E-mail: [email protected] . Address forcorrespondence: FrancescoTrotta, AgenziaItaliana delFarmaco,Via delTritone 181,00187 Rome,Italy. cated [6,10,11]. indi- are treatments pharmacological many which for co-morbidities present patients the of most and 9]; [8, disease the control to required often are diabetics about 20% and population general the of 5% than more Italy,(in population the of proportion large a affects disease The treatment. of continuity the modify may adherence study to ting [1-6]. of outcome the influence and adherence affect turn in may polypharmacy, and comorbidities ageing, as such factors, Several outcome. clinical of INTRODUCTION did notnegativelyaffectadherence. substance, same the of generics) between as well (as products unbranded and branded Conclusions. 72%, respectivelyamongnon-switchers,singleandmultipleswitchers. with patients among 26% reaching tions, never (61.0% switchers prescrip- multiple of number the with increased switchers were multiple of proportion The switched). 15.7% and switch single a experienced 23.3% patients, these Of substances. generic the of one least at prescribed were 9211 lation) Results. tions (MedicationPossessionRatio,MPR),wasestimated. prescrip- by covered 2011 in days of proportion the as defined adherence, on switching use generic with substances off-patent three the to relevant Switching 2011. during switches of ber of two prescriptions. Single and multiple switchers were identified according to the num- was defined as the dispensing of two different products of the same substance in a series study.the in Switching included were 2011 and 2010 in antidiabetics of prescriptions 2 Materials andmethods.All elderly residents of the Umbria Region who received at least whether switchingbetweendifferentproductsofthesamesubstanceaffectsadherence. study were to quantify the extent of switches between generic antidiabetics and to verify the of objectives The diseases. chronic for especially concern, for reason a is adherence Introduction. Abstract (a) Diabetes in the elderly population is an ideal set- ideal an is population elderly the in Diabetes predictor well-known a is adherence Treatment Centro NazionalediEpidemiologia,SorveglianzaePromozionedellaSalute,IstitutoSuperioreSanità,Rome,Italy of
h edry 7 yas l) 7; eea anti- several [7]; old) years 75 ≥ elderly the Among the 15 964 patients receiving antidiabetics (14.4% of the elderly popu- elderly the of (14.4% antidiabetics receiving patients 964 15 the Among ≥ (c) DirezioneRegionaleSalute,CoesioneSocialeeSocietàdellaConoscenza,RegioneUmbria,Perugia,Italy 5% (metformin, gliclazide and repaglinide) was quantified. The effect of effect The quantified. was repaglinide) and gliclazide (metformin, 5% The possibility that variation in packaging and pill appearance may reduce n lel ptet tetd ih niibtc, h sbttto between substitution the antidiabetics, with treated patients elderly In Generic substitution of antidiabetic Generic substitutionofantidiabetic Francesco Trotta, n te hrceitc that characteristics the and drugs in the elderly does not drugs intheelderlydoesnot (a,b) , RobertoDaCas ≥ treatments 11 prescriptions. MPR was 62%, 62% and 62% 62%, was MPR prescriptions. 11 of thesamesubstance. products) branded/generic all (of packages different different include treatments cological pharma- since diabetes, as such condition chronic a adherence [12, 13]. The issue is of great relevance for patients’ reduce ultimately and confusion create may appearance each time a new prescription is dispensed for prolonged periods of time. The change in package substancesdifferent many receive who elderly among especially generics), between switches and generics, and names brand between switches (i.e., substitution generic of effect the on raised was attention for son - rea specific A indications. prescribed the following affect may it concern a is there expenditure, care health reduce to opportunity vn huh h ue f eeis s n important an is generics of use the though Even Ann IstSuperSanità2014 (a) , MarinaMaggini affect adherence (b) Agenzia ItalianadelFarmaco,Rome,Italy DOI: 10.4415/ANN_14_04_07 and GiuseppeTraversa the attitude of patients in patients of attitude the (a)
, MariangelaRossi |
Vol. 50,No.4:333-340 • anti-diabeticdrugs • genericsubstitution • adherencetomedications Key words substances and (a) (c)
