4). In study A, in which headache response at 30 minutes was assessed as a secondary end-point, there was a clear difference in headache response between ‘Zomig Rapimelt’ and placebo at 30 minutes (16% vs 10%, p=0.054; figure 3).This study also demonstrated that ‘Zomig Rapimelt’ provided an improvement in headache (1-point improvement in headache pain intensity) from 30 minutes (22% vs 15% for placebo; p=0.039). In study C, in which headache response at 30 minutes was the primary efficacy end-point, 16% of migraine attacks treated with ‘Zomig Rapimelt’ responded at 30 minutes compared with 13% of attacks treated with placebo (p<0.05; figure 4).When 30-minute response rates from studies A and B were pooled, the overall response was 20.1% for ‘Zomig Rapimelt’ and 12.7% for placebo (p<0.005).[17] This fast onset of action is consistent with pharmacokinetic observations that ‘Zomig Rapimelt’ is bioequivalent to the conventional tablet, which has also been shown to induce a significantly better response than placebo as soon as 30 minutes after dosing.[16,17] ‘Zomig Rapimelt’ was able to achieve significantly greater pain-free rates than placebo as early as 1 hour after dosing in all 3 studies. Figure 5 shows that, in study B, a pain-free outcome at 1 hour was achieved in 13.3% of attacks treated with ‘Zomig Rapimelt’ compared with 8.1% of attacks treated with placebo (p<0.005). A pooled analysis of studies A and B showed that 1-hour pain-free rates were significantly higher for ‘Zomig Rapimelt’ than placebo (7.8% vs 3.4%; p<0.05).[19] 75 'Zomig Rapimelt' 2.5 mg ** Response rate (patients [%]) Placebo 50 ** 25 * 2 ho ur ur 1 ho s te in u 30 m s 0 Time post-dose Figure 3. Headache response rates at 30 minutes to 2 hours after dosing with ‘Zomig Rapimelt’ 2.5 mg or placebo, in study A.[20] *p=0.054 vs placebo; **p<0.0001 vs placebo. 75 'Zomig Rapimelt' 5 mg Response rate (attacks [%]) Placebo ** 50 ** 25 * ho ur s 2 ho ur 1 30 m in ut es 0 Time post-dose Figure 4. Headache response rates from 30 minutes to 2 hours after dosing with ‘Zomig Rapimelt’ 5 mg or placebo, in study C.[22] *p<0.05 vs placebo; **p<0.0001 vs placebo. 11 ‘Zomig Rapimelt’ provides high and lasting relief from migraine headache High and sustained efficacy Headache response at 2 hours, which was the primary efficacy outcome in study A and a secondary outcome in study C, occurred in significantly greater proportions of patients treated with ‘Zomig Rapimelt’ than in patients who received placebo (figures 3 and 4).There was a 63% headache response at 2 hours in patients receiving ‘Zomig Rapimelt’ in study A compared with a 22% placebo response rate (p<0.0001). In study C, these were 59% and 31%, respectively (p<0.0001).The high 2-hour headache responses seen in studies A and C were sustained (defined as headache response at 2 hours with no recurrence of headache pain for 24 hours) over a 24-hour period in 40% and 43% of patients, respectively (vs 12% and 16%, respectively, for placebo). Pain-free rate at 2 hours was the primary efficacy end-point of study B; approximately twice the proportion of attacks treated with ‘Zomig Rapimelt’ than those treated with placebo were pain-free at 2 hours (40.1% vs 19.8%; p<0.001; figure 5).This pain-free outcome was sustained (defined as patients with no pain at 24 hours postdosing and no need for re-medication, or free from headache recurrence from 2 to 24 hours) in 31.1% of attacks treated with ‘Zomig Rapimelt’ and 14.6% of those treated with placebo (p<0.001). 75 'Zomig Rapimelt' 2.5 mg Pain-free rate (attacks [%]) Placebo 50 ** 25 * ho ur s 2 r ho u 1 30 m in ut es 0 Time post-dose Figure 5. Pain-free rates from 30 minutes to 2 hours after dosing with ‘Zomig Rapimelt’ 2.5 mg or placebo, in study B.[21] *p<0.005 vs placebo; **p<0.001 vs placebo. 