Outcomes of long-acting injectable antipsychotics use in pregnancy: A literature review.

BACKGROUND: Women with a history of serious psychotic disorders are at increased risk of disease relapse during pregnancy. Long-acting injectable (LAI) antipsychotics have been widely used to improve adherence and prevent relapse in patients with various severe psychotic disorders, but there is a lack of high-quality data from previous research on the safety of LAI antipsychotics during pregnancy. AIM: To summarize relevant data on maternal, pregnancy, neonatal, and developmental outcomes from published cases of LAI antipsychotic use in pregnancy. METHODS: A literature search was performed through November 11, 2023, using three online databases: PubMed/MEDLINE, Scopus, and Web of Science. Case reports or case series that reported information about the outcomes of pregnancy in women who used LAI antipsychotics at any point in pregnancy, with available full texts, were included. Descriptive statistics, narrative summation, and tabulation of the extracted data were performed. RESULTS: A total of 19 publications satisfied the inclusion criteria: 3 case series, 15 case reports, and 1 conference abstract. They reported the outcomes of LAI antipsychotic use in 74 women and 77 pregnancies. The use of second-generation LAI antipsychotics was reported in the majority (n = 47; 61.0%) of pregnancies. First-generation LAI antipsychotics were administered during 30 pregnancies (39.0%). Most of the women (approximately 64%) had either satisfactory control of symptoms or no information about relapse, while approximately 12% of them had developed gestational diabetes mellitus. A minority of cases reported adverse outcomes such as stillbirth, spontaneous abortion, preterm birth, low birth weight, congenital anomalies, and neurological manifestations in newborns. However, there were no reports of negative long-term developmental outcomes. CONCLUSION: Currently available data seem reassuring, but further well-designed studies are required to properly evaluate the risks and benefits of LAI antipsychotic use during pregnancy.

Priapism associated with anti-seizure medications: a pharmacovigilance study and a review of published cases.

BACKGROUND: Recently, case reports of priapism associated with the use of some anti-seizure medications began to emerge in the literature. We aimed to investigate if there is a potential safety signal of priapism among individual anti-seizure medications and to search the literature for relevant published cases. RESEARCH DESIGN AND METHODS: We conducted a disproportionality analysis using OpenVigil 2.1 to query the United States Food and Drug Administration's Adverse Event Reporting System (FAERS) database. Literature search was conducted in PubMed/MEDLINE, Scopus and Web of Science up to 12 July 2023. RESULTS: We identified positive signal of priapism for valproic acid and its derivatives (n = 23, chi-squared = 59.943, PRR = 4.566), gabapentin (n = 20, chi-squared = 9.790, PRR = 2.060), lamotrigine (n = 16, chi-squared = 8.318, PRR = 2.120), levetiracetam (n = 16, chi-squared = 10.766, PRR = 2.329), topiramate (n = 14, chi-squared = 28.067, PRR = 3.972) and carbamazepine (n = 8, chi-squared = 6.147, PRR = 2.568), as well as published cases of priapism associated with these drugs. We also found published cases of priapism for pregabalin and phenytoin in the literature and FAERS, and at least one reported adverse event of priapism in FAERS for clonazepam, lacosamide, ethosuximide, oxcarbazepine, and vigabatrin in which they were considered primary suspect. CONCLUSIONS: Our study identified signals for priapism for several anti-seizure medications, but these results need to be confirmed in well-designed pharmacoepidemiological studies.

Potential Novel RNA-Targeting Agents for Effective Lipoprotein(a) Lowering: A Systematic Assessment of the Evidence From Completed and Ongoing Developmental Clinical Trials.

ABSTRACT: An increase in blood lipoprotein (a) [Lp(a)] levels, mostly genetically determined, has been identified as an independent risk factor of atherosclerotic cardiovascular disease. No drug has yet been approved that markedly lowers Lp(a) and thereby reduces residual cardiovascular risk. The aim of this article was to critically review the evidence from clinical development studies to date on the efficacy and safety of new RNA-based therapeutics for targeted lowering of Lp(a). PubMed/MEDLINE, Scopus, Web of Science, and ClinicalTrials.gov were searched without any language or date restriction up to November 5, 2022, and a total of 12 publications and 22 trial records were included. Several drugs were found that are currently in various stages of clinical development, such as the antisense oligonucleotide pelacarsen and the small interfering RNA molecule olpasiran and drugs coded as SLN360 and LY3819469. Among them, pelacarsen has progressed the most, currently reaching phase 3. All these drugs have so far shown satisfactory pharmacokinetic properties, consistently high and stable, dose-dependent efficacy in lowering Lp(a) even by more than 90%, with an acceptable safety profile in subjects with highly elevated Lp(a). In addition, reports of early clinical trials with pelacarsen imply a promising suppressive effect on key mechanisms of atherogenesis. Future research should focus on confirming these beneficial clinical effects in patients with lower average Lp(a) levels and clearly demonstrating the association between lowering Lp(a) and reducing adverse cardiovascular outcomes.

