Contents 4 Adverse events

In guidance document ICH E3, Structure and Content of Clinical Study Reports, the FDA defines treatment-emergent signs and symptoms (TESS) as events not seen at baseline and events that worsened even if present at baseline. As simple as that may sound, it can sometimes be quite difficult to program. The important data variables that come into play are dosing record dates and times, adverse event start and stop times, and adverse event severity. All of these data variables need to be completed accurately for TESS to be calculated properly. 

Figure VI-5 Adverse event cumulative table of contents...

Precipitates can develop in parenteral nutrition admixtures because of a number of factors such as the concentration, pH, and phosphate content of the amino acid solutions, the calcium and phosphorus additives, the order of mixing, or the mixing process. The consequences can be serious. In one cohort study of hospitalized patients who received peripheral parenteral nutrition, a subgroup developed unexplained chest pain, dyspnea, cardiopulmonary arrest, or new interstitial infiltrates on chest radiograph. A change in the amino acid source of a parenteral nutrition mixture was associated with respiratory adverse events that ranged from interstitial infiltrates to sudden death. The events apparently resulted from infusion of calcium phosphate precipitate in an opaque admixture, and the deposition of the crystals in the pulmonary microvasculature (147). 

The data sheet is called the package insert in Japan, as it can be found in the drug packaging. The data sheet is drafted by the company and checked and completed by the authorities after the NDA review and the recommendation for approval. The content has been defined by the MHLW notification, and was revised in May 1997. Besides general information on the product, the most important entries are warnings, precautions and contraindications, and a list of adverse events quantitatively reported. These entries will be revised if necessary, with the safety data regularly analyzed for the periodic safety update report however, an ad hoc revision is made at any time in case of serious events. 

The momentum of international harmonization efforts will continue to improve the ability with which adverse events are classified, analyzed and communicated. Paper-based system will be replaced by electronic transmission of adverse event information. The WHO monitoring program will extend the Bayesian artificial neural networks for analysis of the large amounts of adverse event data at its disposal.In the United States, efforts are underway at the FDA to improve the content and format of product prescribing information. 

Both prepared and unprepared Sichuan aconite are available commercially. Sichuan aconite contains aconitine, a toxic alkaloid that affects the heart and the central nervous system (Bensky et al. 2004). Due to aconitine content, the unprepared root is highly toxic and is the primary herb associated with serious adverse events in traditional Chinese medicine hospitals in Hong Kong (Chan 2002 Chan et al. 1994a, 1994c Poon et al. 2006). Processing of Sichuan aconite root greatly reduces the content of aconitine (Chen and Chen 2004). The prepared root, that has been processed to reduce toxicity, is the subject of this entry. 

Table 1.1). SchimmeTs summary bears a remarkable resemblance in both content and tone to the findings of the major record reviews of adverse events of the 1980s and 1990s. Schimmel remarked that the economic loss and emotional disturbance suffered by many patients were beyond the scope of the study, yet could not be considered insignificant complications of their medical care. Today we still have yet to assess the full economic consequences of harm to patients and have barely addressed the emotional trauma.

Tables 4.1 and 4.2 summarize the main types of studies of errors and adverse events, and their respective advantages and limitations. Thomas and Petersen s original source version has been separated into two separate tables and the content has been adjusted in particular, a section on case analysis has been added. Case analyses, usually referred to as root cause analysis or systems analysis, share some of the features of morbidity and mortality meetings, but are generally more focused and follow a particular method of analysis (Vincent, 2003) (Chapter 8).

While the bulk of literature on iron chelation concerns P-thalassemia, in patients with thalassemia intermedia abnormal regulation of iron homeostasis may lead to iron overload, even in the absence of transfusions. In an open study in 11 patients with thalassemia intermedia, deferasirox 10-20 mg/kg/day for 24 months was associated with significant reductions in liver iron content and serum ferritin concentrations in the first 12 months, which continued during the second part of the study no serious adverse events were recorded [9 ]. 

Drug formulations Salt and sugar content, osmolality, total volume infused, concentration, and total dose appear to be associated with a risk of adverse events [39"]. Sucrose-containing products are associated with an increased risk of acute renal failure [41 ]. 

Drug formulations In a single-dose, open, randomized, two-way, crossover study in 28 fasted healthy adults a capsule formulation of tizanidine hydrochloride was compared with the capsule contents administered in applesauce they were not bioequivalent [80 ]. The drug was more available (90% Cl = 103-134%) when the contents were sprinkled on to apple sauce. A total of 31 adverse events were reported by 17 of the 28 subjects 15 who took the intact capsule reported 18 events and 11 who took the contents reported 13 events. There were no serious adverse events. 

Von Willebrand factor/factor VIII concentrates play a key role in the treatment of patients with von Willebrand disease. The von Willebrand factor multimer fraction is very effective in achieving hemostasis. The available products differ in production techniques, von Willebrand factor multimer content, and activity. No serious adverse events have been related to Haemate P/Humate P in clinical trials. Non-serious adverse events include allergic symptoms in under 6% of patients, chills, phlebitis, edema, pain in the limbs, and pseudothrombocytopenia in a few patients. No cases of thrombosis have been reported in clinical trials, although caution should be taken in patients with von Willebrand disease who have other thrombotic risk factors [8 ]. 

The importance of sorption isotherms is generally in the evaluation of the water content in food at which the adverse effects on the food quahty can be minimised. This is usually the moment when other layers are formed around the monomolecular layer of water (vicinal water), which is the instant when the multilayer water arises. Most adverse events in storage of foods with medium and low water content, such as crystallisation of amorphous sugars (e.g. lactose in powdered or condensed milk), agglomeration of powder materials, stickiness or re-crystallisation of water and formation of large crystals in frozen products (e.g. in ice cream) relates to water content, its activity and storage temperature, and are therefore... 

Thomas J. Moore, Michael R. Cohen, and Curt D. Furberg, Serious Adverse Drug Events Reported to the Food and Drug Administration, 1998-2005, Archives of Internal Medicine 167, no. 16, 2007, pp. 1,752-1,759. Also available online. URL http //archinte.ama-assn.org/cgi/content/short/167/16/1752. Downloaded April 14, 2009. 

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