12 Relief of migraine-associated symptoms Where present, migraine-associated nausea, photophobia and phonophobia were improved by ‘Zomig Rapimelt’ in all 3 studies. For example, in study B, nausea resolved 2 hours after dosing with ‘Zomig Rapimelt’ in 66.3% of attacks where present at baseline (vs 38.9% for placebo; p<0.001; figure 6). Photophobia and phonophobia resolved at 2 hours in 59% of attacks each (vs 37.7% and 41%, respectively, for placebo; p<0.001 for both symptoms; figure 6). Similarly, in patients who had symptoms at baseline in study C, nausea had resolved in 57% of attacks (vs 45% for placebo; p<0.05), photophobia in 47% of attacks (vs 26% for placebo; p<0.0001) and phonophobia in 52% of attacks (vs 31% for placebo; p<0.0001) at 2 hours after administration of ‘Zomig Rapimelt’. ‘Zomig Rapimelt’ effectively resolves all symptoms associated with migraine In study A, 52% of patients were free from nausea, 46% from photophobia and 53% from phonophobia 2 hours after dosing with ‘Zomig Rapimelt’ (compared with 32%, 25% and 26%, respectively, for placebo). 'Zomig Rapimelt' 2.5 mg Placebo Resolution of associated symptoms (attacks [%]) 75 * * * 50 25 a N au se ho bi on op Ph Ph ot op ho b ia a 0 Figure 6. Resolution of migraine-associated symptoms 2 hours after dosing with ‘Zomig Rapimelt’ 2.5 mg or placebo in study B.[21] *p<0.001 vs placebo. 13 ‘Zomig Rapimelt’ helps patients to regain control of life Resumption of daily activities As assessed in studies B and C, ‘Zomig Rapimelt’ aided resumption of daily activities in patients in whom these activities were impaired during migraine attacks. In study B, patients were able to resume activities within 2 hours of taking ‘Zomig Rapimelt’ in 55.8% of attacks (vs 34.0% for placebo; p<0.001; figure 7). Similarly, in study C, patients were able to return to normal daily activities in 52% of attacks 2 hours after dosing with ‘Zomig Rapimelt’ (vs 26% for placebo; p<0.0001). Resumption of daily activities was not assessed in study A. As mentioned on page 7, ‘Zomig Rapimelt’ is bioequivalent to ‘Zomig’ conventional tablet and will therefore demonstrate similar clinical characteristics. Accordingly, ‘Zomig Rapimelt’ is expected to provide rapid, long-lasting and reliable efficacy both within and between patients, as shown by ‘Zomig’ conventional tablet. Resumption of daily activities (attacks [%]) 75 'Zomig Rapimelt' 2.5 mg Placebo *** *** 50 ** 25 * ho ur s 2 ho ur s ur ho 1 1. 5 30 m in ut es 0 Time post-dose Figure 7. Ability to resume normal activities of daily living 30 minutes to 2 hours after dosing with ‘Zomig Rapimelt’ 2.5 mg or placebo in study B.[21] *p=0.06 vs placebo; **p<0.005 vs placebo; ***p<0.001 vs placebo. 14 Tolerability As predicted by pharmacokinetic observations regarding the bioequivalence of ‘Zomig Rapimelt’ to the conventional oral tablet, ‘Zomig Rapimelt’ is well tolerated in the acute treatment of migraine. Adverse events most commonly reported in patients treated with ‘Zomig Rapimelt’ 2.5 mg and 5 mg in placebocontrolled studies A, B and C included the typical triptan class effects of throat tightness, paraesthesia, dizziness, somnolence and asthenia (table II).The majority of adverse events were transient, of mild to moderate intensity, and did not lead to withdrawal. Indeed, no patients were withdrawn from study A because of adverse events after taking ‘Zomig Rapimelt’, and only 1.1% (3/282) and 2.1% (7/329) of patients were withdrawn from studies B and C, respectively. ‘Zomig Rapimelt’ is well tolerated Table II. Adverse events reported by >2% of patients in any treatment group in study A,[20] study B[21] or study C[22] Adverse event (% patients) Total Tightness Paraesthesia Dizziness Somnolence Asthenia Nausea Hyperesthesia Myalgia Vasodilation Heaviness Dry mouth Aggravation reaction Hypertonia Pharyngitis Study A Study B Study C Placebo (n=240) ‘Zomig Rapimelt’ 2.5 mg (n=231) Placebo (n=284) ‘Zomig Rapimelt’ 2.5 mg (n=282) Placebo (n=329) ‘Zomig Rapimelt’ 5 mg (n=342) 12.1 0 0.8 0.8 1.7 1.3 1.3 0 27.3 2.6 2.2 2.6 3.0 3.5 2.2 2.2 11.6 0.4 1.1 2.5 2.1 0.7 2.1 0 26.6 5.0 4.6 5.3 4.6 2.1 2.1 1.1 11.4 0.3 0.3 2.0 2.0 0.9 0 29.5 6.4 5.2 4.9 4.6 3.6 3.3 1.4 0.7 1.8 0.7 1.4 2.5 1.4 1.8 0 1.4 0 1.8 0.6 0.9 0.3 0.3 0 3.3 3.3 2.4 2.4 2.1 2.1 2.1 Abbreviation: n = number of patients. 