Kounis Syndrome Associated With the Use of Diclofenac.

BACKGROUND: Diclofenac is a widely used analgesic, anti-inflammatory, antipyretic drug. In several case reports, its use was associated with the occurrence of Kounis syndrome. The aim of this review was to investigate and summarize published cases of Kounis syndrome suspected to be associated with the use of diclofenac. METHODS: Electronic searches were conducted in PubMed/MEDLINE, Scopus, Web of Science, Google Scholar, and the Serbian Citation Index. RESULTS: Twenty publications describing the 20 patients who met inclusion criteria were included in the systematic review. Specified patient ages ranged from 34 to 81 years. Eighteen (90.0%) patients were male. Five patients (25.0%) reported a previous reaction to diclofenac. Reported time from the used dose of diclofenac to onset of the first reaction symptoms ranged from immediately to 5 hours. Diclofenac caused both type I and type II Kounis syndrome, with the presence of various cardiovascular, gastrointestinal, dermatologic, and respiratory signs and symptoms. Most patients experienced hypotension (n = 15 [75.0%]) and chest pain (n = 12 [60.0%]). The most frequently reported finding on electrocardiogram was ST-segment elevations (n = 17 [85.0%]). Coronary angiogram showed normal coronary vessels in 9 patients (45.0%), with some pathologic findings in 8 patients (40.0%). CONCLUSION: Clinicians should be aware that Kounis syndrome may be an adverse effect of diclofenac. Prompt recognition and withdrawal of the drug, with treatment of both allergic and cardiac symptoms simultaneously, is important.

Mirtazapine-induced Acute Pancreatitis in Patients With Depression: A Systematic Review.

OBJECTIVE: Antidepressant-induced pancreatitis is a rare, albeit serious, adverse effect, with a frequency of occurrence that is not equally distributed among antidepressant drugs. The goal of this study was to investigate the association and causal relationship between mirtazapine treatment of patients with depression and pancreatitis. METHODS: The study was designed as a systematic review of the literature, accompanied by the description of a new case of mirtazapine-associated acute pancreatitis. RESULTS: Nine cases of mirtazapine-associated pancreatitis have been reported, involving 7 female patients and 2 male patients with a mean age of 46.4 years (range: 26 to 83 y of age). All of the patients were hospitalized, with an average length of stay of 16.2 days (range: 3 to 34 d). In 6 cases, "de-challenge" followed by improvement was reported. The patients for whom the outcome was reported (7 of 9) recovered completely. CONCLUSION: Although a rare adverse effect, mirtazapine-induced pancreatitis should be considered when patients taking mirtazapine report abdominal discomfort.

Meta-analysis of peripheral insulin-like growth factor 1 levels in schizophrenia.

OBJECTIVE: We aimed to investigate if there is a significant difference in peripheral insulin-like growth factor 1 (IGF-1) levels between schizophrenia patients and healthy controls and to determine whether a difference exists before and after initiation of antipsychotics. METHODS: PubMed/MEDLINE, Scopus, and Web of Science were searched up to March 27, 2022. Original clinical studies of any type that reported peripheral blood, serum or plasma IGF-1 levels measured after fasting in schizophrenia patients and/or healthy control group were selected based on inclusion and exclusion criteria. Data were analyzed using Meta-Essentials: Workbooks for meta-analysis and pooled through random-effects meta-analyses. RESULTS: Twelve publications met eligibility criteria. Schizophrenia patients under antipsychotic treatment had significantly lower peripheral IGF-1 levels compared to healthy controls (n = 632, Hedges' g -0.42, 95% CI from -0.79 to -0.04, p = .006, I2  = 70.38%), while no significant difference was found between schizophrenia patients regardless of the antipsychotic treatment status and healthy controls, as well as between antipsychotic naïve or free schizophrenia patients and healthy controls, and before and after initiation of antipsychotic treatment. However, high heterogeneity was observed and its potential sources in some of the subgroup analyses included sample type and region. CONCLUSIONS: Schizophrenia patients under antipsychotic treatment seem to have lower peripheral IGF-1 levels compared to healthy controls. Additional studies with larger and more homogenous samples are needed to confirm these findings.