333 Original articles and reviews 334 Francesco Trotta, Roberto Da Cas, Marina Maggini et al.
Few studies estimated the frequency of substitu- identify co-morbidities associated with diabetes (e.g., tion between generics of the same substance [14-16] users of antihypertensives, antiparkinsons); ii) quanti- and there are controversial findings on the effect of fy the extent of polytherapy, defined as the number of switching between generics on treatment adherence different substances at the Vth ATC level (other than [17-21]. Moreover, no study has been conducted in antidiabetics) prescribed during 2011. the diabetes setting. The list of off-patent drugs, both originator and The objectives of the study were to quantify the ex- copies, marketed in Italy is regularly updated by the tent of switches between generic antidiabetics and to Italian Medicines Agency [22]. Off-patent medicines reviews
verify whether switching between different products were classified as branded and unbranded. Branded of the same substance affects adherence. products are defined as medicines sold under a pro-
and prietary name, whereas unbranded generics are sold
MATERIALS AND METHODS under their international non-proprietary name (i.e., Study population the name of the substance). The study was conducted in the population of the Drug consumption was evaluated in terms of: pre- Umbria Region (907 000 inhabitants in 2011), Ita- scriptions received; number of packages; total gross articles
ly. All residents are covered by the Italian National expenditure; and defined daily doses (DDDs: the Health Service (NHS), which provides comprehen- daily maintenance dose for the main indication in sive hospital and outpatient care. adults). Two indicators of drug use were calculated: Outpatients receive prescriptions from General the prevalence of use (by dividing the number of drug riginal Practitioners (GPs) and obtain medicines covered users by the overall resident population); the DDDs O by the NHS from local community pharmacies or per 1000 users per day (the mean number of doses in some cases directly from local health units (both consumed every day by 1000 patients included in the types of distribution were considered for the analy- cohort). sis). For each prescription, the following information is available at regional level: patient code (which is Identification of switches anonymized before any subsequent use), date of pre- Only generic antidiabetics with a use of generics scription, drug substance, marketing authorization ≥ 5% (in terms of DDDs for each substance) were code (indicating the specific brand or generic prod- considered for the analysis of switches. Only patients ucts), number of packages. Prescription data were filling at least 2 prescriptions of the same substance linked through the anonymized code to the regional during 2011 were included. The dispensing date of database of enrollees to retrieve age and gender. No the first prescription of an off-patent antidiabetic in information is available on prescriptions issued during 2011 was the index date. the hospitalization and on medicines use in nursing Switches were defined as the dispensing of two homes. different products (any of the brand and unbranded The eligible population included the elderly aged packages) of the same substance in a series of two ≥ 75 years who were resident in the Region in 2010 prescriptions in 2011. Three main switching catego- and 2011. Patients were considered to be on treat- ries were defined: ment with antidiabetics if they had filled at least two • no switch: patients who received the same products prescriptions of antidiabetics (identified through the during the entire follow up; international Anatomical Therapeutic Chemical clas- • single switch: patients who experienced only one sification system, ATC code A10) both in 2010 and switch (from A to B) or who had a total of two switch- 2011. Furthermore, to ensure that subjects were still es involving a switch back to the first product (from using health care services at the end of 2011, patients A to B to A); were required to have at least a prescription (of any • multiple switch: patients with three or more switch- drug) during the last trimester of 2011. Subjects who es, as well as two switches within three different prod- met the eligibility criteria were included in the study ucts (from A to B to C). cohort to investigate the utilization patterns of anti- diabetics in 2011. Adherence to the antidiabetic therapy Adherence to the generic antidiabetics included Therapeutic categories and indicators for usage in the analysis was determined using the medication The following classes of antidiabetics were consid- possession ratio (MPR) calculated by dividing the ered: i) insulins (ATC A10A); ii) biguanides (ATC theoretical duration of the prescription (we assumed A10BA); iii) sulphonamides (ATC A10BB); iv) glita- that 1 prescription covered 30 days of therapy) by the zones (ATC A10BG); v) dipeptidyl peptidase-4 (DPP- number of days between the first and last prescription 4) inhibitors (ATC A10BH); vi) alpha-glucosidase in- (plus the days covered by the last prescription). hibitors (ATC A10BF); vii) fixed-dose combinations (ATC A10BD); viii) other blood glucose lowering RESULTS drugs (ATC A10BX). Descriptive analysis of the selected cohort All other prescriptions (different from antidiabet- In the Umbria Region, 15 964 subjects ≥ 75 years ics) issued during 2011 were classified according to (14.4% of the elderly population) received at least 2 pre-specified 15 clinical subgroups (Supplementary Ta- prescriptions of antidiabetics per year in 2010-2011 ble S1, available online at www.iss.it/anna) in order to: i) and were included in the study (Table 1). Antidiabet- 335 Impact of generic substitution of antidiabetics on adherence
