Systematic review: adherence issues in the treatment of
`ulcerative colitis
`S. V. KANE
`
`Section of Gastroenterology. Depart-
`ment of Medicine, The University of
`Chicago, Chicago, IL, USA
`
`Correspondence to:
`Dr S. V. Kane, Section of
`Gastroenterology, Department of
`Medicine, The University of Chicago,
`5841 South Maryland Ave, MC 4076,
`Chicago, IL 60637, USA.
`E-mail:
`skane@inedicine.bsd.uchicago.edu
`
`Publication data
`Submitted 5 June 2005
`First decision 18 August 2005
`Resubmitted 29 November 2005
`Resubmitted 15 December 2005
`Accepted 16 December 2005
`
`SUMMARY
`
`Ulcerative colitis is a chronic inflammatory and debilitating disease
`requiring lifelong treatment. First-line therapy for ulcerative colitis is 5-
`aminosalicylic acid, which suffers from poor patient adherence outside
`the clinical trial setting.
`
`Formulations to deliver 5-aminosalicylic acid to the disease activity
`site, both orally and topically, are often inconvenient and require mul-
`tiple daily dosing. Such regimens can interfere with normal life and
`reduce the overall quality of life, negatively impacting on treatment
`adherence and leading to poorer long-term outcomes. These include
`increased morbidity with an elevated risk of symptomatic relapse, poss-
`ible greater risk of colorectal cancer and higher overall costs of care.
`
`Ulcerative colitis patients cite treatment regimen complexity, tablet
`quantity and dose frequency as key negative influencers of adherence.
`Solutions to these issues include addressing patient concerns, simplify-
`ing daily regimens and utilizing new formulations such as micropellet
`and multimatrix oral formulations, rectal gel and once-daily supposit-
`ory formulations.
`
`This review examines the prevalence and impact of non-adherence to
`5-aminosalicylic acid therapy among patients with ulcerative colitis, as
`well as drug delivery strategies that may enhance dosing regimens to
`improve patient acceptability, adherence and long-term clinical out-
`comes. It is a combination of understanding patient behaviour, recogni-
`zing signs of non-adherent behaviour and utilizing management
`strategies to change behaviour that will improve patient outcomes.
`
`Aliment Pharmacol Ther 23, 577-585
`
`2006 The Author
`Journa compilation 0 2006 Blackwell Publishing Ltd
`doi:10.1111/j.1365-2036.2006.02809.x
`
`577
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`578 S. V. KANE
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`INTRODUCTION
`
`Ulcerative colitis (UC) is a chronic inflammatory dis-
`ease that primarily affects the colonic mucosa. Ulcera-
`tive colitis is most commonly diagnosed in patients
`aged between 15 and 35 years although it can affect
`patients of any age and either sex.' The annual inci-
`dence of UC in western European countries and the
`USA is estimated to be six to eight cases per 100 000
`individuals, with the prevalence of UC reaching 70-
`150 cases per 100 000 individuals.' The course of the
`disease is generally relapsing-remitting, with patients
`experiencing few or no gastrointestinal symptoms in
`between symptomatic flare-ups (relapses).
`The cause of UC is unknown; however, over-stimu-
`lation of an inadequately regulated mucosal immune
`system appears to be a major pathophysiological path-
`way, perhaps in response to the colonic bacterial pop-
`ulation itself.2-4 As the precise underlying cause of UC
`remains unclear, therapy is aimed at the treatment of
`symptoms and the maintenance of remission. 5-Ami-
`nosalicylic acid (5-ASA) is the current standard of care
`typically used as first-line treatment of mild-to-mod-
`erate UC and is efficacious and well tolerated for the
`treatment of active diseases and the maintenance of
`remission.6
`Both oral and topical formulations to deliver 5-ASA
`to the site of disease activity are inconvenient and, for
`oral formulations, require multiple daily dosing with
`many tablets per dose. Such demanding regimens can
`interfere with the normal life of the patient and reduce
`his or her overall quality of life. The additional burden
`of a complex and inconvenient dosing regimen has a
`negative impact on adherence to treatment in a variety
`of clinical settings and can lead to poorer long-term
`outcomes.'-12 This is particularly true in chronic med-
`ical conditions such as UC where patients may be
`required to take their medication throughout their life
`even during periods of symptomatic remission (quies-
`cence). Indeed, 'real-world' compliance rates for
`patients with chronic medical conditions requiring
`long-term pharmacotherapy are generally estimated to
`be approximately 50%13 and may even be as low as
`30% for certain conditions." This review will examine
`the prevalence and impact of non-adherence to 5-ASA
`therapy among patients with UC and examine ways in
`which making drug delivery methods and dosing regi-
`mens more acceptable and less intrusive for patients
`could improve adherence and long-term clinical out-
`
`comes. This review has focused on UC because there is a
`lack of data regarding medication adherence in Crohn's
`disease. Further studies are needed to investigate the
`impact of adherence on outcomes in these patients.
