Serious adverse events indication

In terms of efficacy, data such as the number of infusions needed and treatment outcome rAHF-PFM were effective in preventing and controlling bleedings in patients with severe hemophilia A. In safety and immunogenicity studies, no serious adverse events reported to date have been deemed related to rAHF-PFM. The incidence rates for the most common non-serious adverse events indicate that drag-related adverse events were similar or even lower in number and in nature to those observed in chnical trials with other rFVlll concentrates. To date, no inhibitors have been reported. The first rAHF, Recombinate, was developed by Baxter and became commercially available in 1992. Its long record of efficacy and safety has made Recombinate the standard for care in hemophiha A therapy [9-11]. rAHF-PFM, Advate , received market authorization in 2003 in the US and in 2004 in Europe. 

All these studies indicate that the incidence of serious adverse events in such studies is very low and is comparable with the normal hazards of everyday life. Nevertheless, it must always be remembered that the volunteer is placing his or her welfare in the trust of the research physician, who therefore bears an enormous responsibility. 

Phase 1 dose-escalating and PK studies of Vatalanib were performed on a wide spectrum of tumors including colorectal, RCC, NSCLC, AML, ghoblas-toma, and prostate cancer. Dose ranged up to 2000 mg once daily or 1000 mg twice daily by oral administration. In most studies, results in patients with advanced solid tumors indicated that treatment was well tolerated with no drug-related serious adverse events. Tumor volume reduction was observed in some patients. The MTD was not reached with doses up to 1500 mg/day. The optimal dose was determined as 1250 mg/day. Measurable responses of tumor volume reduction were observed in 19% and 4% of the patients with RCC and ghoblastoma, respectively. Over 50% of patients achieved stable disease [282]. 

Ketorolac tromethamine Ketorolac is indicated for the short-term (up to 5 days) management of moderately severe acute pain that requires analgesia at the opioid level. It is not indicated for minor or chronic painful conditions. Increasing the dose beyond the label recommendations will not provide better efficacy but will result in increasing risk of developing serious adverse events. 

In addition to considerations of efficacy and futility, it will usually be appropriate in most long-term trials to consider safety in an ongoing way. This is not new and we have always, for example, looked at accumulating data on individual serious adverse events and considered stopping (or modifying) trials if these are indicative of problems with the trial or with the treatments. 

A meta-analysis of randomized controlled trials (totaling 1051 patients) and large-scale observational studies (totaling 10,725 patients) of horse chestnut extract indicated that no serious adverse events were reported in the trials and studies and that treatment with horse chestnut extract did not significantly increase mild adverse events (Siebert et al. 2002). 

A systematic review of adverse events reported in clinical trials of St. John s wort indicated that data from 35 doubleblind randomized trials showed that dropout and adverse event rates in patients receiving St. John s wort extracts were similar to placebo, lower than with older antidepressants, and somewhat lower than with SSRI antidepressants. Dropout rates due to adverse events ranged from 0 to 5.7% in 17 observational studies that included 35,562 patients. No serious adverse events were reported in any of the studies (Knuppel and Linde 2004). 

A meta-analysis of clinical trials of passionflower in the treatment of anxiety indicated that no serious adverse events were reported and that passionflower was generally well tolerated (Miyasaka et al. 2007). 

A review of clinical studies of stinging nettle leaf indicated that no serious adverse events were reported in five clinical studies with a total of 10,368 participants taking 670 mg twice daily of a dried hydroethanolic extract ( 9.7 g dried leaf) for 3 to 52 weeks. Minor gastrointestinal upset or allergic reaction occurred in 1.2 to 2.7% of participants (ESCOP 2003). Abdominal gas was reported in 3 of 19 patients... 

A review of clinical trials of stinging nettle leaf preparations indicated that no serious adverse events were reported in any of the trials. Mild gastrointestinal discomfort or allergic reaction was reported in 1.2 to 2.7% of the... 

A review of 15 clinical studies of stinging nettle root, with a total of over 16,000 participants, indicated that no serious adverse events were reported in any of the studies. Daily doses taken by participants were up to 756 mg of hydroalcoholic dry native extract for up to 6 months, although several studies included doses of 300 mg daily for 24 months. Adverse events reported in the studies were primarily mild gastrointestinal upset, with fewer than 5% of participants experiencing such events (ESCOP 2003). In a study of stinging nettle root extract, adverse events deemed probably or possibly related to treatment occurred in approximately 1% of the 1319 participants (Kaldewey 1995). 

Systematic reviews of several dozen clinical trials (all subcutaneous injections of 1 to 200 mg) indicated that European mistletoe is generally very well tolerated, with no serious adverse events reported. Minor localized reactions at the injection site are sometimes associated with injections of European mistletoe, but such effects are not expected after oral use (Horneber et al. 2009 Kienle et al. 2009 Stein and Berg 2000). 

Epoetin delta differs from the other erythropoietin derivatives in that it is produced in a human cell line using gene-activation technology. It has been approved in Europe but not in the USA for the treatment of anemia associated with chronic kidney disease. In patients with cancer and anemia who were given epoetin delta, possible treatment-related serious adverse events were hypertension, increased serum creatinine, and peripheral vascular disease [99 ]. There was a correlation with higher doses, suggesting that a dose of 150 lU/kg would be most appropriate to start with for this indication. 

IBS (alosetron) Because of serious Gl adverse events, some fatal, alosetron is indicated only for women with severe diarrhea-predominant IBS who have ... 

These findings from special renal studies and the clinical trial data indicate that inhibition of Cox-2 does not eliminate the renal effects of NSAIDs because Cox-2-derived prostanoids are involved in normal renal function. However, the kidney contains considerably more Cox-1 than Cox-2, and the localization of the two isoforms is different It is not yet known whether the Cox-2 inhibitors will be safer in subgroups of patients prone to develop acute renal failure with NSAIDs, such as those patients with severe volume depletion, congestive heart failure, or hepatic cirrhosis with ascites (Bosch-Marce et al., 1999). Also, it is not known whether rare events, such as interstitial nephritis or papillary necrosis, will occur with long-term use of Cox-2 inhibitors, although studies in animals suggest that such events may be related to Cox-1 inhibition, since only Cox-1 is found in the papilla. Therefore, Cox-2 inhibitors may not produce these serious adverse effects (Khan etal., 1998). 

The development of new medicinal products for narrower indications in serious, and usually poorly understood, diseases such as multiple sclerosis and motor neurone disease has resulted in a closer approximation of study subjects selected for the controlled clinical trial to the patients encountered in clinical practice. Many of these products are biologically derived, and while efficacy in the two situations may be similar, longer and larger trials will be needed to fully appreciate adverse event profiles. 

An analysis of the rates of serious cardiovascular adverse events (mortality, myocardial infarction, thrombotic strokes) in clinical studies involving tadalafil indicated that adverse events were no more frequent than in the general population of men with erectile dysfunction. ... 

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