The reported cases show severe clinical courses and are, to some extent, a result of off-label use. Due to the absence of individual risk factors and presence of variable onset patterns, risk minimization measures should focus on restricting use to defined clinical situations and providing concise risk information for patients and healthcare professionals.

While European annual reporting rates based on spontaneous reports suggest an annual diLQTS/TdP incidence of 0.26 per million in Germany, we estimated a considerably higher incidence of diLQTS/TdP in an active surveillance approach. Further measures are warranted to better sensitize physicians against this potentially life-threatening drug-induced adverse event.

Summary Drug‐induced immune haemolytic anaemia is a rare but serious condition. This study investigated the possibility of drug aetiology of immune haemolytic anaemia (IHA) in 134 patients with new onset of IHA who were identified in the Berlin Case‐Control Surveillance Study between 2000 and 2009. Single drugs related to IHA in three or more patients and assessed more than once as a certain or probable cause of IHA in a standardized causality assessment included diclofenac, fludarabine, oxaliplatin, ceftriaxone and piperacillin. In a case‐control study including all 124 IHA cases developed in outpatient care and 731 controls, significantly increased odds ratios (OR) were observed for beta‐lactam antibiotics (OR = 8·8; 95% confidence interval [CI] 3·2–25·2), cotrimoxazole (OR = 6·5; CI 1·1–37·9), ciprofloxacin (OR = 6·9, CI 1·3–38·5), fludarabine (OR = 22·2; CI: 2·8–454·5) and lorazepam (OR = 5·3; CI: 1·2–21·2). Excluding new onset cases with a chronic IHA disease course, an increased risk became also apparent for diclofenac with an OR of 3·1 (CI 1·3–7·0). This is the first case‐control study investigating drugs as risk factors for IHA. It corroborates an increased risk for several drugs that have been implicated as a cause of IHA in the standardized causality assessment of individual cases.

MIA persists as a severe condition in current pharmacotherapy. The continuous increase of metamizole applications should be critically assessed, especially in regard to indications in the outpatient setting and with respect to metamizole treatment duration.

The strength of the association between regular analgesic intake (RAI) and end-stage renal failure (EF) has been insufficiently established until now. A case-control study was conducted to estimate the relative risks (RR) of EF after RAI (defined as consumption of 15 or more analgesic doses per month for a continuous period of at least 1 year) for cumulative drug intake, single-ingredient analgesics, combinations, and specific compounds. The case group included all patients with EF undergoing renal replacement therapy in the area of West Berlin (1984–1986, n = 921). Control subjects, matched to cases by sex, age, and nationality, were selected from a group of patients in outpatient clinics. Matching was possible for 517 cases. The RR of EF after RAI of any analgesic was 2.44 (95% confidence interval: 1.77–3.39) and after RAI of combination drugs 2.65 (95% confidence interval 1.91–3.67). No significant increase was found, however, after RAI of single-ingredient analgesics. The RR after RAI of combination drugs and for the most preferred analgesic ingredients (phenacetin, paracetamol, acetylsalicylic acid, phenazones, caffeine) increased with dose. Furthermore, a dose-time-related RR after RAI of the longest used preparation was found. Thus, the results clearly show an increased RR of EF after RAI related to both dose and exposure time of mixed analgesic compounds, but not for the use of only single-ingredient analgesics.

AIMDrug-induced liver injury (DILI) is often responsible for acute liver failure, drug withdrawal, boxed warnings or drug non-approval. Therefore, we conducted a case-control study to determine the hepatotoxic risk of a wide range of drugs. METHODSThe Berlin Case-Control Surveillance Study FAKOS included all 51 Berlin hospitals in a hospital network. Between 2002 and 2011, 198 patients with acute idiopathic hepatitis, 377 inpatient controls and 708 outpatient controls were ascertained. Case patients were thoroughly validated using anamnestic, clinical, laboratory and histological data. Drug exposure was obtained in a face-to-face interview. A possible drug aetiology was assessed in individual patients by applying the updated Council for International Organizations of Medical Sciences (CIOMS) scale. Drug risks were further quantified [odds ratios (OR) with 95% confidence intervals (CI)] in a case-control design with unconditional logistic regression analysis. Drug intake in the last 28 days before index date was considered for the analysis. RESULTSThe study corroborated hepatotoxic risks for a number of drugs, including phenprocoumon (OR 3.3, 95% CI 1.5, 6.7), amiodarone (OR 5.5, 95% CI 1.3, 21.2), clozapine (OR 34.6, 95% CI 2.8, 824.9) and flupirtine (OR 40.2, 95% CI 5.5, 856.9). Increased risks were also suggested for less commonly reported substances such as angiotensin II receptor blockers, atypical antipsychotics and for biperiden, a drug never before reported to be hepatotoxic. CONCLUSIONSOur study identified a large number of drugs as possible causes of hepatotoxicity. The observed risk for seldom reported substances highlights the need for further post-authorization safety studies not exclusively focusing on drugs already labelled as potentially hepatotoxic. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Drug-induced liver injury (DILI) accounts for almost every second acute liver failure and often leads to drug withdrawal, boxed warnings or drug non-approval.• Dose-related and thus predictable DILI is a rarity, making a quantification of the hepatotoxic risk of drugs necessary. WHAT THIS STUDY ADDS• This study is the first to quantify the hepatotoxic risk of flupirtine, irbesartan, clozapine and olanzapine, drugs previously associated with DILI in case reports.• A novel hepatotoxic risk is suggested for biperiden, highlighting the need for post-authorization safety studies considering also older drugs not labelled as hepatotoxic.

Habitual risks from smoking and intake of laxatives significantly contribute to the development of UC, especially of the renal pelvis and ureter cancer. Intake of at least 1 kg of analgesic substances (anilides, pyrazolones) as calculated from this study base is associated with increased but not significant risks for RPC. These data underline that restrictive and educational measurements focusing on common habits would have a strong impact on preventing UC in Germany.

Our findings are generally in agreement with those of earlier case-control studies. The spectrum of drugs causing acute agranulocytosis has not changed considerably over recent years, despite many newly marketed drugs. Evidence for induction of agranulocytosis by some new pharmaceuticals is supported.