`For this review, a Medline search was conducted for
`full publications in various languages using the search
`terms: 'medication adherence', 'ulcerative colitis and
`adherence', 'ulcerative colitis and maintenance', 'non-
`compliance and ulcerative colitis', 'ulcerative colitis
`and quality of life', '5-ASA and ulcerative colitis'.
`Only those citations that discussed the impact of
`adherence to ulcerative colitis management were
`included. The references of appropriate articles were
`then reviewed for additional papers not otherwise
`found during the search.
`
`PATIENT NON-COMPLIANCE WITH 5-ASA
`TREATMENT REGIMENS
`
`Compliance (a term often used interchangeably with
`adherence) can be defined as the extent to which a
`person's behaviour (in taking medication or otherwise)
`coincides with the advice of their physician or health
`adviser. While clinical trials report excellent rates of
`compliance with 5-ASA therapy, in the order of 80%
`of patients or more,15-17 participants are generally bet-
`ter motivated and under close medical supervision
`compared with those receiving therapy outside the
`clinical trial setting. Adherence rates in prospective,
`community-based studies are much lower (40-60%)13'
`18 and are often particularly poor among patients in
`symptomatic remission18-21 with as many as 60% of
`patients failing to adhere to a prescribed dose regimen
`and taking less than 70% of their prescribed mcdica-
`tion.18. 20. 21
`In an early study of compliance with sulfasalazine
`therapy in patients with inflammatory bowel disease,
`van Hees and van Tongeren22 used serum concentra-
`tions of sulfapyradine (a sulfasalazine metabolite) as a
`proxy for measuring compliance to oral sulfasalazine
`treatment. A total of 51 patients prescribed a mainten-
`ance dose of sulfasalazine just prior to hospital dis-
`charge were followed up for 1-6 months. Of these, 21
`patients (41%) had significantly lower levels of sulfa-
`pyradinc (>25% lower) at follow-up compared with 24
`in-patients whose medication was supervised. Further-
`more, another 171 outpatients were followed up for
`between 1 and 4 years. Among this group of patients,
`21 (cid:9)
`( 1 2%) had no detectable serum sulfapyradine,
`
`© 2006 The Author, Aliment Pharmocol Ther 23, 577-585
`Journal compilation © 2006 Blackwell Publishing Ltd
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`SYSTEMATIC REVIEW: ADHERENCE IN ULCERATIVE COLITIS 579
`
`despite claiming compliance, suggesting that they had
`in fact failed to take their medication as prescribed.22
`Reasons for patient non-adherence differ widely,
`depending on patient characteristics, disease type and
`treatment regimen, making it difficult to characterize
`patients likely to be non-adherent. A variety of factors
`have been reported to be associated with non-adher-
`ence to 5-ASA therapy among patients with UC
`(Table 1). These include disease duration,23 male gen-
`der,18 single status,18 full-time employment and three
`times daily dosing.21 The reasons given by patients
`themselves for non-adherence are also varied and
`include forgetfulness, questioning the need for medi-
`cation during periods of disease quiescence, incon-
`venient regimens and need for large numbers of
`tablets (Table 2).19. 20
`
`Table 1. Factors associated with non-adherence to
`5-ASA medication among patients with ulcerative
`colitis] 8, 19.
` 23
`21.