15 Patient Preferences ‘Zomig Rapimelt’ is a convenient treatment for patients Patients need migraine treatments to be rapidly and highly effective.[10,14] However, different triptans have been found to have broadly similar efficacy profiles when used in clinical practice, so it is difficult to differentiate between triptans on an efficacy basis alone. With the increasing choice of migraine therapies and drug formulations available, patient preference is an important factor to consider when selecting the most appropriate migraine therapy. A survey of migraineurs found that 73% of patients would prefer to use tablets that dissolve in the mouth without the need for fluids.[10] As migraine can affect sufferers at any time, patients also need a treatment that can be taken anywhere, immediately after the onset of an attack.‘Zomig Rapimelt’ dissolves rapidly on the tongue without the need for fluid intake, facilitating early treatment in situations where fluids are not readily available. Such early treatment of migraine has been shown to improve treatment outcomes.[18] Preference compared with conventional tablets Patients prefer ‘Zomig Rapimelt’ to conventional tablets 16 In efficacy study A, 469 patients provided general treatment preference and acceptability data for ‘Zomig Rapimelt’. Overall, 70% of these patients preferred ‘Zomig Rapimelt’ to conventional tablets (figure 8). Most patients considered ‘Zomig Rapimelt’ to be easier to handle (92%) and a more convenient treatment option (78%) than conventional tablets, while 70% stated that it could be taken earlier in the course of a migraine attack than a conventional tablet. Patient preference for ‘Zomig Rapimelt’ over conventional tablets was not 100 Patients (%) 75 50 25 th Pr ef er ov er co nv en tio na an M lt ab co or le nv e c t en on t v i th on en an al ie ta nt co Can bl nv ta et en ke tio s o na o l t ne ab r Ea le sy t to Li ha ke nd th le e or an ge ta st e 0 Figure 8. Preference for and acceptability of ‘Zomig Rapimelt’, as specified by patients from study A.[20] affected by the presence of nausea (70% and 69% for patients with and without nausea at baseline, respectively), while 80% liked the orange flavour. In a recent multicentre, randomised, open-label, crossover study patients with an established diagnosis of migraine received ‘Zomig Rapimelt’ 2.5 mg or a conventional sumatriptan tablet 50 mg for the acute treatment of 2 consecutive migraine attacks of any intensity (intention-to-treat population of 186 patients).[23] Overall,‘Zomig Rapimelt’ was preferred to the conventional sumatriptan tablet by significantly more patients (60.1% vs 39.9%; p=0.013). Patients prefer ‘Zomig Rapimelt’ to sumatriptan In terms of efficacy, significantly more patients considered ‘Zomig Rapimelt’ a more effective treatment than sumatriptan conventional tablet (77% vs 63%; p=0.0063).‘Zomig Rapimelt’ was also considered to be the least disruptive, easiest and most convenient therapy to take by most patients, and therefore the best treatment for maintenance of an active lifestyle (figure 9).Very high percentages of patients agreed that ‘Zomig Rapimelt’ allows attacks to be treated anywhere (91.4%) and any time (90.2%). Importantly, 95.5% of patients who had a history of difficulty swallowing tablets considered 17 Patients find ‘Zomig Rapimelt’ more convenient and easy to take than sumatriptan 'Zomig Rapimelt' 2.5 mg Sumatriptan oral tablet 50 mg 100 Patients (%) 75 * ** ** ** ** 50 25 Le C on si de re d an ef f tre ect at ive m as en t t op dis Ea tio rup si n tiv es to e to ta pt ke io n t o M ta os ke tc o En op nv ab t e le ion nie s to nt m of a ta ke ac int e tiv n e an lif ce es ty le 0 Figure 9. Patient preferences for and opinions of ‘Zomig Rapimelt’ 2.5 mg and conventional oral sumatriptan 50 mg in a study by Dowson and Charlesworth.