Teratogenic effects of drugs

Klinički pokusi na trudnicama se ne provode iz etičkih razloga. Rezultat toga je nedostatak podataka o djelovanju lijekova u trudnoći. Lijekovi mogu proći kroz posteljicu i uzrokovati teratogene nuspojave na embrij/fetus. Tipične manifestacije teratogeneze su smrt fetusa, zastoj rasta, nepravilan razvoj organa te razvoj karcinoma kasnije u životu. Budući da je oko 50% trudnoća neplanirano, postoji velika mogućnost izloženosti fetusa teratogenom lijeku, posebno tijekom prvog tromjesečja. Cilj ovog diplomskog rada je analiza prijava sumnji na teratogeni učinak lijekova na embrij/fetus iz svjetske baze nuspojava VigiBase i europske baze nuspojava EudraVigilance te usporedba podataka s obzirom na prijave iz hrvatske nacionalne baze nuspojava VigiFlow. Provedena je retrospektivna opservacijska studija prijava sumnji na nuspojave lijekova na embrij/fetus korištenjem podataka iz hrvatske nacionalne baze VigiFlow u organskom sustavu Prirođeni, obiteljski i genetski poremećaji, zaprimljene do ožujka 2018. godine. Podaci su analizirani s obzirom na prijavljene djelatne tvari i prirođene anomalije. Poseban je osvrt dan na sadržaje sažetaka opisa svojstava lijekova (eng. Summary of Product Characteristics, SmPC) te na postojeće dodatne mjere minimizacije rizika (eng. Risk Minimization Measures, MMR) i program prevencije trudnoće (eng. Pregnancy Prevention Programme, PPP). Prema broju prijava sumnji na nuspojave teratogenih lijekova ističu se lijekovi s djelovanjem na živčani sustav, među kojima antiepileptici: fenitoin, karbamazepin, valproatna kiselina, gabapentin, topiramat i lamotrigin. Od anksiolitika ističe se diazepam. Najčešće prijavljivane kongenitalne anomalije su kardiovaskularne anomalije. Za mnoge prijavljene djelatne tvari sigurnost primjene u trudnoći nije dovoljno istražena te nedostaju dodatna upozorenja u SmPC-u i u uputi o lijeku. Za poboljšanje sigurnosti primjene lijekova u trudnoći i za smanjivanje rizika nastanka kongenitalnih poremećaja uzrokovanih lijekovima, važnu ulogu ima spontano prijavljivanje nuspojava u postmarketinškoj fazi lijeka te konstantan rad na MMR-ovima uključujući i provođenje PPP-a, kao i edukacija zdravstvenih radnika i žena reproduktivne dobi.For ethical reasons, clinical trials on pregnant women are not performed. As a result, there is a lack of data on the effect of drugs on pregnancy. Drugs may pass through the placenta and cause teratogenic side effects on the embryo/fetus. Typical manifestations of teratogenesis are fetal death, growth failure, improper organ development and cancer development later in life. Since about 50% of pregnancies are unplanned, there is a great potential for fetal teratogenic exposure, especially during the first trimester. The objective of the master thesis is to analyze the reports of teratogenic effects of medicinal products on embryo/fetus from global database VigiBase and European database EudraVigilance, as well as to compare with the suspected adverse drug reactions (ADRs) reports from Croatian national database VigiFlow. A retrospective observational study of suspected ADRs reports in system organ class (SOC) Congenital, familial and genetic disorders from Croatian national database VigiFlow, received by March 2018 was performed. Data on ADRs reports were given by HALMED's pharmacovigilance department. Suspected ADRs reports were analyzed with regard to reported active substances and congenital anomalies. A special review is given on Summary of product characteristics (SmPC), additional Risk minimisation measures (RMM) and Pregnancy prevention programme (PPP). According to the number of reported teratogenic side effects, medicinal products with effect on nervous system stand out, especially antiepileptics such as phenytoin, carbamazepine, valproic acid, gabapentin, topiramate and lamotrigine. Of the anxiolytics, diazepam is noted. The most commonly reported congenital anomalies are cardiovascular anomalies. For many reported active substances, safety in pregnancy has not been adequately investigated and there are no additional warnings in SmPC and package leaflets (PL). To improve the safety of drug use in pregnancy and reduce the risk of congenital drug-induced disorders, spontaneous reporting of side effects in postmarketing phase of medicinal product and the constant work on MMRs, including the implementation of PPP, as well as education of health workers and women of reproductive age play an important role