ics represented 21.5% of the per capita pharmaceuti- Table 1 cal expenditure (200 out of 931 euro) and 20% of the Characteristics of the antidiabetics users included DDDs prescribed in this population. in the study cohort In addition to antidiabetics, each subject received a Total subjects, N (prevalence, %) 15 964 (14.4) median of 10 different substances during 2011, high- lighting a high level of polypharmacy, and 25% of the Gender, N (prevalence, %) diabetic patients was treated with at least 14 substanc- Male 6550 (15.4) es (Table 1). Only 1% of the diabetic patients (147 out Female 9414 (13.9) reviews of 15 964) received no prescriptions in addition to an- tidiabetics (thus considered as having no comorbidi- Age class, N (prevalence, %)
ties), whereas more than 80% received prescriptions 75-79 y 6400 (14.9) and in at least three different therapeutic categories. Anti- 80-84 y 5276 (15.0) hypertensives and antiaggregants-anticoagulants were 85-89 y 3115 (13.6) the most frequently prescribed drugs (prevalence of use 90.2% and 69.3% respectively) (Table 1). This level ≥ 90 y 1173 (12.2) articles of use, together with the proportion of patients re- Total drug expenditure (euro) 931 ceiving lipid-lowering drugs (42.0%), suggests cardio- DDDs/1000 users-die vascular diseases as the principal comorbidity in this diabetic cohort. Drugs acting on the nervous system Antidiabetics 1078 (i.e. antidepressants, pain medications and antipsy- Any drugs (including antidiabetics) 5588 riginal chotics) were frequently prescribed, identifying the O Median number of substances prescribed 10 (7-14) group of nervous and psychiatric disorders as the sec- in 2011 in addition to antidiabetics (IQR) ond chronic comorbidity. A further 20.2% of diabetic patients received prescriptions of respiratory drugs. Drug classes most frequently prescribed Gender did not influence the prescription patterns in 2011 in addition to antidiabetics, % of users* of antidiabetics, whereas the increasing age had a negative association with prevalence of use (Table 1) Antihypertensives 90.2 and DDDs/1000 users-die (data not shown). Most Antiaggregants/Anticoagulants 69.3 of the antidiabetic prescriptions concerned patented Antibiotics 60.7 medicines (68%), whereas the remaining 32% consist- ed of branded (20%) and unbranded generics (12%). Antacids-Antiulcer drugs 54.4 Metformin was the most frequently prescribed an- Lipid lowering drugs 42.0 tidiabetic (prevalence of use 6.8%), followed by insu- NSAIDs 37.4 lins (5.1%) and sulphonamides (3.5%) (Table 2). Very Antidepressants 22.5 few patients were treated with newer oral antidiabetic agents such as a DPP-4 inhibitors or pioglitazone Respiratory drugs 20.2 (prevalence of use, 0.1% for each class). Pain medications (opioids) 18.0 During 2011 each patient received an average of 12 Prostate medication 13.9 prescriptions of antidiabetics (i.e. 1 prescription per month) corresponding to 17 drug packages per year Antiglaucoma drugs 11.3 (1.4 packages per month) and around 1.1 doses per Thyroid medications 8.5 day, which is coherent with a treatment model of a Antipsychotics 5.2 chronic diseases (Table 2). These data suggest that el- Antiparkinsons 5.2 derly diabetic patients were followed up monthly by GPs and that each prescription of antidiabetics typi- Osteoporosis medications 4.7 cally covered 1 month of treatment. The yearly cost of *: for details on the drug classes definitions see Table S1. treatment per user varied among drug classes, from a DDD: defined daily dose; IQR: interquartile range. minimum of 33-42 euro for metformin and sulphona- mides to 327-406 euro for DPP-4 inhibitors and insu- keted in Italy ranged from 4 for repaglinide to 18 for lins (Table 2). gliclazide. Most of the patients (51.4%) received only one an- tidiabetic drug and, within monotherapy, 41% were Analysis of switching among generics users of metformin. The proportion of patients receiv- and its impact on adherence ing two antidiabetics during 2011 was 35.7%, and the The analysis was conducted on the 9211 patients remaining 12.9% were prescribed more than two an- receiving at least one of the three substances availa- tidiabetics. ble as generics: metformin, gliclazide and repaglinide Among antidiabetics, generics were only available (glimepiride was excluded since 97% of the prescrip- for metformin, gliclazide, glimepiride, and repaglinide tions were still relevant to the branded originator). (Table 2). The use of unbranded generics was higher The majority of diabetic patients (61.0%) did not for gliclazide and repaglinide (61% and 48% of the switch during the year. The proportion of non-switchers DDDs) whereas it represented only 3% of the DDDs was similar for the three substances, ranging from 62.5% of glimepiride. The number of generic products mar- with metformin to 57.9% with repaglinide (Table 3). Pa- 336 Francesco Trotta, Roberto Da Cas, Marina Maggini et al.
