Selection of adverse drug reactions
To examine the effect of duration of treatment on RTTO, angioedema and hepatitis were selected as two well-studied ADRs, providing examples of mechanistically diverse conditions which differ in expected latency.
Angioedema is typically an abrupt ADR, classified according to the underlying pathophysiology [6]. Allergic histamine-mediated and pseudoallergic cyclooxygenas inhibition-mediated angioedema occur within hours of exposure to the offending drug, the former being dependent on prior sensitization. However, bradykinin-mediated angioedema associated with angiotensin-converting enzyme inhibitors (ACEI) is an exception, as it may occur during the first week of therapy or be delayed up to several months [7]. None of the other drugs studied in our analysis (see section 2.4) have been documented to induce angioedema by a bradykinin-mediated mechanism. Therefore the time-to-onset for angioedema is expected to be short for the majority of the studied drugs.
Drug induced hepatitis is commonly divided into intrinsic and idiosyncratic reactions [8], where the dose dependent reactions in the intrinsic category mainly are caused by acetaminophen toxicity [9,10]. In contrast, idiosyncratic hepatitis has no immediate relationship to dose, although a dose threshold has been suggested [11,12]. Among the proposed underlying mechanisms, immune-mediation is suggested to cause liver injury with latencies as short as 1-8 weeks, while non-immune mediated reactions may take up to one year [9]. The median time-to-onset of drug-induced liver injury was found to be 42 days (range 20-117 days) in a prospective observational study [13]. However, biochemical signs of drug induced hepatitis by acetaminophen is known to present within 24 hours from intoxication [14].
The basis for our analysis were the MedDRA Preferred Terms (PTs) describing the two selected ADRs: ‘Angioedema’ and ’Hepatitis’. These PTs contain a range of Lowest Level Terms (LLTs) reflecting the same medical concept as the corresponding PT, expressed by synonyms and lexical variants [15]. After a review of all LLTs for both of the PTs in MedDRA, LLTs indicating that the ADRs had been aggravated were excluded e.g. ‘Angioedema aggravated’, ‘Angioneurotic edema aggravated’, ‘Angioneurotic oedema aggravated’ and ‘Hepatitis aggravated’. In addition, LLTs indicating too unspecific conditions such as ‘Edema vascular’, ‘Oedema vascular’ and ‘Hepatitis in other infectious diseases classified elsewhere’ were removed from the dataset, as well as LLTs referring to a specific inappropriate subtype of the ADR e.g. ‘C1 esterase deficiency acquired’ and ‘Syncytial giant cell hepatitis’. An overview of the studied MedDRA PTs and included LLTs after applying the exclusion of the above mentioned are presented in Table S1.