Croatian Agency for Medicinal Products and Medical Devices

Zagreb, Croatia

Croatian Agency for Medicinal Products and Medical Devices

Zagreb, Croatia

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Skvrce N.M.,Croatian Agency for Medicinal Products and Medical Devices | Arapovic S.,Croatian Agency for Medicinal Products and Medical Devices | Krnic D.,Croatian Agency for Medicinal Products and Medical Devices | Sarinic V.M.,Croatian Agency for Medicinal Products and Medical Devices | And 4 more authors.
Psychiatria Danubina | Year: 2010

Background: The objective of analysis of ADRs caused by drugs that pertain to the A TC group N (nervous system), as reported to the Croatian Agency for Medicinal Products and Medical Devices for the period from March 2005 to December 2008, was to examine the types of ADRs collected in said period, the profile of reporters and the possible impacts this could have on prescribing this group of medicinal products in the future. Subjects and methods: A retrospective observational study of ADRs was performed. Drugs causing ADRs were grouped according to the A TC drug classification, and subsequently entered into a database. Data were analyzed in respect of total number, gender, age, type, seriousness, expectedness, outcome, system organ class, suspected drug and reporter. Results: The findings showed that 15% of all reported ADRs were caused by drugs from the A TC group N 60% of these were caused by drugs belonging to the ATC subgroups N05 (psycholeptics) and N06A (antidepressants). A significant increase in the percentage of serious ADRs in the examined groups of medicinal products was observed. Analysis of expectedness showed that the share of unexpected ADRs is very high. Conclusion: The distribution of reporters is not satisfactory. The Agency, as regulatory authority, cannot undertake certain measures to improve the safe use of medicinal products without having reports. Only reporting of ADRs can result in changes to benefit all patient populations. Our joint aim should be avoiding a great number of ADRs and maintaining overall safe use of medicinal products. © Medicinska naklada.TypeofStudy:An open, retrospective, observational study examining the types of adverse drug reactions (ADRs) caused by antidepressants (including Ludiomil) and antipsychotics as reported to the Croatian Agency for Medicinal Products and Medical Devices from March 2005 to 2008 and to evaluate the profile of reporters and the possible impacts this could have on prescribing this group of medicinal products in the future.Patients:An unspecified number of patients, 58.7% female and 48.3% male patients aged 17 to 86 years had ADRs; an unspecified number were on antidepressants (Ludiomil, sertraline, fluvoxamine, escitalopram, paroxetine, venlafaxine, tianeptine, citalopram, fluoxetine, mirtazapine, amitriptyline, moclobemide and reboxetine) and antipsychotics (olanzapine, clozapine, haloperidol, risperidone, sulpiride, ziprasidone, quetiapine, fluphenazine, levomepromazine and promazine).DosageDuration:Dosage and duration not stated.AdverseEffects:An unspecified number of patients had adverse reactions (2 [1.1%] events): nervous system disorders (headache, tremor, dizziness, neuroleptic malignant syndrome, restless legs syndrome, parkinsonism and somnolence), psychiatric disorders (insomnia, restlessness, suicidal ideation and libido decreased), gastrointestinal disorders (nausea, dry mouth and salivary hypersecretion), General disorders and administration site conditions (asthenia and peripheral edema), weight increased, reproductive system and breast disorders (erectile dysfunction).Results:A total of 370 adverse reactions were reported. The distribution of types of reported ADRs is as follow: 89.4% of ADRs pertaining to type A, 7.6% pertaining to type B and 2.9% pertaining to type F. 1. 41.7% ADRS were unexpected. The overview of the percentage of each group concerning the outcome of ADRs resulted in the following: 52.5% were recovered/resolved, 25.0% were unknown, 4.4% were not recovered/not resolved, 7.1% were recovering/resolving, 6.3% were recovered/resolved with recurrences, and 0.8% were fatal. The most frequently reported ADRS were weight gain (n=19), headache (n=14), insomnia (n=13), nausea (n=12), tremors (n=9) and restless leg syndrome, restlessness, neuroleptic malignant syndrome, dizziness, erectile dysfunction and suicidal ideation with 6 reports (n=6). 