Table 2 Use of antidiabetics by drug class in 2011. Substances available as generics are reported in italics
ATC Prevalence Prescriptions/ Packages/ Cost/ %DDD %DDD %DDD code of use (%) users users users Patented Branded Unbranded Biguanides Metformin A10BA02 6.8 9 15 33 - 64 36
reviews Insulins A10A 5.1 8 9 406 100 - -
Sulphonamides A10BB 3.5 8 11 42 9 59 32
and Gliclazide A10BB09 1.8 7 9 50 - 39 61
Glimepiride A10BB12 1.3 8 11 29 - 97 3 Fixed-dose combinations A10BD 2.5 9 15 86 80 20 - Other blood glucose A10BX 1.7 7 8 77 2 51 47
articles lowering drugs
Repaglinide A10BX02 1.7 7 8 68 - 52 48 Alpha glucosidase A10BF 0.3 8 11 90 100 - - inhibitors (i.e. acarbose)
riginal Glitazones A10BG 0.1 8 9 225 100 - -
O (i.e. pioglitazone) DPP-4 inhibitors A10BH 0.1 6 7 327 100 - - Total 14.4 12 17 200 68 20 12 ATC: anatomical therapeutic chemical classification; DDD: defined daily dose; DPP-4 inhibitors: Dipeptidyl peptidase-4 inhibitors.
Table 3 Characteristics of patients treated with generic antidiabetics by category of switching. For each characteristics the total number of pa- tients may be obtained by adding the number of patients in the three switching categories (no switch; single switch; multiple switch)
Metformin Gliclazide Repaglinide No Single Multiple No Single Multiple No Single Multiple switch switch switch switch switch switch switch switch switch 4515 1318 1389 1166 459 246 977 458 251 Subjects (62.5) (18.2) (19.2) (62.3) (24.5) (13.1) (57.9) (27.2) (14.9) Gender 1842 591 612 437 195 99 386 195 113 Male (60.5) (19.4) (20.1) (59.8) (26.7) (13.5) (55.6) (28.1) (16.3) 2573 727 777 729 264 147 591 263 138 Female (64.0) (17.4) (18.6) (63.9) (23.2) (12.9) (59.6) (26.5) (13.9) Age groups 2162 606 637 445 171 94 390 178 107 75-79 (63.5) (17.8) (18.7) (62.7) (24.1) (13.2) (57.8) (26.4) (15.9) 1480 406 484 380 164 81 338 165 85 80-84 (62.4) (17.1) (20.4) (60.8) (26.2) (13.0) (57.5) (28.1) (14.5) 668 238 210 253 81 57 191 82 47 85-89 (59.9) (21.3) (18.8) (64.7) (20.7) (14.6) (59.7) (25.6) (14.7) 205 68 58 88 43 14 58 33 12 90+ (61.9) (20.5) (17.5) (60.7) (29.7) (9.7) (56.3) (32.0) (11.7)
Number of thera- peutic categories* 38 7 12 20 5 2 5 8 4 0 (66.7) (12.3) (21.1) (74.1) (18.5) (7.4) (29.4) (47.1) (23.5) 631 163 169 162 71 44 117 57 32 1-2 (65.5) (16.9) (17.5) (58.5) (25.6) (15.9) (56.8) (27.7) (15.5) 3846 1148 1208 984 383 200 855 393 215 ≥3 (62.0) (18.5) (19.5) (62.8) (24.4) (12.8) (58.4) (26.9) (14.7) Median switches of multiple 4 (3-5) 3 (3-4) 3 (3-5) switchers (IQR)
*: for the definition of therapeutic categories see table S1; IQR: interquartile range. 337 Impact of generic substitution of antidiabetics on adherence
tients with a single switch ranged from 27.2% for re- year). On one hand, the likelihood of switching was paglinide to 18.2% for gliclazide. Multiple switches not influenced by patients’ characteristics such as were observed on average in 15.7% of the patients age, sex and number of therapeutic categories. On and the median number of switches was comparable the other hand, non-switchers, patients with a single for the three selected antidiabetics. The likelihood of switch and multiple switchers, were equally likely to switching did not vary by gender, age subgroups and adhere to the antidiabetic treatment where a generic number of therapeutic categories (especially when is available. Adherence data by intensity of switching taking into account that only a few patients were in- were consistent for the three substances (metformin, reviews cluded in some categories). repaglinide and gliclazide), thus suggesting that these The probability of switching rises with the increas- findings may apply to other off-patented drugs and
ing number of prescriptions for the same substance generic substitutions. and
(Figure 1). The proportion of non-switchers was on av- In the only comparable analysis, Kalisch et al. [15] erage 78% in the group receiving 2-3 prescriptions and investigated the generic substitution of metformin; the progressively decreased up to an average of 56% in majority of patients were non-switchers, 14% received a case of 11 or more prescriptions. The opposite trend single switch and 7% were multiple switchers. Our find- articles was observed for multiple switchers with a maximum ings are also comparable with others that focused on of 26% among subjects with ≥ 11 prescriptions. The different chronic therapies (e.g., calcium channel block- proportion of patients with a single switch (about 20% ers, selective serotonin reuptake