Tocilizumab-induced pancreatitis: case report and review of data from the FDA Adverse Event Reporting System.

WHAT IS KNOWN AND OBJECTIVE: Tocilizumab (TCZ) is a humanized monoclonal antibody acting against the IL-6 receptor. It is a drug used in the treatment of rheumatoid arthritis and can be either given intravenously every 4 weeks or subcutaneously once a week. Known adverse events (AE) associated with TCZ include: infections of the upper respiratory tract, arterial hypertension, hypercholesterolaemia and hypertriglyceridaemia. Here, we present the first well-documented case of TCZ-induced acute pancreatitis (AP) and a systematic review of the literature including data from the Food and Drug Administration Adverse Event Reporting System (FAERS) database. METHODS: Patient data collection was performed within the Berlin Case-Control Surveillance Study. A literature search for TCZ-induced AP was conducted. Analysis of the FAERS database concerning TCZ-associated pancreatic AE from the period of 2009 until the first quarter of 2013 was conducted. RESULTS AND DISCUSSION: A 40-year-old man presented with a 2-day history of progressive upper abdominal pain with elevated serum lipase and triglyceride levels. Biliary pancreatitis was ruled out by abdominal sonography and CT scan. Cessation of intravenously administered TCZ resulted in improvement of the patient's condition and a decline in elevated laboratory values, suggesting a probable relationship between TCZ intake and AP. Analysis of the FAERS database retrieved 52 cases of TCZ-associated AP that accounted for 70% of all pancreatic AE in association with TCZ use. Further literature search detected three additional cases in which TCZ use was associated with AP. WHAT IS NEW AND CONCLUSION: Physicians should be aware of the probable association between TCZ use and AP. Targeted post-authorization studies are needed to confirm and quantify the risk of TCZ-induced AP.

Drug-induced acute pancreatitis: results from the hospital-based Berlin case-control surveillance study of 102 cases.

BACKGROUND: Drug toxicity is a well-known cause of acute pancreatitis (AP). Although many drugs have been associated with AP, the magnitude of the risk of most of them remains largely unknown. AIM: To determine the pancreatotoxic risk of a wide range of drugs. METHODS: The hospital-based Berlin case-control surveillance study, including all 51 Berlin hospitals in a hospital network, ascertained 102 cases with idiopathic AP (IAP) and 750 controls between 2002 and 2011. Patients with IAP were thoroughly validated using anamnestic, clinical or laboratory data. Drug exposure was obtained in a face-to-face interview. Possible drug aetiology was assessed in individual patients through a standardised causality assessment applying the criteria of the World Health Organization. Drug risks were further quantified [odds ratios (OR) with 95% confidence intervals (CI)] in a case-control design with unconditional logistic regression analysis. RESULTS: The pancreatotoxic risk of several drugs, including azathioprine (OR 5.1; 95% CI 1.9-13.5), fenofibrate (OR 12.2; 95% CI 2.3-69.1), mesalazine (OR 3.3; 95% CI 1.1-9.5) or angiotensin-converting enzyme inhibitors, was corroborated by case-control analysis and causality assessment. Causality assessment suggested a pancreatotoxic potential, among others, for mercaptopurine or the seldom reported leflunomide, and alluded to a novel risk for tocilizumab. Case-control analysis showed an increased risk for two phytotherapeutics: harpagophytum and valerian radix. CONCLUSIONS: Our study quantified the pancreatotoxic risk of different drugs and phytotherapeutics. The findings corroborate previous results from the literature but also indicate risks for substances not previously reported, highlighting the need for further controlled studies on pancreatic toxicity.

Unused drugs returned to the pharmacy--new data.

INTRODUCTION: Although the increasing costs in the health system in Germany is a frequently discussed topic, the amount of the so-called unused drugs which patients and customers bring back to pharmacies does not seem to diminish. In 1988, the authors conducted a study to document this problem. Ten years later, in 1998, a second study with the same design was done. The new data are compared with the results of the first study. METHODS: The study was carried out in a public pharmacy in Berlin, Germany, 1998. All drugs returned unused were documented during a period of 12 months. The drugs were counted and classified according to therapeutic groups and to prescription or OTC status. The remaining amount in each package was determined in relation to the package size. The prices of the drugs were obtained from the "Rote Liste 1997". RESULTS: 10,603 unused drug-packages were collected (1988: n = 5,164). The 10 most frequent indication groups showed nearly the same ranking as the German annual report of prescribed drugs (GKV-Index 1988, same result). Only 17% of the returned drugs were for self-medication (1988: 12%). The value of the original medicines amounted to approximately DM 232,920 (1988: DM 100,000), therefore, the average drug price was DM 22 (1988: DM 19). On an average, packages contained 65% (1988: 70%). 24% of the drug packages returned contained the original content, i.e. were unused (1988: 31%). 39% of the returned packages contained 51-99% of the original contents (1988: 35%) and 37% contained up to 50% of the original contents (1988: 34%). CONCLUSIONS: Although patients in Germany had to pay a higher prescription charge in 1998 than in 1988, the amount of unused drugs has increased. The reasons for this non-compliant behavior have not yet been analyzed. The results of this study suggest the need for further research for the reasons of non-compliance.