`
`Age
`Diagnosis of left-sided disease
`Disease duration
`Full-time employment
`History of >4 concomitant medications
`Male gender
`New patient status
`Patient-physician discord
`Single status
`Three-times daily dosing
`
`Table 2. Reasons given for non-adherence to 5-ASA
`therapy among pafients with ulcerative colitis19- 20
`
`Patient beliefs and perceptions
`Denial of illness
`Forgetfulness
`Unable to see the need for medication during periods of
`symptom quiescence
`Health-care professional-driven
`Lack of a supportive relationship
`Lack of adequate information
`Economic
`Costs of filling prescriptions
`Medication-related
`Complicated dosing regimen
`Fear of side effects
`Impact of schedule on daily life
`Large number of tablets
`
`© 2006 The Author, Aliment Pharmacol Ther 23, 577-585
`Journal compilation © 2006 Blackwell Publishing Ltd
`
`n Non-adherent Adherent
`
`0-6
`
`6-12
`Time (months)
`
`12 -12
`
`Figure 1. Frequency of symptomatic recurrence according
`to adherence with 5-ASA therapy among adult patients
`with ulcerative colitis followed for 6, 12 and
`24 months.19
`
`In a study of 99 patients with quiescent UC whose
`adherence to 5-ASA medication was monitored for
`2 years (Figure 1), 39 patients experienced a recur-
`rence of their symptoms and 32 (82%) of these were
`non-adherent to their prescribed medication. Of the
`59 patients who remained in symptomatic remission,
`20 (34%) were not adherent to their prescribed
`(P = 0.01).19 By 6 months into this
`medication
`study, 12 patients (12%) had recurrence of their dis-
`ease, all of whom were non-adherent. By 12 months,
`19 of 86 patients relapsed, 13 (15%) of whom were
`non-adherent. By 24 months, eight of the remaining
`66 patients had a recurrence of their disease, six
`(9%) of whom were non-adherent. Patients who did
`not adhere to their medication had more than a
`five-fold greater risk of disease recurrence than
`adherent patients (hazard ratio 5.5; 95% confidence
`interval 2.3-13.2, P < 0.001). When asked their rea-
`sons for non-adherence to their prescribed regimen,
`21 (30%) patients who responded said there were
`too many pills, 14 (20%) did not think they needed
`that much medication and 35 (50%) said they 'just
`forgot'.19 In some cases, 'forgetting' to take medica-
`tion can be regarded as a form of illness denial
`since multiple daily dosing may make patients
`acutely aware of their chronic illness status.
`Inconvenient and intrusive drug delivery formula-
`tions can also be associated with reduced adherence.
`Rectal formulations of 5-ASA, for example, are associ-
`ated with leakage, problems with retention and bloat-
`ing.24 Using a large prescription pharmacy database,
`Kane and tianauer25 showed that refill rates for rectal
`therapies were very low compared with those for oral
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`580 S. V. KANE
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`therapies. Moreover, patients can be uncomfortable if
`others are aware of their medical condition, which
`may be emphasized by multiple daily dosing of oral
`medication or the use of rectal formulations, partic-
`ularly those which require several daily applications.
`
`CLINICAL IMPACT OF NON-ADHERENCE TO
`THERAPY FOR UC
`
`The implications of non-adherence to 5-ASA therapy
`among patients with UC include increased morbidity
`with a greater risk of symptomatic relapse, reduced
`quality of life and a possible increased risk of colorec-
`tal cancer.
`Prospective studies have shown that patients who
`adhere to their prescribed 5-ASA regimen have a
`reduced risk of symptomatic relapse compared with
`non-adherent patients. Among 95 patients with UC who
`were followed for up to 10 years after their initial diag-
`nosis, all patients experienced at least one relapse dur-
`ing the follow-up period.26 Those patients with a
`diagnosis of pancolitis or left-sided colitis had the high-
`est risk of relapse, typically experiencing their first
`recurrence within 2-3 years of diagnosis, while those
`with distal colitis experienced their first relapse within
`9-10 years of diagnosis.26 Kane et a1.19 found that those
`patients with quiescent UC who failed to adhere to their
`prescribed 5-ASA regimen had a 61% chance of relapse
`compared with just 11% among patients who did adhere
`to their prescribed therapy, a difference which was sta-
`tistically significant (P = 0.001).
