Adverse events spontaneous

The causality or treatment relatedness of clinical investigation cases is determined by the reporting healthcare professional or the sponsor, and is based on a reasonable suspected causal relationship between patient exposure to the suspect drug and the occurrence of the adverse event. Spontaneous reports about marketed products are always taken to imply that the reporter has assessed an adverse event with causality by the reported product (and are thus also always adverse events per se). 

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... 

Because ARMS is a form of passive surveillance that is based on spontaneous reports, it has a number of limitations. Most importantly, it cannot establish a definitive, causal relationship between the ingestion of an incriminated substance and the occurrence of symptoms. Since people are exposed daily to a myriad of food ingredients, it is inherently difficult to attribute an adverse event to a specific food substance. Moreover, symptoms reported are often vague or general in nature. Other confounders, which were discussed by Bradstock et al. (1986), include ... 

In Phase I and II studies, T)tpe A reactions are by far the most frequent. T)tpe B are rare, which is fortunate as some can be serious or even fatal. Table 7.1 shows the number of subjects that need to be studied to give a good chance (95%) of detecting an adverse event when there is no background incidence. The problem is many orders of magnitude worse if the adverse reaction closely resembles spontaneous disease that has a background incidence in the trial population. 

Since then there have been many publications and reviews of the UK yellow card system and spontaneous reporting systems internationally.A summary of the capabilities and limitations of the method is given in Table 15.6. Although these have been discussed in the greatest detail over the past three decades, the obligations that exist for pharmaceutical companies in the reporting of adverse events to the regulatory authorities at both national and international levels make it essential to review them in this chapter. 

In the evaluation of safety in the postmarketing phase, regulatory agencies are greatly more restricted in their enthusiasm for data derived from some of the methods available than from others. Indeed, the EC national agencies separately and the CPMP collectively have developed a legislative framework that is predominantly concerned with spontaneous adverse event monitoring and which is, for all practical purposes, silent on the matter of safety data collected by other methods. 

Fletcher AP. An appraisal of spontaneous adverse event monitoring. Adv Drug React Toxicol Rev 1992 11 213-27. 

In the past decade, there has been increased emphasis on drug safety, and more public visibility of safety problems. The volume of reports now exceeds 250000 spontaneous reports per year, and adverse events are highlighted in the medical press and also in the general media. The FDA has released extensive proposed new regulations for post-approval reporting that in part move to harmonise requirements with ICH recommendations for periodic safety update reports (PSURs)... 

In addition to the required reporting of spontaneously reported and literature adverse events, there is a requirement for an NDA annual report... 

Published case reports on alprazolam show a slightly different profile (266, 267, 268 and 269). Four patients had taken the drug for 4.5 months or less one had also taken chlorpromazine and trazodone and a fifth patient had taken alprazolam (3 mg/day for 26 weeks) and phenelzine (45 mg/day for 13 weeks), abruptly stopping both. According to the FDA s Spontaneous Adverse Event Reporting System, more seizures have been reported with alprazolam than with all other BZDs combined (270). The next highest incidence was reported for lorazepam. The FDA report stated the following ... 

DSHEA severely limited when the FDA could take action to protect the public and what actions could be taken. The burden of proof to show harm is now placed on the FDA. Moreover, dietary supplement manufacturers are not required to report adverse dietary supplement events. In fact, between 1994 and 1999 fewer than 10 of the 2500 adverse events associated with dietary supplements and reported to the FDA were reported by the manufacturer (53). The Office of Inspector General concluded the spontaneous adverse event reporting system has difficulty generating signals of possible public health concern due to limited medical information, product information, manufacturer information, consumer information, and ability to analyze trends (57). One weight loss supplement manufacturer is reported to have withheld from the FDA 14,684 complaints of adverse events regarding ephedra, which included heart attacks, strokes, seizures, and deaths (53). 

Information in the PI is typically based on the studies submitted by a drug s manufacturer. The FDA has also utilized spontaneous adverse event case reports as a tool in the evaluation of drug-grapefruit juice interaction labeling. Other sources of data that contribute to labeled information include studies or case reports from the medical literature. 

Wysowski DK, Green L. Serious adverse events in Norplant users reported to the Food and Drug Administration s MedWatch Spontaneous Reporting System. Obstet Gynecol 1995 85(4) 538-42. 

In an observational study of spontaneous adverse events reports gatifloxacin was associated with much higher rates of hypoglycemia and hyperglycemia (477 reports per 107 retail prescriptions) compared with ciprofloxacin (4 reports), levofloxacin (11 reports), and moxi-floxacin (36 reports) (437). 

A 6-week, multicenter, double blind, randomized comparison of quetiapine (mean dose 455 mg/day) and haloperidol (8 mg/day) has been carried out in 448 patients with schizophrenia (66). By day 42, the total score on the Positive and Negative Symptom Scale (PNSS) was equally reduced in the two groups. There were 69 withdrawals among the 221 patients who took quetiapine and 80 among the 227 who took haloperidol. Of the patients who took quetiapine, 154 (70%) had one or more spontaneously reported adverse events, whereas 171 (75%) of... 

Worsening of psychosis could have been an adverse event of topiramate in a 50-year-old woman with a long history of a schizoaffective disorder treated with risperidone 4 mg/day, venlafaxine 300 mg/day, and topiramate 200 mg/day (652). Her behavior worsened after topiramate was introduced. After it was withdrawn her mood, spontaneous speech, and psychomotor activity improved. 

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