Occupational risk factors for renal cell carcinoma: agent-specific results from a case-control study in Germany. MURC Study Group. Multicenter urothelial and renal cancer study.

BACKGROUND: This case-control study was conducted to estimate the renal cell cancer (RCC) risk for exposure to occupation-related agents, besides other suspected risk factors. METHODS: In a population-based multicentre study, 935 incident RCC cases and 4298 controls matched for region, sex, and age were interviewed between 1991 and 1995 for their occupational history and lifestyle habits. Agent-specific exposure was expert-rated with two job-exposure matrices and a job task-exposure matrix. Conditional logistic regression was used to calculate smoking adjusted odds ratios (OR). RESULTS: Very long exposures in the chemical, rubber, and printing industries were associated with risk for RCC. Males considered as 'substantially exposed to organic solvents' showed a significant excess risk (OR = 1.6, 95% CI : 1.1-2.3). In females substantial exposure to solvents was also a significant risk factor (OR = 2.1, 95% CI : 1.0-4.4). Excess risks were shown for high exposure to cadmium (OR = 1.4, 95% CI : 1.1-1.8, in men, OR = 2.5, 95% CI : 1.2-5.3 in women), for substantial exposure to lead (OR = 1.5, 95% CI : 1.0-2.3, in men, OR = 2.6, 95% CI : 1.2-5.5, in women) and to solder fumes (OR = 1.5, 95% CI : 1.0-2.4, in men). In females, an excess risk for the task 'soldering, welding, milling' was found (OR = 3.0, 95% CI : 1.1-7.8). Exposure to paints, mineral oils, cutting fluids, benzene, polycyclic aromatic hydrocarbons, and asbestos showed an association with RCC development. CONCLUSIONS: Our results indicate that substantial exposure to metals and solvents may be nephrocarcinogenic. There is evidence for a gender-specific susceptibility of the kidneys.

[Risk factors for urothelial carcinoma: drinking measures, smoking and other life style-related risk factors--results of the Berlin Urothelial Study (BUS)]. / Risikofaktoren für das Urothelkarzinom: Trinkmenge, Rauchen und andere lebensstilbezogene Risikofaktoren--Ergebnisse der Berliner Urothelstudie (BUS).

With the exception of smoking and several occupational exposures there is little knowledge about risk factors for urothelial cancer. A case control study in the area of former West Berlin was performed from 1990-1995 to investigate the role of several lifestyle risk factors, such as smoking, drinking behaviour and regular intake of analgesics and laxatives. The study includes 647 hospital-based incident cases with bladder cancer (n = 571), renal pelvis cancer (n = 51), and ureter cancer (n = 25), and 647 population-based controls which were matched individually by sex and age. Data analyses were carried out using standard methods for case control studies (conditional multiple logistic regression analysis). Odds ratios (OR) and 95% confidence intervals (CI) were applied as effect parameter. Statistically significantly increased odds ratios were observed for current smoking (OR: 3.46, 95% CI: 2.50-4.78), previous but now abandoned smoking (OR: 1.51, 95% CI: 1.09-2.81), and for regular intake of laxatives (OR: 2.52, 95% CI: 1.56-4.09). Furthermore, an increased risk for urothelial cancer was observed for daily consumption of three and more litres of cold drinks (OR: 2.65 95% CI: 1.12-6.24). The results underline that lifestyle factors other than smoking may contribute to a higher risk of urothelial cancer.

Occupational risk factors for urothelial carcinoma: agent-specific results from a case-control study in Germany. MURC Study Group. Multicenter Urothelial and Renal Cancer.

BACKGROUND: This multicentre population-based case-control study was conducted to estimate the urothelial cancer risk for occupational exposure to aromatic amines, polycyclic aromatic hydrocarbons (PAH), and chlorinated hydrocarbons besides other suspected risk factors. METHODS: In a population-based multicentre study, 1035 incident urothelial cancer cases and 4298 controls matched for region, sex, and age were interviewed between 1991 and 1995 for their occupational history and lifestyle habits. Exposure to the agents under study was self-assessed as well as expert-rated with two job-exposure matrices and a job task-exposure matrix. Conditional logistic regression was used to calculate smoking adjusted odds ratios (OR) and to control for study centre and age. RESULTS: Urothelial cancer risk following exposure to aromatic amines was only slightly elevated. Among males, substantial exposures to PAH as well as to chlorinated solvents and their corresponding occupational settings were associated with significantly elevated risks after adjustment for smoking (PAH exposure, assessed with a job-exposure matrix: OR = 1.6, 95% CI: 1.1-2.3, exposure to chlorinated solvents, assessed with a job task-exposure matrix: OR = 1.8, 95% CI: 1.2-2.6). Metal degreasing showed an elevated urothelial cancer risk among males (OR = 2.3, 95% CI: 1.4-3.8). In females also, exposure to chlorinated solvents indicated a urothelial cancer risk. Because of small numbers the risk evaluation for females should be treated with caution. CONCLUSIONS: Occupational exposure to aromatic amines could not be shown to be as strong a risk factor for urothelial carcinomas as in the past. A possible explanation for this finding is the reduction in exposure over the last 50 years. Our results strengthen the evidence that PAH may have a carcinogenic potential for the urothelium. Furthermore, our results indicate a urothelial cancer risk for the use of chlorinated solvents.