`Several studies have highlighted the impact of
`symptomatic UC on the quality of life and established
`a direct relationship to disease severity.21-29 Using the
`Inflammatory Bowel Disease Questionnaire (IBDQ), the
`Medical Outcomes Study 36-Item Short-Form Survey
`and the Illness Perception Questionnaire, Han et al.27
`found that symptom-related disease activity correlated
`with disease-specific quality of life. Further analysis
`using a multivariate regression modelling approach
`showed that disease activity was the major explanat-
`ory factor for decrements in each of the four subdo-
`mains of the IBDQ as well as the total score." Similar
`results have been reported in German populations of
`adult patients with UC.28' 3° Among 109 adults with
`UC, patients reported significant reductions in both
`general and health-related aspects of life satisfaction
`as measured using the Questions on Life Satisfaction
`(modules) compared with a control sample of the Ger-
`man population.3° A further study in 112 patients with
`
`UC confirmed these observations and showed that dis-
`ease activity was a significant predictor of reduced
`health-related life satisfaction.28
`The lifetime risk of colorectal cancer among patients
`with UC is estimated to be approximately 20%.31 Non-
`adherence to medication may significantly increase
`this risk. In a study of 175 patients with UC, the inci-
`dence of cancer over 10 years was significantly higher
`(P < 0.001) in patients who were either non-adherent
`or in whom medication (sulfasalazine) was discontin-
`ued upon the advice of a physician (31%), compared
`with those on maintenance therapy (3%). Moody
`et al.32 concluded that patients who did not adhere to
`sulfasalazine therapy, or whose treatment was stopped,
`were significantly more likely to develop colorectal
`cancer than those who adhered to the therapy. Epide-
`miological studies have taken the opposite approach to
`examine the impact of adherence to regular 5-ASA
`therapy on cancer risk.33-36 Results of a case-con-
`trolled study of 18 969 patients showed that the risk
`of developing colorectal cancer was reduced among
`patients who adhered to 5-ASA therapy compared
`with patients who did not (adjusted odds ratio_
`0.60).35 In an earlier case-control study of patients
`with UC, Eaden et af." found that regular mesalazine
`(mesalamine) therapy reduced the risk of colorectal
`cancer risk by 81% compared with no treatment (P
`0.006). Similarly, a retrospective case-control study
`showed that a history of at least 3 months of pharma-
`cological therapy for UC, especially with sulfasalazine,
`had a protective effect for colon cancer.34 A recent
`systematic review and meta-analysis of nine observa-
`tional studies involving almost 2000 patients and 334
`cases of colorectal cancer concluded that 5-ASA ther-
`apy is protective for colorectal cancer in patients with
`UC.36
`
`ECONOMIC IMPACTS OF NON-ADHERENCE
`TO THERAPY FOR UC
`
`In the USA, non-adherence to prescribed, long-term
`medical therapy has been estimated to cost as much as
`US$100 billion each year and accounts for 10% of all
`hospital admissions."' 38 The largest proportion of this
`cost (70%) appears to be due to decreased productivity
`and premature death, with direct medical costs
`accounting for the remaining 30% (hospital admissions
`25% and unnecessary nursing home admissions 5%).38
`As failure to adhere to a prescribed 5-ASA regimen
`in patients with UC is associated with an increased risk
`
`© 2006 The Author, Aliment Pharmocol Ther 23, 577-585
`Journal compilation © 2006 Blackwell Publishing Ltd
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`SYSTEMATIC REVIEW: ADHERENCE IN ULCERATIVE COLITIS 581
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`Oral ASA
`
`Surgery
`
`Topical ASA
`
`Immunosuppressants
`
`Other drugs
`
`—Laboratory tests
`
`X-rays
`
`.1:mussnum
`.:;14111111141,1111
`
`Endoscopy
`
`Figure 2. Proportion of total
`direct costs associated with the
`care of patients with ulcerative
`colitis in 1 year.'
`
`Inpatient services
`
`Outpatient services
`
`of symptomatic relapse, non-adherence is likely to
`accrue significant additional costs for society in terms
`of increased utilization of healthcare services.