Amoxicillin-associated Stevens-Johnson syndrome or toxic epidermal necrolysis: systematic review.

Our aim was to explore and summarize available cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) suspected to be associated with amoxicillin reported in the literature. Electronic searches were conducted in several databases. Fifty-one publications describing a total of 64 patients who satisfied inclusion criteria were included in the review. The age of the patients ranged from 1.5-80 years (median: 24.5 years). TEN, SJS and SJS/TEN overlap were diagnosed in 30 (46.9%), 28 (43.8%) and 1 (1.6%) patients, respectively. SJS/TEN may occur promptly after administration of amoxicillin, but it could also be a delayed adverse effect. The total length of hospital stay ranged from 3-70 days (median: 16 days). Amoxicillin-induced SJS/TEN is accompanied by frequent occurrence of serious complications, long-term ocular and skin sequelae and high mortality rate. Clinicians should be aware that amoxicillin alone or combined with clavulanic acid can cause SJS/TEN in patients of all ages.

Alopecia associated with the use of selective serotonin reuptake inhibitors: Systematic review.

We aimed to systematically review published cases of alopecia (hair loss) associated with selective serotonin reuptake inhibitors (SSRIs). Four electronic databases were searched up to November 16, 2021. Thirty-eight publications describing 71 patients with a total of 81 episodes of alopecia met inclusion criteria. Patients' age ranged from 7 to 85 years and 80.3% were female. Alopecia most commonly affected scalp (98.6%). Reported time to onset ranged from 3 days to 5 years (median: 8.6 weeks). Discontinuation of the suspected SSRI led to recovery in 63.0% of episodes. Clinicians should be aware of this possible adverse effect of SSRIs.

Delirium associated with the use of macrolide antibiotics: a review.

OBJECTIVE: This review aimed to explore and summarise available cases of delirium suspected to be associated with the use of macrolide antibiotics reported in the literature and the United States Food and Drug Administration's Adverse Event Reporting System (FAERS) database. METHODS: Electronic searches of the literature were conducted in four online databases: PubMed/MEDLINE, Scopus, Web of Science and Serbian Citation Index (SCIndeks). A search of FAERS database was also conducted to supplement the findings of the literature search. Descriptive statistics, narrative summation and tabulation of the extracted data were made. RESULTS: Cases of delirium which satisfied inclusion criteria were found for clarithromycin, azithromycin, erythromycin and telithromycin. Delirium was described in patients of various age groups, including children. Drug-drug interactions may have contributed to its occurrence in some of the cases. Average time to onset of delirium was 2.5 days for azithromycin and 3.3 days for clarithromycin. CONCLUSIONS: Considering that these drugs may be a possible cause of delirium, clinicians should be aware that timely recognition of this possible side effect can lead to earlier discontinuation of the culprit drug, reduce time spent in a delirious state and improve patients' outcomes.KEY POINTSCases of delirium which satisfied inclusion criteria were found for clarithromycin, azithromycin, erythromycin and telithromycin.Cases of delirium were described in patients of various age groups, including children.Drug-drug interactions may have contributed to the occurrence of delirium in some of the cases.Time to onset of delirium ranged from 2 to 3.5 days (mean: 2.5 days) for azithromycin and from 1 to 7 days (mean: 3.3 days) for clarithromycin.Cessation of the macrolide antibiotic seems to be the best management strategy, although some of the patients may, in addition, require antipsychotics.

Acute Hydroxychloroquine Overdose: A Review of Published Pediatric Cases With Confirmed Hydroxychloroquine Exposure.