inhibitors, statins) [15, of the users) was relatively stable with the increasing 16]. Around 80% of patients were non-switchers or ex- number of prescriptions. perienced a single switch, and the proportion of multi- riginal Switches between generic antidiabetics did not im- ple switchers ranged between 19 and 24%. O pact negatively on treatment adherence (Figure 2). Our results are also coherent with others in the Similar level of adherence were observed across the cardiovascular setting and in postmenopausal women three switching categories for the three substances with osteoporosis: adherence was not found to be in- (metformin, gliclazide and repaglinide). Overall, the fluenced by generic switches among antihypertensive median MPR was 62%, 62%, and 72% among non- agents and alendronate, respectively [18-21]. Howev- switchers, single and multiple switchers respectively er, in specific settings such as those involving psychiat- (Figure 2d). Since the number of prescriptions is as- ric and neurological conditions, the effects of generic sociated with both the probability of switching and substitution are still unclear. In particular, two studies treatment adherence, we also restricted the analysis by Hartung et al. [23] and Duh et al. [24] investigated to patients who received more than 5 prescriptions. the effect of generic substitution of antiepileptics on The differences between the three switching catego- a clinical outcome (i.e. the rate of hospitalization) and ries were even smaller, with the median MPR ranging showed opposite findings. from 75% to 77% (Supplementary Figure S1, available The cohort of patients included in our study can online at www.iss.it/anna). be considered representative of an elderly popula- tion with diabetes. The proportion of patient receiv- DISCUSSION ing either a single antidiabetic (considered as a proxy The possibility that variation in packaging and pill of monotherapy) or two substances (considered as a appearance may affect adherence is a reason for con- proxy of dual therapy) is consistent with the published cern. For instance, Kesselheim and colleagues [17] literature [11, 25, 26]. Also the proportion of patients showed, in a recent article, that changes in pill colors treated with metformin as monotherapy is similar to and shapes increased the risk of non-adherence among that found in other countries [27-31]. Newer drugs epileptic patients. If this effect were confirmed, sub- such as DPP-4 inhibitors were prescribed to a minor- stituting patented originators with generic alterna- ity of patients. Diabetes represents a good example of tives, as well as switching between different generics, a chronic condition. On average, each patient includ- may carry a risk for patients’ outcome, especially in ed in the study received more than 5 daily doses of any case of chronic diseases. drug (5588 DDDs per 1000 subjects per day) and, Our study does not support this concern. In the en- in addition to antidiabetics, a median of 10 different tire elderly population of patients who received anti- substances during the year. The type of comorbidities diabetics in the Umbria Region, the substitution be- identified through prescriptions, their estimated fre- tween branded and unbranded product, as well as be- quency, as well as the high rate of polypharmacy fully tween generics, did not negatively affect adherence. reflect findings of other reports [25, 32-35]. For the three antidiabetics with a generic equiva- As for other studies that used prescription data- lent included in our analysis, 61.0% of the patients bases, a limitation of our analysis is that the calcu- received the same package during the year (non- lation of adherence depended on pharmacy records. switchers) and 23.3% experienced only one package For instance, prescriptions may overestimate adher- substitution (single switch). As expected, the likeli- ence if a drug is collected but not used. Furthermore, hood of any switching increased with the number of we calculated the MPR assuming that 1 prescription prescriptions. Among patients with more than 11 pre- covers 1 month of therapy, which may slightly modify scriptions (of each substance), 18% did switch once, the estimates, but is not expected to impact on the and 26% experienced multiple switching (if combined comparisons between the three switching categories. 44% of patients did switch at least once during the It should be pointed out that the MPR in our study 338 Francesco Trotta, Roberto Da Cas, Marina Maggini et al.