`The costs associated with the medical care of patients
`with UC are considerable, particularly for those who
`require hospitalization. In Canada, the mean cost of
`each hospital admission for UC was CAN$3726, with
`higher costs for those patients requiring surgical inter-
`vention.39 In a Swedish survey of healthcare costs in
`1994, hospital admissions accounted for 58% of all
`direct costs associated with inflammatory bowel dis-
`ease (IBD; UC and Crohn's disease together).4° In the
`USA, the total annual medical cost for UC patients
`was estimated to be between US$0.4 billion and
`US$0.6 billion, with an average annual medical cost
`of US$1488 per patient in 1990.41 Most recently, the
`cost of caring for patients with IBD, including 307
`patients with UC and 172 with Crohn's disease, has
`been assessed in the UK.42 Over a 6-month period, the
`total direct cost of caring for patients with IBD ranged
`from UKE73 (approximately US$129) to UKE33 254
`(US$58 980). The mean cost of care over 6 months for
`patients with UC was UKE1256 (US$2228) and, while
`only 67 (14%) patients with IBD required hospitaliza-
`tion during the 6-month assessment period, they
`accounted for 49% of the total secondary care costs
`(Figure 2).42 Among this group of patients, disease
`relapse was associated with a two- to three-fold
`increase in costs for those who did not require hospital
`care and a 20-fold increase for those who were hospit-
`alized (Figure 3).42 Patients who experience sympto-
`matic relapse will also accrue costs associated with
`additional diagnostics and treatment."
`
`© 2006 The Author, Aliment Pharmacol Ther 23, 577-585
`Journal compilation © 2006 Blackwell Publishing Ltd
`
`— 10.000
`
`0
`E
`
`8.000
`
`6.000 -
`
`2,000 -
`
`Quiescent disease
`
`Ambulatory patients (cid:9)
`
`Hospitalized patients
`
`Symptomatic relapse
`
`Figure 3. Direct costs associated with symptomatic
`relapse of ulcerative colitis.'
`
`The personal economic cost to patients of non-
`adherence and subsequent symptomatic relapse may
`also be considerable. Prospective studies have sugges-
`ted that patients with IBD, including those with UC,
`are likely to experience periods of unemployment or
`inability to work and subsequent loss of earnings at
`some point during their working life.44-46 Patients
`who pay for their own medication may accumulate
`increased medication costs as higher dose regimens
`are required more often to manage symptomatic epi-
`sodes compared with lower doses during maintenance
`therapy.
`Reducing the risk of symptomatic relapse by
`improving patient adherence to treatment is likely to
`offer considerable personal and societal economic
`benefits. For example, in a small-scale study of 42
`patients with UC, intermittent combined oral and top-
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`582 S. V. KANE
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`ical therapy significantly reduced the number of relap-
`ses and, while drug costs were increased, the overall
`costs of managing symptomatic relapse fell by 48%.42
`
`IMPROVING COMPLIANCE
`
`There are a variety of reasons why patients fail to
`adhere to a prescribed 5-ASA regimen, ranging from
`concerns about potential side effects and complicated
`dosing regimens to a belief that medication is not
`necessary during periods of symptom quiescence
`(Table 2). Therapeutic relationship can also influence
`adherence just as much as individual clinical and psy-
`chosocial characteristics.23 In a prospective study of
`153 patients with IBD, 41% of patients were non-
`adherent to medication 2 weeks after a clinic visit.
`Eighty-one percent of these patients were not inten-
`tionally non-adherent; reasons for this included for-
`getfulness or carelessness in taking medication.
`Intentional non-adherence was associated with
`patient-physician discordance, disease duration, lack
`of certainty that treatment would help and failure to
`schedule of a follow-up appointment.
`Addressing barriers to treatment adherence resulting
`from patient beliefs is a complex and controversial
`issue and a variety of interventions have been pro-
`posed, most of which appear to offer only limited
`long-term improvements in 'real-world' settings."