OBJECTIVES: This review aimed to explore and summarize information from available cases of pediatric acute hydroxychloroquine overdose with confirmed hydroxychloroquine exposure to give the clinicians a helpful perspective for its better recognition and management. METHODS: Electronic searches were conducted in PubMed/MEDLINE, Web of Science, Scopus, EBSCO and Serbian Citation Index. The abstracts from 2 toxicology conferences were manually checked for additional relevant publications, as well as reference lists of the retrieved publications. Descriptive statistics, narrative summation, and tabulation of the extracted data were made. RESULTS: Nine publications and a total of 9 patients were included in the review. Reported age of the patients varied from 2.5 to 16 years (median, 16 years). There were more female patients (77.8%). Estimated total ingested hydroxychloroquine dose was reported in 7 cases (77.8%), and it ranged from 4.0 to 20.0 g (median: 12.0 g). Four patients (44.4%) ingested hydroxychloroquine with a coingestant. Altered mental status (100.0%), cardiotoxicity (88.9%), hypotension (77.8%), and hypokalemia (55.6%) were the most commonly reported clinical manifestations. The majority of the patients were hospitalized (88.9%). More than half of the patients (55.6%) were reported to be treated in the intensive care unit. Most frequently reported therapeutic measures were the following: administration of intravenous fluids/infusions (77.8%), vasopressors (77.8%), bicarbonate therapy-sodium bicarbonate (66.7%), potassium replacement (55.6%), and intubation/ventilation (55.6%). Three patients (33.3%) died. CONCLUSIONS: Management of acute hydroxychloroquine overdose in children should be symptomatic and tailored to observed clinical manifestations. There is a need for additional investigations to better understand the impact and effectiveness of various treatment options.

Risk factors for potential drug-drug interactions of statins in patients with acute coronary syndrome

Abstract The aim of our study was to assess risk factors for potential drug-drug interactions (pDDIs) of statins across different phases of treatment of acute coronary syndrome (ACS) patients: from the point of first medical contact to the coronary angiography (first phase), after coronary angiography to the last day of hospitalization (second phase) and at discharge from hospital (third phase). This was a post hoc analysis of the data collected during the retrospective observational cohort study conducted at the Clinic for Cardiology of the Clinical Centre Kragujevac, Serbia. Patients prescribed statins were identified from the original study population: 156, 240 and 236 patients for the first, second and third phases, respectively. At least one statin pDDI was present in 113 (72.4%), 161 (67.1%) and 139 (58.9%) patients in the first, second and third phases, respectively. Heart failure, arrhythmias after ACS, CRP, triglycerides, length of hospitalization, number of prescribed drugs, antiarrhythmic drugs, and clopidogrel seem to increase the risk of statin pDDIs in at least one treatment phase. Physicians should be vigilant to the possibility of statin pDDIs in ACS patients who have factors that may increase their rate.

A review of published cases of Stevens-Johnson syndrome and toxic epidermal necrolysis associated with the use of acetaminophen.

PURPOSE: Acetaminophen (paracetamol) is a widely used analgesic and antipyretic. In several studies, its use was associated with the occurrence of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). This narrative review aimed to explore and summarise available cases of SJS/TEN suspected to be associated with acetaminophen reported in the literature. MATERIALS AND METHODS: Electronic searches were conducted in PubMed/MEDLINE, Web of Science, Scopus and Serbian Citation Index (SCIndeks). Case reports or case series which reported detailed clinical description of the patients diagnosed with SJS, TEN or SJS/TEN overlap which was caused or suspected to be most likely caused by acetaminophen with available full text were included in the review. RESULTS: Twenty-nine publications describing a total of 36 patients which satisfied inclusion criteria were included in the review. The age of the patients ranged from 3 to 77 years (median: 32.5 years). There were 15 female (41.7%) and 15 male (41.7%) patients, while for 6 patients (16.7%) gender was not reported. TEN, SJS and SJS/TEN overlap were diagnosed in 24 (66.7%), 10 (27.8%) and 2 (5.6%) patients, respectively. Reported time from the first dose of acetaminophen to the onset of the first symptoms of SJS/TEN ranged from promptly to 21 days, with a median of 3 days. Use of some form of supportive and symptomatic care was reported in 28 patients (77.8%). Systemic corticosteroids were reported to be administered in 25 patients (69.4%) and intravenous immunoglobulin in 16 patients (44.4%). All patients survived. Long-term consequences (sequelae) were reported in 5 patients (13.9%). CONCLUSIONS: Clinicians should be aware that SJS/TEN may be an adverse effect of acetaminophen and keep in mind that its prompt recognition and withdrawal of the culprit drug along with supportive care is of utmost importance.