17.1% of ADRs were noted in patients treated with olanzapine, 9.1% on clozapine, 6.9% on haloperidol, 5.1% on risperidone, 4.0% on sulpiride, 2.9% on ziprasidone, 2.3% on quetiapine, 0.6% on fluphenazine, 0.6% on levomepromazine, 0.6% on promazine, 12.0% on sertraline, 8.6% on fluvoxamine, 9.1% on escitalopram, 8.0% on paroxetine, 2.9% on venlafaxine, 2.3% on tianeptine, 1.7% on citalopram, 1.7% on fluoxetine, 1.7% mirtazapine, 1.1% Ludiomil, 0.6% amitriptyline, 0.6% moclobemide and 0.6% reboxetine. No significant correlation between the number of ADRs for each suspected drug and the pharmacoeconomic score (daily defined dose/1000/day) of drug consumption was noted.AuthorsConclusions:It is assumed that too few observed ADRs are actually being reported to the Agency. It is important to emphasize that the portion of hospital psychiatrists of the total number of reporters is pronouncedly low, when serious and severe ADRs are most commonly presented in hospitalised patients or patients are being hospitalised because of severe ADRs. The profile of ADRs for the analysed group N drugs differs in comparison with the profile of adverse reactions for other medicinal products. The group N drugs had a greater incidence of serious ADRs, exceeding the mean value of 25% which is usual for medicinal products. It is important to stress the signal of an appearance of cardiovascular ADRs, for example cardiac arrhythmia, QT interval prolongation and reports of sudden deaths that can be caused by malignant cardiac arrhythmia. It is necessary to pay greater attention to patients who have risk factors for developing these kinds of ADRs, and to report every suspicion that a medicinal product caused a sudden death. Also, it is important to note that there is a high share of unexpected ADRs among the spontaneous reports, which are very significant for further monitoring of the safety profile of N group drugs. In Croatia, psychiatrists are confronted with ADRs in theft daily practice. It is evident that they are dealing with them frequently and that recommendations are given for individual cases. The Agency, as regulatory authority, cannot undertake certain measures to improve the safe use of medicinal products without having reports on the reactions that occur in daily practice. Only reporting of ADRs can result in changes to benefit all patient populations. When adverse reactions are reported, some signals can be identified and can result in changes of posology (dose recommendations), special warnings and precautions for use, or recommendations for special patient groups. This then results in avoiding a great number of ADRs and maintaining overall safe use of medicinal products.FreeText:Drugs causing ADRs were grouped according to the Anatomical-Therapeutic-Chemical (ATC) drug classification, and subsequently entered into a database. ADRs can be divided into certain types. Characteristics of type A: they are common (≥1%), foreseeable, dose-dependent, with low mortality and may withdraw after a period of adaptation. They result from the excessive pharmacological effect of the drug. Characteristics of type B: they are not expected, not dose-dependent, the mechanism is not always known, they appear during the time of usage of the drug, with a low frequency (<1%), they have high mortality, usage of suspected drug must be discontinued and an appropriate anti-allergic treatment must be applied. They are independent of the main pharmacological effect of the drug. A type F adverse reaction means therapeutic failure. ADRs were considered serious if ADR resulted in death, ADR was life threatening, the ADR required inpatient hospitalization or prolongation of existing hospitalization, the ADR resulted in persistent or significant disability/incapacity, the ADR was a congenital anomaly/birth defect, or the ADR was another important medical event. If a suspected ADR, in association with the specific medicinal product, is related to signs and symptoms of recognized reactions that are listed in the product information for that medicinal product, the adverse reaction is expected. If it is not the case, the adverse reaction is classified as unexpected. 6 categories of ADR outcomes: recovered/resolved, unknown, not recovered/not resolved, recovering/resolving, recovered/resolved with recurrences, fatal-reaction may be contributory. Reporters were classified into the following groups: hospital/non-hospital psychiatrist, general practitioner, hospital/non-hospital specialist other than psychiatrist, pharmacist, Marketing Authorisation Holder and other healthcare professional.