`Adherence can be encouraged by open communication
`between physician and patient. To establish a good
`therapeutic relationship, patients should be given time
`to discuss concerns and ask questions; physicians
`should use open questions, an appropriate tone and
`not under- or over-estimate the patient's level of
`understanding.
`Providing patients with simpler, less intrusive drug
`delivery methods requiring more convenient dosing
`regimens has been proven to improve patient compli-
`ance in a range of clinical settings including hyperten-
`sion,49 human immunodeficiency virus infection,50
`angina pectoris51 and osteoporosis52 and should
`address some of the reasons given by patients for non-
`adherence with 5-ASA therapy.18•19 For example,
`patients have been reported to prefer once-daily oral
`dosing of 5-ASA to divided-daily dosing (two or three
`times per day)53 and a recent pilot study of a novel
`oral formulation of 5-ASA found that adherence to
`oral therapy was higher than adherence to a rectal for-
`mulation of 5-ASA (97 vs. 87.50/0).17 In another small
`pilot study, patients were randomized to receive either
`
`once-daily or conventional (twice or three times daily)
`mesalazine for maintenance of UC.53 After 6 months,
`patients in the once-daily arm appeared more satisfied
`with their regimen and consumed more medication
`overall than those in the conventional arm (90% vs.
`76%; P — 0.07). Similar numbers of patients experi-
`enced relapse in each group. Thus, once-daily oral for-
`mulations of 5-ASA are likely to become a viable
`therapeutic option due to their ability to offer compar-
`able efficacy, improved adherence and long-term clin-
`ical outcomes.
`
`NEW FORMULATIONS OF 5-ASA
`
`A number of novel oral and rectal formulations of
`5-ASA are in development which, it is hoped, will
`prove more acceptable to patients and so enhance
`their long-term adherence with treatment.
`A novel oral formulation of 5-ASA that provides
`delayed and extended drug delivery, SPD476, has been
`shown to be efficacious for the induction of clinical
`remission and improvement in symptoms following
`once-daily dosing of 2.4 or 4.8 g.54' S5 SPD476 con-
`tains a high dose of 5-ASA (1.2 g) formulated in a
`multi-matrix system comprising lipophllic and hydro-
`philic coats to ensure constant, homogenous and timed
`release of the active drug throughout the colon."
`A preliminary clinical study in 79 patients with UC
`suggested that this novel oral formulation may prove
`more effective in achieving remission compared with a
`conventional 5-ASA enema formulation." The results
`of two large-scale, randomized, controlled clinical tri-
`als have extended these results and demonstrated a
`clear benefit for the novel oral formulation in terms of
`reducing symptoms and improving remission rates
`compared with placebo."' 55 In both studies, a signifi-
`cantly greater percentage of patients given once-daily
`SPD476 for 8 weeks achieved remission compared
`with those given placebo [29.2% for SPD476 4.8 g vs.
`12.9% for placebo (P < 0.00;54 40.5 and 41.2% for
`SPD476 2.4 and 4.8 g vs. 22.1% for placebo
`(P < 0.01)51.
`Similarly, micropellet formulations may require less
`frequent dosing and appear to provide a slower, more
`prolonged release of active drug as indicated by
`plasma concentration data.56' 57 Gamma-scintigraphy
`studies have been conducted to determine the timing
`and site of release of active drug within the digestive
`tract.56' 57 In a study among 24 healthy volunteers, a
`single dose of a micropellet formulation (1.5 g sachet)
`
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`SYSTEMATIC REVIEW: ADHERENCE IN ULCERATIVE COLITIS 583
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`provided comparable systemic exposure and released
`active drug at approximately the same time and same
`site (terminal ileum and ascending colon) as an equiv-
`alent single dose of Claversal (SmithKline French,
`Middlesex, UK) tablets (3 x 500 mg mesalazine tab-
`lets).57 A further study in 14 healthy male volunteers
`yielded similar results when a single dose of a micro-
`pellet formulation (500 mg sachet) was compared with
`a single Salofalk (Falk Pharma, Freiburg, Germany)
`tablet (500 mg mesalazine).56 The efficacy of the
`micropellet formulation was comparable to a conven-
`tional, prolonged-release tablet formulation in 227
`patients with mild-to-moderate UC, offering similar
`improvements in the UC disease activity score, excel-
`lent compliance rates (97%) and no difference in terms
`of the incidence or nature of side effects.15 In this
`study, patients reported a preference for the twice
`daily dosing offered by the micropellet formulation
`compared with four times daily dosing.15
`A once-daily, slow-release 5-ASA suppository inser-
`ted prior to bedtime has been developed and shown to
`be comparable to a twice-daily 5-ASA suppository in
`patients with ulcerative proctitis, whose disease was
`limited to within 15 cm of the anal margin, in terms
`of efficacy (disease activity index), safety .and compli-
`ance (>95% in both groups) over 6 weeks.58
`Conventional suspension and foam enema formula-
`tions for delivery of 5-ASA within the colon as far as
`the splenic flexure have proved particularly effective.