Urothelial cancer at different tumour sites: role of smoking and habitual intake of analgesics and laxatives. Results of the Berlin Urothelial Cancer Study.

BACKGROUND: In Germany about 20000 new cases of urothelial cancer (UC) and about 7500 deaths from bladder cancer alone occur each year. Among the manifold risk factors, little research has been done on the role of smoking and the habitual intake of analgesics and laxatives-practices that are common in parts of the German population. The aim of this study is to define the proportion of risk derived from these preventable habits for the development of UC at its different sites. Subjects and methods. A case-control study in the area of the former West Berlin was performed from 1990 to 1995 including all newly diagnosed incident cases of UC from the eight hospitals of the study area. Study subjects and population-based controls individually matched by age (+/-2 years) and sex were evaluated by a standardized face-to-face interview about the lifelong exposure to cigarette smoking, analgesics, and laxatives. Adjusted risk analysis was carried out for the main exposure variables in relation to the different sites of UC in the bladder, ureter, and renal pelvis. RESULTS: Six hundred and forty-seven cases of UC (571 bladder, 25 ureter, and 51 renal pelvis) and an identical number of controls were included in the analysis (response rate in cases, 84.6%; in controls, 70.2%). Smoking increased the risk of bladder cancer (BC) by an odds ratio (OR) of 3.22 (95% confidence interval (CI) 2.29-4.52), that of ureter (URC) or renal pelvis cancer (RPC) together by OR 6.20 (95% CI 2.04-18.81), and that of RPC alone by OR 5.91 (95% CI 1.47-23.66). Ex-smoking was associated with an increased risk for BC (OR 1.55, 95% CI 1.10-2.19). Intake of more than 1 kg of phenacetin in analgesic mixtures was associated with an OR of 5.28 for RPC (intake of > or = 1 kg paracetamol, OR 3.27; > or = 1 kg pyrazolones, 1.12) and 0.75 for BC (not significant). Laxatives significantly increased the risk of BC (OR 2.14, 95% CI 1.26-3.63) and RPC/URC (OR 9.62, 95% CI 1. 01-91.24) in both sexes. CONCLUSION: 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.

[Analgesics and laxatives as risk factors for cancer in the efferent urinary tract--results of the Berlin Urothelial Carcinoma Study]. / Analgetika und Laxantien als Risikofaktoren für Krebs der ableitenden Harnwege--Ergebnisse der Berliner Urothelkarzinom-Studie (BUS).

A retrospective case-control study (1990-1995), the Berlin Urothelial Cancer Study (BUS), examined analgesics and laxatives as risks for the induction of urothelial cancer in renal pelvis, ureter and bladder. Especially for renal pelvis cancer could observe substance and dose specific risk of compound analgesics. The analgesic substances Phenacetin, Paracetamol, Acetylsalicylic acid (ASA) and Pyrazolones were assessed. Besides a risk of contact laxatives (chemical or anthranoide ingredients) for urothelial cancer was found, not yet described. The highest risk shows the anthranoide plant Senna. Thus this study confirms the risk of specific analgesic ingredients and found an evidence for a new risk of contact laxatives. As both, analgesics and contact laxatives, are typical OTC--("Over the counter") products, a severe controlling is demanded and for laxatives further studies are needed.

[Chronic use of analgesics]. / Daten zum chronischen Schmerzmittelgebrauch.

Quantitative aspects of longterm analgesic intake are presented, based on a case-control-study on the relation between regular analgesic intake and endstage renal failure in the area of West Berlin (1984-86). Lifetime analgesic consumption of more than 1000 persons were investigated. A total of 285 longterm analgesic users (185 cases = 35.8%; 100 controls = 19.3%) were detected. An odd ratio of 2.44 (95% CI: 1.77-3.39) was computed. Regular analgesic intake was defined as an intake of at least 15 analgesic doses per month continuously over a period of at least 12 months. 90% of the regular users preferred mixed analgesics compounds, in most cases with the psychotropic additive caffeine.

Regular analgesic intake and the risk of end-stage renal failure.

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.