[23] *p<0.01 vs conventional sumatriptan tablet; **p<0.0001 vs conventional sumatriptan tablet. ‘Zomig Rapimelt’ to be easier to take than the conventional sumatriptan tablet (vs 4.5% for sumatriptan tablet), as did 59.6% of patients with nausea and/or vomiting at baseline (vs 40.4% for sumatriptan tablet). Preference compared with other orally disintegrating tablets In a recent patient preference study a total of 171 patients with an established history of migraine assessed the taste and ease of use of ‘Zomig Rapimelt’ 2.5 mg and rizatriptan ODT 10 mg during a migraine-free period.[24] Results showed that 81% of patients liked ‘Zomig Rapimelt’ overall, compared with 68% who liked rizatriptan ODT (p<0.05). Similarly, 84% of patients would be likely to use ‘Zomig Rapimelt’ again, compared with 71% who would use rizatriptan ODT again (p<0.05). Overall, when all formulation attributes were taken into consideration, 70% of patients preferred ‘Zomig Rapimelt’ to rizatriptan ODT (27%; p<0.001).‘Zomig 18 ‘Zomig Rapimelt’ is preferred to rizatriptan orally disintegrating tablet 'Zomig Rapimelt' 2.5 mg Rizatriptan ODT 10 mg 100 Patients (%) 75 50 25 un d ho ers w ta to nd op en Ea si er to to ta of ke pa ou ck t ag e Ea M or e si er co nv en ie to nt us e 0 Figure 10. Patient preferences for package attributes of zolmitriptan and rizatriptan orally disintegrating tablets.[24] Rapimelt’ was also the preferred product with respect to various aspects of taste (table III) and, in an overall taste assessment, significantly more patients preferred ‘Zomig Rapimelt’ than rizatriptan ODT (73% vs 24%; p=0.01).The product packaging of ‘Zomig Rapimelt’ was also preferred over rizatriptan ODT (figure 10). Of the 37 adverse events reported in the study, 23 occurred in association with rizatriptan ODT and 14 in association with ‘Zomig Rapimelt’. Table III. Patient preference data for ‘Zomig Rapimelt’ and the rizatriptan ODT formulation[24] Like the taste of the product Strength of taste is ‘just about right’ Sweetness is ‘just about right’ Taste is not too bitter Experienced an aftertaste Aftertaste was ‘unpleasant’ Aftertaste was ‘just about right’ Agree that it does not leave a bad taste Agree that it has no medicine taste ‘Zomig Rapimelt’ 2.5 mg (patients [%]) Rizatriptan ODT 10 mg (patients [%]) 70 68 71 71 56 13 74 77 67 46 35 55 36 89 28 40 38 46 p<0.05 for all comparisons. 19 Post-marketing Experience The results of a 3-month non-comparative, non-interventional post-marketing surveillance study have confirmed ‘Zomig Rapimelt’ to be a highly effective, well-tolerated, convenient and preferred migraine therapy in real life. Efficacy analysis was performed on the data from 14 543 patients, and data were available for 13 913 patients who remained in the study for ≥76 days. For the first migraine attack of the study period, headache pain had improved within 2 hours of taking ‘Zomig Rapimelt’ in 94% of patients (figure 11). Improvement of migraine Improved ability to perform activities of daily living/functional capacity Patients (% ) 100 75 50 25 ho ur s >2 2 ho ur s r ho u 1 30 m in ut es 0 Time post-dose Figure 11. Percentage of patients with improvement in migraine and percentage of patients with improved ability to perform activities of daily living/functional capacity from 30 minutes to >2 hours after dosing with ‘Zomig Rapimelt’ in a post-marketing surveillance study.