Safety analyses serious adverse events

The UK Committee of Safety of Medicines has previously warned that paroxetine appeared to be no more effective than placebo in the treatment of depression in adolescents and might be associated with a greater risk of self harm (SEDA-28, 16). In a meta-analysis of both published and unpublished placebo-controlled trials of SSRIs in childhood and adolescent depression, only fluoxetine seemed clearly to be associated with a positive benefit-harm balance (26). The evidence of efficacy for sertraline and citalopram was doubtful, while the risk of serious adverse events was significantly increased. Additionally, for both drugs the risk of suicidal behavior was numerically increased. In regard to venlafaxine, the risk of suicidal behavior was significantly greater than placebo. 

There has been a meta-analysis of 15 trials from Africa, Europe, and Asia of the use of varying doses of artesunate plus lumefantrine compared with several alternative antimalarial drugs in 1869 patients conducted by the manufacturers Novartis into its clinical safety and tolerability in the treatment of uncomplicated malaria (13). The most common adverse events were gastrointestinal—nausea (6.3%), abdominal pain (12%), vomiting (2.4%), anorexia (13%)—or central nervous—headache (21%) or dizziness (16%). There were 20 serious adverse events with artesunate plus lumefantrine, but only one (hemolytic anemia) was possibly due to artesunate plus lumefantrine. There was no QT prolongation associated with artesunate plus lumefantrine. 

Data from the interim analysis showed no study-drug-related serious or non-serious adverse events on the FTP Continuation study. In a foUow-up safety assessment across aU rAHF-PFM studies, one non-ser-ious adverse event was reported in one patient on the PTP Continuation study. This event (strange taste in the mouth) was deemed possibly related to rAHF-PFM, and was completely resolved. 

Davis B, Southworth H (2016) Statistical analysis of cumulative serious adverse event data from development safety update reports. Ther Innov Regul Sci 50 188-194 Xia A, Jiang Q (2014) Statistical evaluation of drug safety data. Ther Innov Regul Sci 48 109-120... 

Systematic reviews In a meta-analysis of the efficacy and safety of huperzine-A 300-500 micrograms/day in Alzheimer s disease, the estimated effect size on the Mini-Mental State Examination (MMSE) and Activity of Daily Living (ADL) increased over the treatment time. Most of the adverse effects were cholinergic and there were no serious adverse events [127 ]. The meta-analysis included four double-bhnd, randomized, placebo-con-trolled trials, with more than 20 participants... 

Systematic reviews The efficacy and safety of sapropterin dihydrochloride in lowering phenylalanine concentration in patients with phenylketonuria has been systematically reviewed [21 ]. Two trials including a total of 135 participants were included in the analysis. No serious adverse events were associated with the use of sapropterin on the short-term. 

The efficacy and safety of paricalcitol therapy in the management of chronic kidney disease has been evaluated. Nine studies with a total of 832 participants were included. There was no significant difference in the risk of hypercalcaemia between paricalcitol and control groups (RR=2.25 95% Cl 0.81-6.26 P = 0.12). Paricalcitol therapy was not associated with a significantly increased risk of cardiovascular and endocrine adverse events compared with controls (RR 1.07 95% Cl 0.84-1.36 P=0.58) [76 ]. No serious adverse events were reported in a meta-analysis of 12 studies examining the impact of vitamin D supplementation on chronic kidney disease in non-dialysis patients [77 ]. 

The efficacy and safety of 1-omithine-L-aspartate for treatment of hepatic encephalopathy in patients with cirrhosis has been evaluated in a meta-analysis of eight randomised controlled trials including a total of 646 patients. There were no significant differences in the frequency of adverse events between the intervention and control groups, and no serious adverse events were reported [100 ]. 

Observational studies In a pooled analysis of data from patients with rheumatoid arthritis treated with rituximab in combination with methotrexate safety analyses were based on 5013 patient-years of rituximab exposure [146 ]. The most frequent adverse event was infusion-related reactions, which occurred in 25% of patients during the first infusion under 1% of infusion-related reactions were considered serious. The overall serious infection rate was 4.31 per 100 patient-years. Infections and serious infections remained stable over time across five courses. Compared with other patients with rheumatoid arthritis and with the general US population, there was no increased risk of malignancy. 

In a pooled analysis of 41 randomized trials of the hepatic safety of celecoxib and non-selective NSAIDs there were fewer hepatobiliary adverse events with celecoxib (1.1%) than diclofenac (4.2%). For ibupro-fen (1.5%) and placebo (0.89%) the incidence of adverse events was comparable to that with celecoxib. The incidence of serious hepatic adverse events was low 0.05% among 24 933 celecoxib-treated patients, and 0.21% among 7639 diclofenac-treated patients [20 ]. However, rare cases of celecoxib-induced liver failure requiring transplantation have been reported [21 ]. 

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