Stevens-Johnson syndrome and toxic epidermal necrolysis associated with the use of macrolide antibiotics: a review of published cases.

Macrolides are one of the most commonly prescribed antibiotics. In several studies, their use was associated with the occurrence of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). This review aimed to explore and summarize available cases of SJS/TEN suspected to be associated with the use of macrolide antibiotics reported in the literature. Electronic searches were conducted in PubMed/MEDLINE, Web of Science, Scopus, and Serbian Citation Index (SCIndeks). Twenty-five publications describing a total of 27 patients were included. Cases of SJS/TEN which satisfied inclusion criteria were found for azithromycin (n = 11), clarithromycin (n = 7), erythromycin (n = 5), roxithromycin (n = 2), and telithromycin (n = 2). The age of the patients ranged from 2 to 77 years (median: 29 years). There were 14 female (51.9%) and 13 male (48.1%) patients. SJS was diagnosed in 16 patients (59.3%), TEN in 10 patients (37.0%), and SJS/TEN overlap in one patient (3.7%). Time to onset of the first symptoms ranged from 1 to 14 days (median: 3 days). All patients received some form of supportive and symptomatic care. Systemic corticosteroids were reported to be administered in 12 patients (44.4%) and intravenous immunoglobulin in five patients (18.5%). Three patients (11.1%) died. Considering that SJS/TEN is a severe and potentially life-threatening reaction, physicians should be aware that they could be adverse effects of macrolide antibiotics and keep in mind that prompt recognition of SJS/TEN and discontinuation of the culprit drug in combination with supportive care is essential.

Antimicrobial treatment of Stenotrophomonas maltophilia invasive infections: Systematic review.

Stenotrophomonas maltophilia can cause serious infections in immunocompromised patients. The aim of this systematic review was to establish what invasive infections in humans are caused by S. maltophilia and to evaluate the optimal choice of antibiotics for their treatment. MEDLINE, EBSCO, SCOPUS, SCINDEKS and GOOGLE SCHOLAR were systematically searched for clinical trials, observational studies, case reports or case series describing invasive infections with S. maltophilia in patients of any age. S. maltophilia may cause invasive infections of various tissues in hospitalized patients. In the great majority of cases it was susceptible to co-trimoxazole, levofloxacin and ceftazidime. In about three fourths of the cases, the treatment was successful, while less than 20% of the patients died. S. maltophilia is increasingly associated with serious invasive infections in hospitalized patients and due to growing trend of resistance to almost all antibiotics requires a careful approach to patients who is harboring this bacterium.

Antimicrobial treatment of Kocuria kristinae invasive infections: Systematic review.

Objective of this systematic review was to establish whether and what invasive infections in humans were caused by Kocuria kristinae, and to evaluate outcomes of administered antibiotic treatment. MEDLINE, EBSCO, SCOPUS, SCINDEKS and GOOGLE SCHOLAR were systematically searched for primary case reports or case series describing invasive infections with K. kristinae. K. kristinae is a pathogen microorganism that could cause invasive infections of various tissues in patients of any age. Majority of the patients had K. kristinae isolated from blood. It was also found in peritoneal fluid, pus, sputum, synovial fluid, bile, fluid from abdominal abscess, throat swab, urine catheter tip and mid-stream urine. Antibiotic treatment was almost universally effective, with only one death reported. Susceptibility was highest to vancomycin, linezolid, rifampicin, teicoplanin, tigecycline, cefotaxime, ampicillin/sulbactam, minocycline and meropenem. Initial treatment of Kocuria kristinae infections should involve parenteral vancomycin in combination with some other antibiotic to which it is susceptible.

Drug-drug interactions in patients with acute coronary syndrome across phases of treatment.