`However, they are often less than acceptable to
`patients and are often associated with side effects such
`as difficulty in retention, abdominal bloating and dis-
`comfort on administration.24 Rectal gels of 5-ASA are
`being developed and appear to be at least as effective
`as conventional enema formulations and more accept-
`able to patients.24' 59 In a randomized, multicenter,
`investigator-blind, parallel-group trial, 103 patients
`with mild-to-moderate left-sided colitis or proctosig-
`moiditis were randomly allocated to mesalazine 2 g
`gel enema (n = 50) and mesalazine 2 g foam enema
`(n = 53) for 4 weeks.24 Remission rates (clinical, endo-
`scopic and histological) were comparable between the
`two groups. Patients in the foam group reported signi-
`ficantly more difficulty in retention (25 vs. 6%,
`P < 0.05), abdominal bloating (50 vs. 26%, P < 0.005)
`and discomfort during administration (48 vs. 26%,
`P < 0.05) compared with the gel formulation and that
`the new mesalazine gel preparation was significantly
`better tolerated than the foam enema.'
`
`© 2006 The Author, Aliment Pharmacol Ther 23, 577-585
`Journal compilation © 2006 Blackwell Publishing Ltd
`
`While several studies have demonstrated the efficacy
`and safety of these novel formulations, none have
`examined changes in adherence, patient quality of life
`and pharmaco-economic implications of less frequent
`dosing within the community practice environment.
`These programs, and many others, remain to be con-
`ducted upon approval of such once-daily formula-
`tions.
`
`CONCLUSIONS
`
`Ulcerative colitis is a chronic medical condition which
`requires patients to take prophylactic medication
`throughout their lives. Despite clinical trials reporting
`excellent compliance to 5-ASA therapy regimens,
`studies have shown that patient compliance is poor,
`outside of the clinical trial setting. Non-adherence to a
`prescribed regimen of 5-ASA has been shown to dra-
`matically increase the risk of symptomatic relapse
`resulting in decreased quality of life and increased
`societal and personal costs, while adherence has long-
`term benefits. Adherence to 5-ASA therapy has also
`been associated with a reduced risk of colorectal can-
`cer compared with non-adherence. The problem of
`treatment compliance is a complex, multifaceted prob-
`lem that is not well understood. When questioned
`directly, patients with UC have cited the complexity of
`the treatment regimen, dose (number of tablets) and
`dose frequency (three to four times daily dosing) as
`key factors that negatively influence compliance.
`Simpler and more convenient dose regimens delivered
`via a practical, acceptable and minimally intrusive for-
`mulation should reduce this barrier to compliance with
`5-ASA therapy, decreasing the risk of symptomatic
`relapse, maintaining patient quality of life and redu-
`cing the overall cost of care for this patient group.
`Several advances in drug delivery technology are now
`in development to provide simple and acceptable drug
`delivery, including micropellet and multi-matrix oral
`formulations as well as rectal gel and once-daily
`suppository formulations.
`
`ACKNOWLEDGEMENTS
`
`The author kindly acknowledges the contributions of
`Tracey Lonergan and Clare Baker for professional
`medical writing support and Karen Middleton for edi-
`torial assistance, with funding for professional writing
`services from Shire Pharmaceuticals Group plc.
`
`FALK00005371
`
`Dr. Falk Ex. 2018
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 7
`
`

`
`584 S. V. KANE
`
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