[19] 20 Ability to perform normal activities had improved within 2 hours of taking ‘Zomig Rapimelt’ in 84% of patients where this was impaired at baseline (figure 11). Nausea was the most common symptom to accompany headache pain in an attack (92%); both nausea and vomiting had decreased within 2 hours of taking ‘Zomig Rapimelt’ in 91% of patients.The disability associated with migraine, which can be assessed by using the Migraine Disability Assessment Scale (MIDAS) questionnaire, was reduced by over half at the end of the study (28.5 at entry vs 11.4 at the end of study). In comparison to the minority of patients (12%) who reported very good or good efficacy with previous therapy, 94% of patients considered ‘Zomig Rapimelt’ to have good or very good efficacy.The tolerability of ‘Zomig Rapimelt’ was considered to be good or very good throughout the study period in 96% of patients. Furthermore, the majority of patients (81%) considered that the advantage of taking ‘Zomig Rapimelt’ without fluid intake was important or very important, and the study also demonstrated that 95% of patients would be willing to continue using ‘Zomig Rapimelt’ in the future. The excellent efficacy, tolerability and convenience benefits of ‘Zomig Rapimelt’ have been confirmed in a real-life setting 21 ‘Zomig Rapimelt’ Product Summary 22 • Bioequivalence with ‘Zomig’ conventional tablet and, therefore, similar efficacy, safety and tolerability benefits • • • • Onset of efficacy as early as 30 minutes • • • • • Convenient and easy to take • Pleasant orange flavour High, sustained efficacy Excellent tolerability profile Favourable patient preference profile compared with other oral triptans The preferred melt tablet for migraine Allows early treatment of migraine Acceptable to patients with nausea Preferred by patients with difficulty in swallowing conventional tablets References 1. International Headache Society. Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Cephalalgia 1988; 8 (Suppl. 7): 1–96 2. Lipton RB, Silberstein SD, Stewart WE. An update on the epidemiology of migraine. Headache 1994; 34: 319–28 3. Osterhaus JT,Townsend RJ, Gandek B, et al. Measuring the functional status and well-being of patients with migraine headache. Headache 1994; 34: 337–43 4. Von Korff M, Stewart WF, Simon DJ, et al. Migraine and reduced work performance: a population-based diary study. Neurology 1998; 50: 1741–5 5. Clarke CE, Macmillan L, Sondhi S, et al. Economic and social impact of migraine. QJ Med 1996; 89: 77–84 6. Ferrari MD. The economic burden of migraine to society. Pharmacoeconomics 1998; 13: 667–76 7. Hu XH, Markson LE, Lipton RB, et al. Burden of migraine in the United States: disability and economic costs.Arch Intern Med 1999; 159: 813–8 8. Lance JW. Current concepts of migraine pathogenesis. Neurology 1993; 43 (6 Suppl. 3): S11–15 9. Lipton RB, Diamond S, Reed M, et al. Migraine diagnosis and treatment: results from the American Migraine Study II. Headache 2001; 41: 638–45 10. MacGregor EA, Brandes J, Eikermann A. Migraine prevalence and treatment patterns: the global Migraine and Zolmitriptan Evaluation (MAZE) survey. Headache 2003; 43: 19–26 11. Goadsby PJ, Hoskin KL. Inhibition of trigeminal neurons by intravenous administration of the serotonin (5HT)1B/D receptor agonist zolmitriptan (311C90): are brain stem sites a therapeutic target in migraine? Pain 1996; 67: 355–9 12. Martin GR, Robertson AD, MacLennan SJ, et al. Receptor specificity and trigemino-vascular inhibitory actions of a novel 5-HT1B/1D receptor partial agonist, 311C90 (zolmitriptan). Br J Pharmacol 1997; 121: 156–64 13. Hughes AM, Dixon R, Dane A, et al. Effects of zolmitriptan (Zomig) on central serotonergic neurotransmission as assessed by active oddball auditory event-related potentials in volunteers without migraine. Cephalalgia 1999; 19: 100–6 14. Lipton RB, Hamelsky SW, Dayno JM.What do patients with migraine want from acute migraine treatment? Headache 2002; 42 (Suppl. 1): 3–9 15. Edmeads J, Findlay H,Tugwell P, et al. Impact of migraine and tension-type headache on lifestyle, consulting behaviour, and medication use: a Canadian population survey. Can J Neurol Sci 1993; 20: 131–7 16. Loder E, Silberstein S, Giammarco R, et al. Oral zolmitriptan exhibits efficacy as early as 30 minutes in menstrually-associated migraine: results of a large multicenter placebo-controlled study. Neurology 2002; 58 (7 Suppl. 3): A414–15 17. Rapoport A, Dowson A, Charlesworth B, et al. Zolmitriptan conventional and orally disintegrating tablets achieve headache response as early as 30 minutes post-treatment: results of a pooled data analysis. Neurology 2003; 60 (5 Suppl. 