The objective of this study is to evaluate potential drug-drug interactions (pDDIs) and risk factors for pDDIs in three phases of an acute coronary syndrome (ACS) treatment: from the point of first medical contact to the coronary angiography (first phase), after coronary angiography to the last day of hospitalization (second phase), and at discharge from hospital (third phase). This retrospective observational cohort clinical study was conducted at the Clinic for Cardiology of the Clinical Centre Kragujevac, a public tertiary care hospital in Kragujevac, Serbia. Micromedex® interaction checker was used to detect pDDIs. This study included 245 ACS patients. All patients were exposed to at least one pDDI in all the phases of treatment. Mean total number of pDDIs was 9.47 ± 6.07, 10.11 ± 6.92, and 6.29 ± 3.66 in first, second, and third phases, respectively. Age, > 6 h from the beginning of the symptoms to admission, primary PCI, STE-ACS, COPD, delirium, hyperlipidemia, hypertension, obesity, systolic blood pressure at admission, TIMI risk score at admission, ALT, LDL, number of physicians who prescribed drugs to a single patient, number of prescribed drugs, and various pharmacological classes increased risk of pDDIs. Mechanical ventilation, dementia, and drug allergy noted in the medical documentation protected against them. Effects of heart failure, diabetes, and aPTT depended on phase of treatment and severity of pDDI. In conclusion, physicians should be vigilant to the possibility of pDDIs in patients harbouring factors that may increase their rate.

Access to orphan drugs - comparison across Balkan countries.

The aim of this study was to compare orphan drug access in a sample of Balkan countries: five EU Member States (Bulgaria, Croatia, Greece, Romania, Slovenia) and two EU Candidates (Serbia, Montenegro). The comparative analysis was based on a cross-sectional study and included medicinal products with an active orphan designation and market authorisation on January 1, 2017. Access to orphan drugs is an ongoing challenge in these countries. Three clusters of countries were identified in terms of orphan drug access: Greece and Slovenia, making the top tier, Romania, Bulgaria, and Croatia, being in the middle, and EU Candidates, Serbia and Montenegro, forming the bottom tier, where a substantial number of EU market approved orphan drugs was not even registered. Available public health resources and market size are probably among the contributing factors for such inequalities. Sizeable part of EMA market authorised orphan medicinal products is not even priced in the Balkan countries. This is a serious issue, which is putting rare disease patients from this region in a particularly vulnerable situation. There is a need for further improvement in accessibility of orphan drugs in the Balkan countries. Cross-border collaboration in the field of pricing, health technology assessment, and reimbursement negotiation of orphan drugs may help to address these challenges.

Risk factors for potential drug-drug interactions in intensive care unit patients.

PURPOSE: To determine risk factors for each severity-based category of potential drug-drug interactions (DDIs) encountered at intensive care unit (ICU) patients. METHODS: This was a retrospective cohort analysis of patients treated at the ICU of the Clinical Center Kragujevac, a public tertiary care hospital in Kragujevac, Serbia. Three interaction checkers were used to reveal drug-drug interactions: Medscape, Epocrates and Micromedex. RESULTS: The study included 201 patients, 66.19±16.11 years of age. Average number of DDIs per patient ranged from 10.49±8.80 (Micromedex) to 29.43±21.51 (Medscape). Antiarrhythmic or anticonvulsant drug prescription, Charlson Comorbidity Index, male sex, length of hospitalization, number of drugs or therapeutic groups prescribed and surgery increased the risk of DDIs in ICU patients, while presence of delirium or dementia and transfer from emergency department to ICU protected against. CONCLUSIONS: The rate of the DDIs in ICU patients at a tertiary care hospital is high, and adversely influenced by number of drugs or drug groups prescribed per patient, antiarrhythmic or anticonvulsant drug prescription, comorbidities, length of hospitalization and surgery. On the other hand, presence of cognitive deficit and transfer from emergency department to ICU protect ICU patients from the DDIs.

Transposition and implementation of EU rare disease policy in Eastern Europe.

INTRODUCTION: А series of European Union (EU) political decisions have made rare diseases one of the cornerstones of the common European health policy. Adopted in 2009, Council Recommendation on an action in the field of rare diseases aimed to serve as a policy-making guideline. However, the implementation report, which followed it, neither performed detailed cross-country comparison, nor assessed the impact of the policies. Areas covered: A 10-indicator set was elaborated to structure the review and to describe rare disease activities in 14 Eastern European countries. Expert commentary: Taking into account all indicators, EU member states outperform candidate and potential candidate countries in terms of rare disease policy planning and implementation. Hungary is the top performer, followed by Bulgaria and Czech Republic. Non-EU countries form the bottom tier, with Serbia being the best ranked among them. While EU adhesion is a major facilitator for planning and adopting rare disease policies, local stakeholders are the triggering factor for their successful implementation. European reference networks are likely to be the future of rare disease activities in the EU. They need to synchronize and closely collaborate with all important EU projects in the field of rare diseases if they are to achieve their objectives.