A. Metformin B. Gliclazide No switch Single switch Multiple switch No switch Single switch Multiple switch 100 100
80 80
60 60 40 % Users
% Users 40 reviews 20 20 0
and 2-3 4-5 6-8 9-10 ≥11 0 2-3 4-5 6-8 9-10 ≥11 Number of prescriptions Number of prescriptions
C. Repaglinide D. Pooled (metformin, gliclazide, repaglinide) No switch Single switch Multiple switch No switch Single switch Multiple switch
articles 100 100
80 80
60 60 riginal 40 40 % Users % Users O 20 20
0 0 2-3 4-5 6-8 9-10 ≥11 2-3 4-5 6-8 9-10 ≥11 Number of prescriptions Number of prescriptions
Figure 1 Distribution of switching categories by number of prescriptions.
A. Metformin B. Gliclazide 100 100
80 80
60 60
MPR (%) 40 MPR (%) 40
20 20
0 0 No switch Single switch Multiple switch No switch Single switch Multiple switch
C. Repaglinide D. Pooled (metformin, gliclazide, repaglinide) 100 100
80 80
60 60
MPR (%) 40 MPR (%) 40
20 20
0 0 No switch Single switch Multiple switch No switch Single switch Multiple switch MPR: medication possession ratio.
Figure 2 Adherence comparison by switching categories. 339 Impact of generic substitution of antidiabetics on adherence
was only adopted to perform comparisons between Acknowledgments the switching categories of the same substance. As An abstract of this work was submitted to the 13th indicated before, a diabetic patient may receive more ISOP annual meeting to be held in Pisa in October than 1 antidiabetic (including more than 1 generic 2013, and was accepted as oral communication. substance included in the analysis). The prescription FT, GT, RDC, MM conceived the study design; FT, database only covers prescriptions issued to outpa- RDC, MR analyzed the data; FT, GT wrote the manu- tients and does not account for drugs administered script; FT, GT, RDC, MM, MR contributed to the in nursing homes and hospitals. This may lead to an discussion and reviewed the manuscript. All authors reviews underestimation of the adherence, even though no ef- approved the final version of the manuscript. GT will fect is expected on the comparison between switching act as guarantor for the paper.
categories. Moreover, we did not take into account The authors wish to thank Stefania Spila Alegiani and several factors (e.g. socio-economic status, life-style) and Carmen D’Amore of the National Centre for Epi- potentially impacting on adherence. demiology, for their comments and suggestions on the final version of the manuscript. CONCLUSIONS This study was conducted by investigators employed articles
Our study indicates that generic substitution in in public institutions and was supported by research the diabetes setting does not influence patients’ funds from the Umbria Regional Health Authority. adherence. This information is particularly useful when considering that even uncertainties of a nega- Conflict of interest statement tive effect on adherence may represent a disincen- The authors have no conflict of interest to disclose. riginal tive in using generic drugs. The fact that our find- The opinions expressed in this article do not neces- O ings are relevant to an elderly population of complex sarily reflects the view of the authors’ institutions. patients with comorbidities supports the view that similar findings may be expected in other chronic Received on 14 March 2014. treatments. Accepted on 15 September 2014.