Elenkov I.J.,Glaxosmithkline | Elenkov I.J.,Fidelta Ltd. | Hrvacic B.,Glaxosmithkline | Hrvacic B.,Fidelta Ltd. | And 22 more authors.
Croatica Chemica Acta | Year: 2013

A series of variously substituted furochromenes, hemiacetals 2, acetals 3, and rearranged compounds 4, were synthesized from variously substituted 4-hydroxycoumarins and evaluated in several in vitro assays, inhibition of mast cell degranulation induced by the activation of Fce receptor type I or calcium ionophore and leukotriene B4 (LTB4) inhibition. The most active derivatives, 3p and 4p (8-iso-propyl substitution in coumarin ring) and 3r (5-methyl-8-chloro substitution), showed significant inhibition of mast cell degranulation (Fctriggered) and LTB4, and exhibited significant local anti-inflammatory activity in PMA induced ear edema in CD1 mice, with potency equal (compounds 3p and 4p) or better (compound 3r) in comparison with zileuton, a reference drug used. It might be a promising direction for developing novel drugs as potential agents for the treatment of allergies and other inflammatory diseases.


Dragojevic S.,Glaxosmithkline | Sunjic V.,Glaxosmithkline | Bencetic-Mihaljevic V.,Glaxosmithkline | Ralic J.,Glaxosmithkline | And 12 more authors.
Journal of Pharmaceutical and Biomedical Analysis | Year: 2011

The stability in aqueous solution of five classes of coumarin dimers (I-. V, compounds 1-. 29) was studied by HPLC-MS/MS at various pH values. The relationship between chemical structure and stability is discussed. It was found that dimeric compounds with strong electron withdrawing groups (EWGs) on the α-carbon to the bridging C-atom are stable at all pH values, whereas other derivatives undergo retro-Michael addition at rates which are also affected by the substituents on the aromatic rings. In some cases formation of stable isomers or oxidation products was observed. In order to evaluate their developability and potential for progression to in vivo studies, representative compounds were tested in an in vitro microsomal stability assay. © 2010 Elsevier B.V.


Ilijas M.,Galapagos Research Center Ltd | Malnar I.,Galapagos Research Center Ltd | Malnar I.,Croatian Agency for Medicinal Products and Medical Devices | Gabelica Markovic V.,Galapagos Research Center Ltd | Stepanic V.,Ruder Boskovic Institute
Journal of Pharmaceutical and Biomedical Analysis | Year: 2013

Physicochemical properties provide reliable guidance in optimization of pharmacological efficiency and ADME profile of small chemical compounds. Their high-throughput determination is regularly based on application of HPLC techniques. In this study CHI and CHI IAM of 32 4-hydroxycoumarin analogs were measured by HPLC with methanol gradient at pHs 2.8 and 7.0. Results were analyzed by PCA in terms of computed descriptors in order to identify space for optimization of their phospholipids affinity and lipophilicity for which predictive software failed to produce reliable estimations. The chromatographic behavior of studied 4-hydroxycoumarins was typical of acidic compounds. The CHI2.8, CHI7.0, CHI IAM2.8 and CHI IAM7.0 values were all considerably cross-correlated in accordance with their prevailing lipophilic character. Structure-retention relationship (SRR) analysis furthermore revealed that H-bond accepting capacity and dipolar interactions with methanol generally shorten their retention times. However, deviations from the linear trends were noticed for R3/R5-substituted derivatives able to form intramolecular contacts with the 4-O(H) group and characterized by more uniform electron density at 2-O and 4-O atoms and quite different acidity/H-bond donating capacity than the rest of derivatives. Thus, CHI and CHI IAM determinations and SRR analysis are fast and efficiently pointed to ways of modifying biological activities of 4-hydroxycoumarins. © 2012 Elsevier B.V.


Davosir Klariae Z.,Croatian Agency for Medicinal Products and Medical Devices | Hafner A.,University of Zagreb | Zubeiae S.,Croatian Agency for Medicinal Products and Medical Devices | Durrigl M.,PharmaS Ltd. | Filipoviae-Greiae J.,University of Zagreb
Chemical and Biochemical Engineering Quarterly | Year: 2012

Conventional and composed cyclosporin A (CsA)-loaded polymeric microspheres (MS) were prepared by spray-drying of CsA/chitosan one-phase system (solutions) and CsA/lecithin/chitosan two-phase system (suspensions). Microspheres were characterised in terms of production yield, entrapment efficiency, size distribution, zeta-potential, thermal properties, swelling ability and drug release profile. Conventional MS were characterised by mean diameter ranging from 1.15 ± 0.91 to 1.27 ± 0.84 μm and CsA entrapment efficiency varying from 72.6 to 87.3%. Composed MS were characterised by larger mean diameter (1.32 ± 1.08 to 1.53 ± 1.15 μm) and higher CsA entrapment efficiency (86.6-94.3%) compared to the corresponding conventional MS. Only composed MS showed swelling ability, which was proportional to chitosan base content in the preparation. In vitro CsA release profile depended on both, the type of the spray-dried system and the chitosan used, as these factors were crucial in determining CsA entrapment pattern and swelling/dissolution ability of MS.

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