1): P03.150 18. Klapper J, Charlesworth B, Soisson T, et al. Treatment of mild migraine with oral zolmitriptan 2.5 mg provides high pain-free response rates and prevents progression to more severe migraine in patients with significant migraine-related disability. Headache 2002; 42: 395 19. AstraZeneca. Data on file 20. Dowson AJ, MacGregor EA, Purdy RA, et al. Zolmitriptan orally disintegrating tablet is effective in the acute treatment of migraine. Cephalalgia 2002; 22: 101–6 21. Tuchman MM, Spierings E, Abu-Shakra, et al. Significant 1 hour pain free rates with zolmitriptan 2.5 mg orally disintegrating tablet in treatment of migraine: results of a large doubleblind, placebo-controlled trial. Eur J Neurol 2002; 9 (Suppl. 2): 154 22. Spierings E, Dodick D, Pearlman E, et al. Zolmitriptan orally disintegrating tablet shows significant efficacy as early as 30 min, and high sustained response rates: results of a large placebo controlled trial. Cephalalgia 2002; 22: 605 23. Dowson A, Charlesworth B. Patients with migraine prefer zolmitriptan orally disintegrating tablet to sumatriptan conventional tablet. Int J Clin Pract 2003; 57(7): 573–6 24. Charlesworth B,Wasiewski W, Moran D. Migraine patients prefer the zolmitriptan orally disintegrating tablet formulation to the rizatriptan wafer tablet formulation: an assessment of taste and ease of use. Headache 2002; 42: 391–2 23 ABBREVIATED CORE DATA SHEET ‘ZOMIG’; ‘ZOMIG RAPIMELT’; ‘ZOMIG NASAL SPRAY’ 1. USES Acute treatment of migraine attacks with or without aura. 2. DOSAGE The recommended dose of ‘Zomig’ tablets and ‘Zomig Rapimelt’ to treat a migraine attack is 2.5 mg. ‘Zomig’ tablets should be swallowed whole with water.The ‘Zomig Rapimelt’ orodispersible tablet rapidly dissolves when placed on the tongue and is swallowed with the patient’s saliva. A drink of water is not required. The recommended dose of ‘Zomig nasal spray’ to treat a migraine attack is 5 mg. It is administered as a single dose into one nostril. For all formulations of ‘Zomig’: If symptoms persist, or return within 24 hours, a second dose has been shown to be effective. If a second dose is required, it should not be taken within 2 hours of the initial dose. If satisfactory relief is not achieved with a 2.5 mg dose, subsequent attacks can be treated with 5 mg doses. In the event of recurrent attacks, it is recommended that the total intake of ‘Zomig’, in a 24-hour period, should not exceed 10 mg. Safety and efficacy of ‘Zomig’ in paediatrics and adults over the age of 65 has yet to be established. Although metabolism is reduced in patients with mild or moderate liver disease (see full prescribing information), no dosage adjustment is required. However, for patients with severe liver disease, a maximum dose of 5 mg in 24 hours is recommended. A maximum intake of 5 mg ‘Zomig’ in 24 hours is recommended in patients taking a MAO-A inhibitor (e.g. moclobemide). A maximum dose of 5 mg ‘Zomig’ in 24 hours is recommended in patients taking cimetidine. Based on the overall interaction profile, an interaction with the cytochrome P450 isoenzyme inhibitors of CYP1A2 cannot be excluded.Therefore, the same dosage reduction is recommended with compounds of this type, such as fluvoxamine and the quinolone antibiotics (e.g. ciprofloxacin). Following administration of rifampicin, no clinically relevant differences in the pharmacokinetics of zolmitriptan or its active metabolite were observed. Concomitant use of other 5HT1B/1D agonists should be avoided within 12 hours of ‘Zomig’ treatment. Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because there is a theoretical basis that these effects may be additive, 24 hours should elapse between the use of ergotamine containing or ergot-type medications (like dihydroergotamine or methysergide) and zolmitriptan. Conversely it is advised to wait at least 6 hours following use of ‘Zomig’ before administering an ergotamine containing preparation. There is no clinical experience of ‘Zomig’ in pregnancy. As with other medicines administered in pregnancy, the benefits for the mother should be weighed against the risks to the foetus.There is no information regarding the passage into human milk. Use is unlikely to result in an impairment of the ability to drive and operate machinery; however, take into account that somnolence may occur. Patients with phenylketonuria should be informed that each ‘Zomig Rapimelt’ orodispersible tablet contains 2.81 mg of phenylalanine (a component of aspartame). 5. SIDE EFFECTS 3. CONTRAINDICATIONS Hypersensitivity to any of the ingredients, uncontrolled hypertension, ischaemic heart disease or coronary vasospasm/Prinzmetal’s angina. 4. PRECAUTIONS A clear diagnosis of migraine must be established. Care must be taken to exclude potentially serious neurological conditions. No data in basilar or hemiplegic migraine. Migraineurs may be at risk of certain cerebrovascular events. Cerebral haemorrhage, subarachnoid haemorrhage, stroke, and other cerebrovascular events have been reported in patients treated with 5-HT1B/1D agonists. ‘Zomig’ should not be given to patients with Wolff-ParkinsonWhite syndrome or arrhythmias associated with other cardiac accessory conduction pathways. In very rare cases, as with other 5HT1B/1D agonists, coronary vasospasm, angina pectoris and myocardial infarction have been reported. In patients with risk factors for ischaemic heart disease, cardiovascular evaluation prior to commencement of treatment is recommended (see Contraindications). As with other 5HT1B/1D agonists, atypical sensations over the precordium have been reported after administration of ‘Zomig’. Where such symptoms are thought to indicate ischaemic heart disease, no further doses of zolmitriptan should be given and appropriate evaluation carried out. As with other 5HT1B/1D agonists, transient increases in systemic blood pressure have been reported in patients with and without a history of hypertension; very rarely these increases in blood pressure have been associated with significant clinical events. As with other 5HT1B/1D agonists, there have been rare reports of anaphylaxis/anaphylactoid reactions in patients receiving ‘Zomig’. 24 The most commonly reported for all ‘Zomig’ formulations: nausea, dizziness, somnolence, warm sensation, asthenia and dry mouth. For ‘Zomig’ Nasal Spray, the most commonly reported: taste disturbance, hyperaesthesia, and discomfort of nasal cavity. Abnormalities or disturbances of sensation have been reported, heaviness, tightness, pain or pressure may occur in the throat, neck, limbs and chest, as may myalgia, muscle weakness, paraesthesia, dysaesthesia. As with other 5HT1B/1D agonists, transient increases in systemic blood pressure, very rarely associated with significant clinical events, have been reported. As with other 5HT1B/1D agonists, there have been rare reports of and hypersensitivity reactions (including anaphylaxis/anaphylactoid reactions, urticaria and angioedema), tachycardia and palpitations. In very rare cases, as with other 5HT1B/1D agonists, angina pectoris, myocardial infarction, headache, gastrointestinal ischaemic events including ischaemic colitis, gastrointestinal infarction or necrosis, which may present as bloody diarrhoea or abdominal pain, have been reported. 6. PRESENTATION Film-coated tablets containing 2.5 mg or 5 mg zolmitriptan. Orodispersible tablets containing 2.5 mg zolmitriptan. Single use nasal spray device containing 5 mg zolmitriptan. Revised: July 2002 Consult full prescribing information before prescribing. Further information available on request. AstraZeneca R&D Alderley Park, Macclesfield, Cheshire SK10 4TG England ZOMIG, ZOMIG RAPIMELT, ZOMIG NASAL SPRAY are Trade Marks of the AstraZeneca Group of Companies. For full prescribing information, please refer to your local PI. ASZAZO1584 Zmg/2003/017 (August 03)