References
1. Pladevall M, Williams LK, Potts LA, Divine G, Xi H, La- Lombardy Region: a large population-based study. Dia- fata JE. Clinical outcomes and adherence to medications betes Res Clin Pract 2011;93:123-30. DOI: 10.1016/j.dia- measured by claims data in patients with diabetes. Diabetes bres.2011.05.004 Care 2004;27:2800-5. DOI: 10.2337/diacare.27.12.2800 12. Gabbay U, Yosef N, Feder-Krengel N, Meyerovitch J. 2. Rubin RR. Adherence to pharmacologic therapy in patients Therapeutic equivalent substitute that is new or unfamil- with type 2 diabetes mellitus. Am J Med 2005;118(Suppl iar to the chronic patient may result in medication er- 5A):27S-34S. DOI: 10.1016/j.amjmed.2005.04.012 ror. Int J Health Care Qual Assur 2012;25:509-18. DOI: 3. Benner JS, Glynn RJ, Mogun H, Neumann PJ, Wein- 10.1108/09526861211246467 stein MC, Avorn J. Long-term persistence in use of statin 13. Greene JA. The substance of the brand. Lancet therapy in elderly patients. JAMA 2002;288:455-61. DOI: 2011;378:120-1. DOI: 10.1016/S0140-6736(11)61077-5 10.1001/jama.288.4.455 14. Kalisch LM, Roughead EE, Gilbert AL. Pharmaceutical 4. Grant RW, O’Leary KM, Weilburg JB, Singer DE, Meigs brand substitution in Australia - are there multiple switch- JB. Impact of concurrent medication use on statin adher- es per prescription? Aust N Z J Public Health 2007;31:348- ence and refill persistence.Arch Intern Med 2004;164:2343- 52. DOI: 10.1111/j.1753-6405.2007.00085.x 8. DOI: 10.1001/archinte.164.21.2343 15. Kalisch LM, Roughead EE, Gilbert AL. Brand substitu- 5. Sabaté E. Adherence to long-term therapies: evidence for ac- tion or multiple switches per patient? An analysis of phar- tion. Geneva: World Health Organization; 2003. maceutical brand substitution in Australia. Pharmacoepide- 6. Nobili A, Garattini S, Mannucci PM. Multiple diseases miol Drug Saf 2008;17:620-5. DOI: 10.1002/pds.1580 and polypharmacy in the elderly: challenges for the in- 16. Ortiz M, Simons LA, Calcino G. Generic substitution of ternist in the third millennium. Journal of Comorbidity commonly used medications: Australia-wide experience, 2011;1:28-44. DOI: 10.15256/joc.2011.1.4 2007-2008. Med J Aust 2010;192:370-3. 7. The diabetic diseases: national prevalence data. 2012. 17. Kesselheim AS, Misono AS, Shrank WH, Greene JA, Available from http://www.epicentro.iss.it/igea/PrimoPi- Doherty M, Avorn J, et al. Variations in pill appearance of ano/prevalenza.asp. antiepileptic drugs and the risk of nonadherence. JAMA 8. American Diabetes Association. Standards of medical care Intern Med 2013;173:202-8. DOI: 10.1001/2013.jamain- in diabetes-2013. Diabetes Care 2013;36(Suppl 1):S11-66. ternmed.997. 9. Associazione Medici Diabetologi, Società Italiana di Dia- 18. Van Wijk BL, Klungel OH, Heerdink ER, de Boer A. betologia. Standard italiani per la cura del diabete mellito Generic substitution of antihypertensive drugs: does it af- 2009‑2010. Torino: Edizioni Infomedica; 2010. fect adherence? Ann Pharmacother 2006;40:15-20. DOI: 10. Struijs JN, Baan CA, Schellevis FG, Westert GP, van den 10.1345/aph.1G163 Bos GA. Comorbidity in patients with diabetes mellitus: 19. Lai PS, Chua SS, Chong YH, Chan SP. The effect of man- impact on medical health care utilization. BMC Health datory generic substitution on the safety of alendronate Serv Res 2006;6:84. DOI: 10.1186/1472-6963-6-84 and patients’ adherence. Curr Med Res Opin 2012;28:1347- 11. Baviera M, Monesi L, Marzona I, Avanzini F, Monesi G, 55. DOI: 10.1185/03007995.2012.708326. Nobili A, Tettamanti M, et al. Trends in drug prescrip- 20. Ude M, Schuessel K, Quinzler R, Leuner K, Müller tions to diabetic patients from 2000 to 2008 in Italy’s WE, Schulz M. Generic switch after ramipril patent ex- 340 Francesco Trotta, Roberto Da Cas, Marina Maggini et al.
