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.

[Pharmacovigilance in Germany : It is about time]. / Pharmakovigilanz in Deutschland : Es wird langsam Zeit.

BACKGROUND: Pharmacovigilance is defined as the activities relating to the detection, assessment, and prevention of adverse drug reactions (ADRs). Although its beginnings in Germany date back more than 50 years, a stagnation in this field has been observed lately. OBJECTIVES: Different tools of pharmacovigilance will be illustrated and the reasons for its stagnation in Germany will be elucidated. CURRENT DATA: Spontaneous reporting systems are an important tool in pharmacovigilance and are based on reports of ADRs from treating physicians, other healthcare professionals, or patients. Due to several weaknesses of spontaneous reporting systems such as underreporting, media bias, confounding by comorbidity or comedication, and due to the limited quality of the reports, the development of electronic healthcare databases was publicly funded in recent years so that they can be used for pharmacovigilance research. In the US different electronic healthcare databases were merged in a project sponsored by public means resulting in more than 193 million individuals. In Germany the establishment of large longitudinal databases was never conceived as a public duty and has not been implemented so far. Further attempts to use administrative healthcare data for pharmacovigilance purposes are severely restricted by the Code of Social Law (Section 75, Book 10). This situation has led to a stagnation in pharmacovigilance research in Germany. CONCLUSIONS: Without publicly funded large longitudinal healthcare databases and an amendment of Section 75, Book 10, of the Code of Social Law, the use of healthcare data in pharmacovigilance research in Germany will remain a rarity. This could have negative effects on the medical care of the general population.

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.

[Mortality and morbidity of small premature infants (<1,500 g) in relation to presentation and delivery mode]. / Mortalität und Morbidität kleiner Frühgeborener ( < 1500 g) in Abhängigkeit von Poleinstellung und Entbindungsmodus.

It is generally recommended in the literature that small premature babies with an expected weight of < 1500 g or < 32 WOP be delivered by cesarean section. The development of some of these small babies from the uterine muscle is very time-consuming and rough. For this reason, we have established the mode of the delivery at the Nuremberg Women's Hospital on the basis of the criteria which also applies to the delivery of mature term babies irrespective of the gestational age and irrespective of their presentation. Of a total number of 10542 babies delivered, 219 babies < 1500 g in weight (2.07%) were born from 1987 to 1991. The extent to which differences in the mode of deliveries spontaneous/cesarean section result from the presentation of the small premature babies was investigates after five years. The mortality and morbidity were calculated separately for babies the weighing between 1500 g and 1000 g and for babies of < or = 999 g. Besides the perinatal and neonatal mortality, the mortality after the 29th day of life was also determined. The following parameters of early morbidity were established: 1. Respiratory distress syndrome++ (none/grade I-grade IV) 2. Intracranial hemorrhages (none/grade I-grade IV) Furthermore, the following parameters of late infant morbidity were determined after the first year of life. 1. Movement capacity (normal/hyperkinetic/apathic) 2. Development of the baby (corresponding to age/ slightly/severely retarded) Severely retarded fetuses with a gestational age of more than 32 weeks and a birth rate of < 1500 g were excluded from all calculations, so that ultimately 176 babies were included in the overall analysis. The total mortality of the children < 1500 g in weight was 14.3%, 15.7% were in the group between 1500 g and 1000 g and 25% were the mortality with regard to the presentation and the mode of delivery. The morbidity results indicate that only the group of babies between 1500 g and 1000 g in weight with breech presentation benefit from cesarean section. In the group of babies < or = 999 g, there are no differences in morbidity with regard to the mode of delivery and the presentation. The results found show that frequencies of cesarean section in excess of 40% improve neither the mortality nor the morbidity of small premature babies. The decision to carry out cesarean section is based more on individual influences and the situation in the hospital in which the delivery takes place than on mortality of the baby or the mother.