Nuspojave antidijabetika prijavljene Hrvatskoj agenciji za lijekove i medicinske proizvode

Abstract

Uvod. Šećerna bolest (ŠB) je kronična i progresivna bolest, zahvaća sve dobne skupine i u stalnom je porastu. Komplikacije dovode do trajnih invalidnosti, poskupljenja zdravstvene skrbi i preuranjene smrti. Upravo iz tih razloga rano otkrivanje i pravovremeno liječenje ŠB mogu donijeti velike uštede u zdravstvu kao i osigurati bolju kvalitetu života bolesnika. Zbog progresivnog tijeka ŠB monoterapija se obično proširuje na liječenje dvojnom ili trojnom kombinacijom antidijabetika kako bi se kroz dulji period održala zadovoljavajuća kontrola glikemije. Dodatno se mora posvetiti pažnja liječenju komorbiditeta, a nerijetko i već nastalih komplikacija, čime se povećava rizik od nuspojava i interakcija te negativno utječe na suradljivost pacijenta. S ciljem optimizacije terapije, liječenje oboljelih zahtijeva individualiziran pristup i kontinuiran nadzor svih čimbenika rizika. Cilj istraživanja. Mogućnosti liječenja oboljelih posljednih su godina proširene dostupnošću novih antidijabetika čiji sigurnosni profil treba još dodatno razjasniti. Poznavanje nuspojava lijekova, osobito u pojedinih skupina bolesnika s posebnim rizicima, jedan je od osnovnih uvjeta za planiranje racionalne farmakoterapije. Stoga je cilj ovog rada prikazati karakteristike nuspojava antidijabetika (ATK skupina A10) prijavljenih Hrvatskoj agenciji za lijekove i medicinske proizvode (HALMED) tijekom sedmogodišnjeg razdoblja (2010.–2016.) te ih usporediti s njihovom nacionalnom potrošnjom u istom periodu. Materijal i metode. Nacionalne sigurnosne prijave pojedinačnih slučajeva nuspojava antidijabetika pretražene su u razdoblju od 01. siječnja 2010. do 31. prosinca 2016. god. pomoću programskog alata VigiLyze svjetske baze nuspojava VigiBase. Slučajevi nuspojava analizirani su do pete razine ATK-a s obzirom na učestalost prijavljivanja, dob i spol bolesnika, pripadnost nuspojave prema klasifikaciji organskih sustava i ozbiljnost nuspojave. Dodatno su razmatrane prijave nuspojava za koje je prijavitelj naznačio da su potencijalno posljedica interakcije lijekova u istodobnoj primjeni, a pritom je korišten interakcijski program Micromedex. Također je dan pregled najvažnijih sigurnosnih regulatornih mjera poduzetih za pojedine antidijabetike u navedenom razdoblju prema podacima iz godišnjih Izvješća o nuspojavama lijekova i arhivi Pisama zdravstvenim radnicima na mrežnim stranicama HALMED-a. Istraživanje kretanja nacionalne potrošnje antidijabetika u istom razdoblju provedeno je na temelju rutinski prikupljenih podataka HALMED-a iz javnih i bolničkih ljekarni o broju izdanih originalnih pakiranja pojedinog lijeka. Podaci o potrošnji iskazani su brojem definiranih dnevnih doza na 1000 stanovnika na dan (DDD/TSD) i financijski u kunama (kn), t e s u u spoređeni s v ažećim h rvatskim terapijskim smjernicama. Rezultati. U ispitivanom razdoblju zabilježeno je 620 prijava sumnji na nuspojave antidijabetika, od čega je 130 ozbiljnih prijava. Uočeni porast prijavljivanja nuspojava antidijabetika može se povezati s nekoliko farmakoepidemioloških pokazatelja, od kojih su najznačajniji porast prevalencije bolesti i posljedično kontinuirani rast ukupne potrošnje antidijabetika (osobito novih kombinacija oralnih antidijabetika). Najzastupljeniji su očekivani probavni poremećaji (27,8 %), a sporadično se bilježe i neke rijetke nuspojave, primjerice laktacidoza (metformin), trombocitopenija (repaglinid), dijabetička ketoacidoza (empagliflozin), pankreatitis (linagliptin, liraglutid, metformin/sitagliptin, metformin/vildagliptin), karcinom gušterače (linagliptin, metformin/vildagliptin) i karcinom mokraćnog mjehura (pioglitazon). Najveći broj slučajeva nuspojava antidijabetika očekivano se bilježi u starijoj populaciji (≥ 65 godina) zbog prisutnih komorbiditeta, politerapije i općenito više prevalencije pretežite ŠBT2. Nešto više nuspojava antidijabetika zabilježeno je u bolesnica (56,6 %) što se pripisuje općenitom obrascu raspodjele učestalosti nuspojava lijekova prema spolu pacijenta. Usklađenost