piry is not associated with decreased pharmacy refill in primary care. Aust Fam Physician 2007;36:477-80. compliance: a retrospective study using the DAPI da- 29. Nathan DM, Buse JB, Davidson MB, Heine RJ, Hol- tabase. J Hypertens 2011;29:1837-45. DOI: 10.1097/ man RR, Sherwin R, et al. Management of hyperglycemia HJH.0b013e32834942be. in type 2 diabetes: A consensus algorithm for the initia- 21. Corrao G, Soranna D, La Vecchia C, Catapano A, Aga- tion and adjustment of therapy: a consensus statement biti-Rosei E, Gensini G, et al. Medication persistence and from the American Diabetes Association and the Euro- the use of generic and brand-name blood pressure-lower- pean Association for the Study of Diabetes. Diabetes Care ing agents. J Hypertens 2014;32:1146-53. DOI: 10.1097/ 2006;29:1963-72. DOI: 10.2337/dc06-9912 HJH.0000000000000130. 30. Walley T, Hughes D, Kendall H. Trends and influences reviews
22. The list of equivalent medicines authorized in Italy. 2013. on use of antidiabetic drugs in England, 1992-2003. Phar- Available from http://www.agenziafarmaco.gov.it/it/con- macoepidemiol Drug Saf 2005;14:769-73. DOI: 10.1002/
and tent/liste-di-trasparenza-e-rimborsabilit%C3%A0. pds.1089 23. Hartung DM, Middleton L, Svoboda L, McGregor JC. 31. Lamberts EJ, Nijpels G, Welschen LM, Hugtenburg JG, Generic substitution of lamotrigine among medicaid pa- Dekker JM, Souverein PC, et al. Long term patterns of tients with diverse indications: a cohort-crossover study. use after initiation of oral antidiabetic drug therapy. Phar- CNS Drugs 2012;26:707-16. DOI: 10.2165/11634260- macoepidemiol Drug Saf 2011;20:351-8. DOI: 10.1002/
articles 000000000-00000. pds.2089 24. Duh MS, Paradis PE, Latrémouille-Viau D, Greenberg PE, 32. Caughey GE, Roughead EE, Vitry AI, McDermott RA, Lee SP, Durkin MB, et al. The risks and costs of multiple-ge- Shakib S, Gilbert AL. Comorbidity in the elderly with neric substitution of topiramate. Neurology 2009;72:2122- diabetes: Identification of areas of potential treatment 9. DOI: 10.1212/WNL.0b013e3181aa5300. conflicts. Diabetes Res Clin Prac 2010;87:385-93. DOI: riginal 25. Bramlage P, Binz C, Gitt AK, Krekler M, Plate T, Deeg 10.1016/j.diabres.2009.10.019. O E, et al. Diabetes treatment patterns and goal achieve- 33. Mazzaglia G, Yurgin N, Boye KS, Trifirò G, Cottrell S, Al- ment in primary diabetes care (DiaRegis) - study protocol len E, et al. Prevalence and antihyperglycemic prescribing and patient characteristics at baseline. Cardiovasc Diabetol trends for patients with type 2 diabetes in Italy: a 4-year ret- 2010;9:53. DOI: 10.1186/1475-2840-9-53. rospective study from national primary care data. Pharma- 26. Colombo GL, Rossi E, De Rosa M, Benedetto D, Gaddi col Res 2008;57:358-63. DOI: 10.1016/j.phrs.2008.03.009 AV. Antidiabetic therapy in real practice: indicators for 34. Nobili A, Franchi C, Pasina L, Tettamanti M, Baviera adherence and treatment cost. Patient Prefer Adherence M, Monesi L, et al. Drug utilization and polypharmacy in 2012;6:653-61. DOI: 10.2147/PPA.S33968 an Italian elderly population: the EPIFARM-elderly pro- 27. Winkelmayer WC, Stedman MR, Pogantsch M, Wie- ject. Pharmacoepidemiol Drug Saf 2011;20:488-96. DOI: ninger P, Bucsics A, Asslaber et al. Guideline-conformity 10.1002/pds.2108 of initiation with oral hypoglycemic treatment for patients 35. Nobili A, Licata G, Salerno F, Pasina L, Tettamanti M, with newly therapy-dependent type 2 diabetes mellitus in Franchi C, et al. Polypharmacy, length of hospital stay, Austria. Pharmacoepidemiol Drug Saf 2011;20:57-65. DOI: and in-hospital mortality among elderly patients in internal 10.1002/pds.2059 medicine wards. The REPOSI study. Eur J Clin Pharmacol 28. Weekes AJ, Thomas MC. The use of oral antidiabetic agents 2011;67:507-19. DOI: 10.1007/s00228-010-0977-0