AMRN
Important Safety Issues With Consideration to Related Drugs
With regard to the only other FDA approved omega-3 fatty acid product (Lovaza), there have been four areas of potential safety concern: increases in LDL-C, liver enzymes, blood glucose, and a possible increase in bleeding risk.
The increase in LDL-C is thought to be due to the increased activity of LPL activity.4 This increased activity enhances the conversion of very low density lipoprotein (VLDL) and intermediate –density lipoproteins (IDL) to LDL-C.
The current Lovaza label states that patients with hepatic impairment should have ALT and AST monitored periodically during therapy . This stems from a greater number of patients with upward shifts in ALT levels, without a concurrent increase in AST shifts in the Integrated Summary of Safety (ISS) of Lovaza monotherapy trials.
Historically, some studies have raised concern that omega-3 ethyl ester consumption could increase fasting plasma glucose (FPG) without corresponding increase in Clinical Review Iffat Nasrin Chowdhury, MD NDA 202057 Vascepa/Icosapent Ethyl 14 HbA1C.5 However, a recent Cochrane meta-analysis suggested that neither the FPG nor the HbA1c increased with omega-3 ethyl ester therapy.
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Pooled data from the Lovaza NDA datasets (post-hoc) showed a slight increase in median FPG in the Lovaza treatment group (median change +6.5mg/dL) as compared to the placebo group (+2 mg/dL).
Metabolism of omega-3 fatty acids, specifically EPA, produces eicosanoids of the thromboxane A3 and leukotriene 5 series, which are associated with reduced platelet aggregation, increased vasodilation, and inhibited leukocyte chemotaxis.
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Omega-3 acid ethyl esters have been shown in vitro to significantly reduce platelet aggregation by reducing production of thromboxane A2 and increasing production of thromboxane A3.
The relationship of these in vitro findings to bleeding risk is much less clear. Currently the labeling for Lovaza includes cautionary statements with regard to bleeding risk. In addition to safety issues related to Lovaza,, ethyl EPA has been investigated in a large study in Japan.
In The Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomized open-la bel, blinded endpoint analysis, 18,645 Japanese patients were randomly assigned to either 1800 mg of EPA plus a statin or statin alone.
Safety concerns in this study included changes in creatine phosphokinase (CPK) and liver enzymes. Adverse effects (AEs) that were more common in the treatment group than in the control group included gastrointestinal disturbances, skin abnormality, and haemorrhage (cerebral, fundus, epitaxis, subcutaneous). No further information on bleeding events is available from the published JELIS report.
The Agency issued a review of the safety of EPA and DHA administered or consumed together in the Federal Register of June 5, 1997 (US FDA Substances Affirmed as Generally Recognized as Safe,
With respect to effects on bleeding time, the FDA concluded that although EPA and DHA appeared to cause small, dose-related increases in bleeding time of unclear clinical relevance, bleeding time increases associated with the use of 3g/day or less of EPA plus DHA either do not occur or are of no adverse significance.
With respect to the effects on glycemic control in type 2 diabetics, the FDA concluded that a dose-related effect is likely, and may be clinically relevant at high daily intake levels, but a daily intake if 3g/day or less of EPA and DHA causes no clinically significant effects on glycemic control.
With respect to effects of EPA and DHA on LDL-C, the FDA concluded that there appeared to be a trend toward increased LDL-C with increased fish oil consumption in all population subgroups, with a magnitude of the increase appearing greater in populations with abnormal blood lipid levels, hypertension, diabetes, and cardiovascular disease.
Numerous studies have shown that both the major omega-3 FA, EPA and DHA, lower serum TG levels, but a study comparing the effects of EPA monotherapy to DHA monotherapy showed that DHA consistently had a more pronounced TG-lowering effect than EPA across all baseline concentrations of TG. This study also showed that DHA may be responsible for an increase in HDL-C whereas EPA may produce a small decrease in TC.
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Thus EPA and DHA have differential effects on lipoprotein metabolism.
All individual SAEs occurred infrequently. The complete study report for the MARINE and ANCHOR trials were searched for additional cases of coronary artery disease, non-cardiac chest pain and subarachnoid hemorrhage and none were found. In addition to the two SAEs of subarachnoid hemorrhage, a search of the literature elicited no reports of subarachnoid hemorrhage in patients taking fish oil products.
In a systematic review by Desai et al, the potential interactions between dietary supplements and anti-platelet drugs were evaluated. Effects on bleeding time were evaluated with the combination of omega-3 FA and acetylsa licylic acid. Compared to baseline, significant increase (p<0.05) in bleeding time of 13-42% and 55-82% were observed with omega-3 FA alone or in combination with acetylsalicylic acid, respectively. In three trials the additional 19-44% increases in bleeding time with
combination therapy over acetylsalicylic acid were significant (p<0.05). The studies evaluated in the review were conducted with treatment durations of omega-3 FA and acetylsalicylic acid between 2 and 25 weeks.
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Harris (2007) summarized clinical trials with omega-3 FA and findings related to bleeding complications. According to that author, the risk for clinically significant bleeding is “virtually nonexistent”.
This reviewer reviewed the narratives of the six cases of subdural hematoma, subdural hemorrhage, and subarachnoid hemorrhage reported in the NDA. There is no definitive answer as to whether omega-3 FA increases the risk for bleeding. Regulatory recommendations with Vascepa and concomitant anticoagulants should convey caution.
Y esto es genial:
Previous studies have demonstrated that the generation of reactive oxygen species and an excessive inflammatory reaction are in involved in the progression of neural damage following brain ischemia. In this study, we focused on the anti-inflammatory and antioxidant properties of eicosapentaenoic acid (EPA). EPA treatment significantly inhibited DNA oxidative damage (P < .05) and accumulation of Iba1-positive cells in the CA1 area at 12 and 72 hours after the induction of isc
hemia, and also decreased apoptotic neurons and neuronal death (P < .001) at 72 hours after ischemia. EPA treatment also significantly improved memory function (P < .05). These findings suggest that EPA inhibits the inflammatory reaction and oxidative damage occurring after ischemic brain injury, and also may contribute to the prevention of neural damage and memory impairment following such injury.
Y con lo que he colgado está toda la información del documento.