propisivanja antidijabetika s hrvatskim terapijskim smjernicama najviše se uočava iz podataka o potrošnji metformina, derivata sulfonilureja i inzulinskih pripravaka, što se odražava i na isto kretanje broja prijava njihovih nuspojava (primjerice, metformin je kao prva linija liječenja ŠBT2 kroz cijelo razdoblje stabilno na prvom mjestu u potrošnji i prijavama nuspojava antidijabetika). Sigurnost primjene lijekova novog mehanizma djelovanja intenzivno se prati pa je i povećano prijavljivanje nuspojava unatoč manjoj potrošnji od standardnih antidijabetika. Za novije antidijabetike razmatran je i velik broj sigurnosnih signala proizašlih iz spontanih prijava nuspojava, od kojih su neki doveli do izmjena u informacijama o lijeku (pioglitazon i karcinom mokraćnog mjehura, vildagliptin i mialgija, SGLT2 inhibitori i dijabetička ketoacidoza) ili povlačenja lijeka s tržišta (roziglitazon i kardiovaskularni rizik). U prijavljenim slučajevima potencijalno uzrokovanim interakcijama lijekova kao najučestalija reakcija prepoznata je hipoglikemija bilo zbog aditivnog učinka kombiniranih antidijabetika ili istodobne primjene s lijekovima u terapiji komorbiditeta (većinom s ramiprilom). Zaključak. Racionalna farmakoterapija i dobro poznavanje sigurnosnog profila antidijabetika ključni su za unaprjeđenje zdravstvene skrbi osoba sa šećernom bolešću. U ovom opservacijskom istraživanju kretanja potrošnje i prijavljivanja nuspojava antidijabetika moguće je prepoznati glavne obrasce propisivanja te potencijalne rizike primjene antidijabetika. Poznavanjem nuspojava antidijabetika u znatnoj se mjeri mogu spriječiti neželjeni učinci i poboljšati ishodi liječenja bolesnika.Background. Diabetes mellitus (DM) is a chronic and progressive metabolic disorder affecting all age groups at epidemic levels worldwide. The complications of DM are the main cause of patient disability, while also leading to an increase in health care costs and premature death. It is therefore important to provide early diagnosis and timely treatment of DM and, in doing so, contribute to achieving significant savings in health care costs and improved quality of life for the patients. Due to the progressive natural course of the disease, in order to maintain glycaemic control over a longer period of time, the monotherapy for DM is commonly intensified by introducing a combination o f t wo o r t hree antidiabetics. Furthermore, treatment of comorbidities and complications is frequently needed which increases the risk of drug use side effects and interactions, and may negatively affects the patient adherence. In order to optimize the therapy for DM, an individualized approach with continuous monitoring of all possible risk factors should be applied in the treatment of DM patients. Objectives. The pharmacotherapeutic options for treating DM have recently been expanded thanks to the emergence of new antidiabetics. However, the safety profiles of such drugs have not been established yet and are subject to additional monitoring. Awareness of possible adverse drug reactions (ADRs), in particular with regard to different groups of patients with special risks, is one of the basic preconditions for planning rational pharmacotherapy. The main objective of this study was therefore to present the characteristics of ADRs of antidiabetic drugs (ATC group A10) reported to the Croatian Agency for Medicinal Products and Medical Devices (HALMED) during a seven-year period (from 2010 to 2016) and to compare the observed ADRs with related drug utilization rates recorded in the same period at the national level. Material and Methods. For the purposes of this study, antidiabetic drug related Individual Case Safety Reports (ICSRs), submitted in the period from January 1, 2010 to December 31, 2016, were searched using VigiLyze, a tool that allows overview and analysis of national data from the global ICSR database - VigiBase. The reported ADRs were analysed up to the fifth level of ATC system in respect of frequency of reporting, age and sex of the patient, system organ class into which the relevant ADR