Adverse events delayed

Temporal Relationships of Adverse Events. The temporal relationship between duration of product exposure and development of an adverse event is important in assessing causality. But how can data on temporal relationships be systematically summarized in a database containing thousands or even hundreds of thousands of subjects Temporal relationships cannot be clearly elicited if only frequencies of adverse events between treatment and control groups are compared. There can be many disparities in the subjects time of exposure or time at risk. Toxic manifestations of drugs may not occur until several months or even years after the initial exposure to the drug. How do we systematically assess delayed toxicity of a previously prescribed drug from the effect of a newly prescribed drug Such a scenario occurred with reported cases of pancreatitis associated with valproic acid therapy, in which some cases appeared several years after therapy [2]. 

The most common adverse events reported with sirolimus are leukopenia (20%), thrombocytopenia (13% to 30%), and hyperlipidemia (38% to 57%).11,31 Other adverse effects include delayed wound healing, anemia, diarrhea, arthralgias, rash, and mouth ulcers. Sirolimus has an FDA black-box warning in newly transplanted liver and lung recipients.11 In liver transplant recipients, use of sirolimus immediately after transplant is associated with an increased risk of hepatic artery thrombosis, graft loss, and death. In lung transplant... 

Watchful waiting and safety-net antibiotic prescriptions are approaches being used more frequently to attenuate microbial resistance and avoid unnecessary adverse events and costs of antibiotics. Observation is practiced extensively in Europe and involves monitoring for 48 to 72 hours after diagnosing AOM to see if spontaneous resolution will occur. Observation or delayed antibiotic therapy should be considered only in otherwise healthy children without recurrent disease (Fig. 69-1) and only if proper follow-up and good communication exist between clinicians and the parent/caregiver.4,5,16... 

Knowing how to prevent and treat adverse events from chemotherapy is an important aspect of patient care. Unmanaged events may result in excess morbidity and cause delays in chemotherapy administration and reduced chemotherapy doses and contribute to treatment failure. 

Adverse events should be tabulated for easy inspection but the case report form should be available and all laboratory data such as blood coimts, renal function and liver function tests should be inspected closely The absence of obvious adverse events does not mean that all is well, and careful scrutiny of data by an experienced physician can often spot problems before they become troublesome. Not infrequently one or more volunteers become imwell during the course of a study, usually due to intercurrent viral infections, and decisions about postponement of study days and subject withdrawal follow-up can be made during these meetings. Data that are missing because of non-attendance of volunteers, for whatever reason, may lead to a delay in the study, with postponement of dose escalation imtil they have caught up. 

Sulfasalazine has been used for the management of RA and ankylosing spondylitis with apparently similar effectiveness as penicillamine and with less toxicity. While 5-aminosalicylic acid is the active agent in inflammatory bowel disease, it is believed that sulfapyridine is mostly responsible for the antirheumatoid effects. Gastrointestinal complaints, dizziness and photosensitivity are the most frequently observed adverse events. With levamisole and also with sulfasalazine and olsalazine a delay of 2-3 months is to be expected before positive responses will be observed. 

Drug interactions Proleukin may affect central nervous system function. Therefore interactions could occur following concomitant administration of psychotropic drugs. Concurrent administration of drugs possessing nephrotoxic, myelotoxic, cardiotoxic, or hepatotoxic effects with Proleukin may increase toxicity in these organ systems. Reduced kidney and liver function secondary to Proleukin treatment may delay elimination of concomitant medications and increase the risk of adverse events from those drugs. Beta-blockers and other antihypertensives may potentiate the hypotension seen with Proleukin. 

Guidance for Industry. Gene Therapy Clinical Trials-Observing Subjects for Delayed Adverse Events, November 2006. http //www.fda.gov/cber/gdlns/gtclin. pdf... 

Halothane is a volatile general anesthetic that was introduced into the practice of clinical anesthesia in 1956. Shortly after its introduction two forms of hepatic injury were noted to occur in patients who received halothane anesthesia. A subclinical increase in blood concentration of transaminase enzymes is observed in 20% of patients and has been attributed to lipid peroxidation caused by the free radical formed by reductive metabolism of halothane as shown in Figure 16.7 (39/ 40). The second form of toxicity is a potentially fatal hepatitis-like reaction that is characterized by severe hepatocellular necrosis and is thought to be initiated by the oxidative formation of trifluoroacetyl chloride (Figure 16.7). Fatal hepatic necrosis occurs in only 1 of 35/000 patients exposed to halothane/ but the risk of this adverse event is greater in females and is increased with repeat exposure/ obesity/ and advancing age (40). Because the onset of halothane hepatitis is delayed but is more frequent and occurs more rapidly following multiple exposures/ and because these patients usually are febrile and demonstrate eosinophilia/ this reaction is suspected... 

The effects of bosentan (62.5 mg bd for 4 weeks followed by either 125 or 250 mg bd for a minimum of 12 weeks) have been studied in a double-blind, placebo-controUed trial in 213 patients with pulmonary arterial hypertension (2). The patients who took bosentan had improved exercise capacity, less dyspnea, and delayed worsening. There were similar results in 32 patients who took bosentan for a minimum of 12 weeks (62.5 mg bd for 4 weeks then 125 mg bd) (4). Bosentan significantly reduced pulmonary vascular resistance. The number and nature of adverse events were similar with bosentan and placebo. 

Two other cases of Bell s palsy, which reversed after interferon alfa withdrawal, have been reported (60). Although the delay in onset (7.5 and 8 weeks) suggested that interferon alfa might be the cause, one patient had no recurrence after rechallenge. A coincidental adverse event cannot therefore be completely ruled out. 

There was no difference in the incidence of adverse effects between iotrolan 320 and iohexol 350 in cardiac angiography for ischemic heart disease in 120 patients (22). There were no serious adverse events. One patient developed mild urticaria after iotrolan. Five patients in each group had mild unspecified delayed reactions. 

The incidence of delayed adverse reactions to various non-ionic monomers in Japanese patients undergoing contrast-enhanced CT has been compared with the incidence in control patients who did not receive contrast. Delayed reactions occurred in 12% of patients who received contrast compared with 10% in the control group. The authors concluded that the frequency of delayed reactions that can be attributed to contrast media is 2.1%. The most common reactions were itching and limited urticaria (28). This report highhghts the difficulty of verifying that adverse events that occur many hours after contrast administration are directly caused by the contrast agent. 

Fluorouracil (370 mg/m ) plus high-dose (175 mg) or low-dose (25 mg) folinic acid and either active or placebo levamisole has been evaluated in 4927 patients with colorectal cancer (23). Levamisole produced a significant excess of adverse dermatological events. Serious unexpected adverse events were rare. The authors concluded that the inclusion of levamisole in chemotherapy regimens for colorectal cancer does not delay recurrence or improve survival. 

The investigator(s) should be responsible for medical decisions in case of adverse events and for notifying the relevant health authorities, the sponsor and, when applicable, the ethics committee, without delay. In the... 

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