is classified, and the seriousness of the same. The ADRs indicated by reporting person as potentially caused by drug interactions were also included in the analysis, for which purpose the Micromedex interaction application was used. The paper also provide a review of the most important safety-related regulatory measures, implemented within the observed period for particular antidiabetic drug, according to the data from Annual ADR Reports prepared by HALMED and the archive of Direct Healthcare Professional Communication letters available on HALMED's website. The national antidiabetic drug utilization trends recorded in the same period were analyzed on the basis of the data that HALMED routinely collects from public and hospital pharmacies concerning the number of original packaging dispensed for individual drug. The antidiabetic drug utilization data, expressed in the number of defined daily doses per 1000 inhabitants per day (DDD/TID) and financially in kunas (HRK), were compared with current Croatian therapeutic guidelines. Results. In the observed period, 620 suspected antidiabetic drug related ADRs were reported, of which 130 serious ones. The observed increase in the number of ADR reports can be ascribed to several pharmacoepidemiological indicators. The most significant among such indicators are the increasing prevalence of the disease and the consequent continuous increase in total antidiabetic drug utilization rates (in particular with regard to the new combinations of oral antidiabetics). The most commonly reported ADRs were gastrointestinal disorders (27.8 %) while some rare and serious ADRs, such as lactacidosis (metformin), thrombocytopenia (repaglinid), diabetic ketoacidosis (empagliflozin), pancreatitis (linagliptin, liraglutide, metformin/sitagliptin, metformin/vildagliptin), pancreatic cancer (linagliptin, metformin/vildagliptin) and urinary bladder cancer (pioglitazone), were recorded in sporadic cases. Most ADRs were reported in the elderly (aged 65 and above), which was expected considering the frequent presence of comorbidities, polypharmacy and the greater prevalence of the predominant DMT2. Slightly more ADRs were recorded in female patients (56.6 %), following the general pattern of patient sex distribution of ADRs. Compliance with the Croatian therapeutic guidelines in prescribing antidiabetics was most evident from the data on the use of metformin, sulfonylureas and insulin preparations, and the related ADR reporting trends were analogous (e.g. metformin, as the first-line treatment choice for DMT2, steadily recorded the highest figures in terms of both utilization and ADR reporting). Despite their lower drug utilization, increased ADR reporting was noticed for antidiabetics with new mechanisms of action as they are medicines under additional safety monitoring. Based on the spontaneous ADR reports, a large number of safety signals in the observed period were identified for these new antidiabetics, some of which resulted in the modification of product information (pioglitazone and bladder cancer, vildagliptin and myalgia, SGLT2 inhibitors and diabetic ketoacidosis) or even withdrawal of the drug from the market (rosiglitazone and cardiovascular risk). Among the ADRs indicated in the reports as potentially caused by drug interactions, hypoglycemia was identified as the most frequently occurring adverse reaction due to either the additive effect of combined antidiabetic drugs or the concurrent use of antidiabetics with drugs in therapy of comorbidities (mostly ramipril). Conclusion. Rational pharmacotherapy and in-depth understanding of the safety profiles of antidiabetics is crucial for improving the health care of patients suffering from DM. This observational study of trends in antidiabetic drug utilization and ADR reporting has helped identify the main patterns applied in prescribing antidiabetics and the potential safety risks associated with such drugs. Awareness of adverse reactions to antidiabetic drugs can significantly contribute to the prevention of unwanted effects and improvement of treatment outcomes