1. Epanova ® - Omega-3- carboxylic acids Manufacturer: AstraZeneca FDA Approval Date: 05/2014

2. Epanova ® - Omega-3-carboxylic acids Clinical Application Indications: Treatment of severe hypertriglyceridemia (≥ 500 mg/dL) as an adjunct to diet Place in therapy: Used after diet changes have failed to lower TG levels adequately

3. Epanova ® - Omega-3-carboxylic acids Clinical Application Contraindications: Known hypersensitivity to Epanova or any of its components

4. Epanova ® - Omega-3-carboxylic acids Clinical Application Warnings and Precautions: LDL-C should be monitored during treatment with Epanova as LDL has increased in some patients ALT/AST should be monitored periodically in patients with hepatic impairment Epanova should be used with caution in patients who have fish allergies

5. Epanova ® - Omega-3-carboxylic acids Clinical Application Pregnancy: C Lactation: Studies with fish oil have shown that excretion into breast milk occurs at higher concentration than that in plasma and the effect of Epanova on infants is not known

6. Epanova ® - Omega-3-carboxylic acids Drug Facts Pharmacology: The mechanism of action is not completely understood. Potential mechanisms of action include: Acyl-CoA:1,2-diacylglycerol acetyltransferase inhibition Increased mitochondrial and peroxismal β-oxidation in the liver

7. Epanova ® - Omega-3-carboxylic acids Drug Facts Pharmacology: The mechanism of action is not completely understood. Potential mechanisms of action include: Decreased lipogenesis in the liver Increased plasma lipoprotein lipase activity EPA and DHA are poor substrates for the enzyme responsible for triglyceride synthesis

8. Epanova ® - Omega-3-carboxylic acids Drug Facts Pharmacokinetics: A Directly absorbed in the small intestine. Cmax 5-9 hours. Steady state concentrations of EPA and DHA are achieved after 2 weeks of repeat daily dosing. D The majority of EPA and DHA is incorporated in phospholipids, triglycerides and cholesteryl esters. Free unesterified fatty acids represent 0.8% of the EPA and 1.1% of the DHA. M EPA and DHA are mainly oxidized in the liver. E Epanova does not undergo renal excretion. EPA half-life is 37 hours, DHA half-life is 46.

9. Epanova ® - Omega-3-carboxylic acids Drug Interactions Drug Interactions – Object Drugs: None

10. Epanova ® - Omega-3-carboxylic acids Drug Interactions Drug Interactions – Precipitant Drugs: None

11. Epanova ® - Omega-3-carboxylic acids Drug Interactions Drug Interactions – Pharmacodynamic interactions: Anticoagulants – may increase bleeding time

12. Epanova ® - Omega-3-carboxylic acids Adverse Effects Common Adverse Effects: PlaceboEpanova 2gEpanova 4g Diarrhea2%7%15% Nausea1%4%6% Abdominal pain or discomfort 2%3%5% Eructation<1%3%

13. Epanova ® - Omega-3-carboxylic acids Monitoring Parameters Efficacy Monitoring: Monitor triglycerides Toxicity Monitoring: Monitor for changes in INR as studies with fish oil have shown an increased bleeding time

14. Epanova ® - Omega-3-carboxylic acids Prescription Information Dosing: 2 or 4 g once daily Dosing is individualized according to response and tolerability. Cost: – Epanova has not reached the market yet and a price has not been set by AstraZeneca

15. Epanova ® - Omega-3-carboxylic acids Literature Review Purpose: To evaluate the efficacy and safety of Epanova (OM3-FFA)…in subjects with severe hypertriglyceridemia (TGs ≥ 500 but < 2000) Design: Double-blind, randomized, parallel, 4-arm study Kastelein, J., et al. Journal of Clinical Lipidology. 2014(8)94-106.

16. Epanova ® - Omega-3-carboxylic acids Literature Review Kastelein, J., et al. Journal of Clinical Lipidology. 2014(8)94-106. Inclusion criteria Exclusion criteria ≥ 18 years oldKnown lipoprotein lipase impairment Not pregnant or lactatingHx of pancreatitis, symptomatic gallstone disease BMI ≥ 20Uncontrolled diabetes (A1c ≥ 9%) Be willing to: maintain customary activity level, follow TLC diet, restrict consumption of fish Cancer in the past 2 years Untreated or on already-established dosing of other lipid-lowering drugs Cardiovascular event in the past 6 months Poorly controlled HTN (≥160/≥100) Abnormal ALT/AST, GFR, BG, platelets or Hgb

17. Epanova ® - Omega-3-carboxylic acids Literature Review Baseline characteristics: Kastelein, J., et al. Journal of Clinical Lipidology. 2014(8)94-106. Placebo (OO)Epanova 2 gEpanova 3 gEpanova 4 g Number9910010199 Men77 (78%)80 (80%)79 (78%)71 (72%) Mean age 51 ± 11 51 ± 10 51 ± 9 53 ± 11 White race95 (96%)93 (93%)92 (91%)88 (89%) Diabetes30 (30%)39 (39%)45 (45%)36 (36%) HTN64 (65%)69 (69%)69 (68%)67 (68%) Statin/CAI users 34 (34%)35 (35%) 34 (34%)

18. Epanova ® - Omega-3-carboxylic acids Literature Review Treatment arms: Olive oil (OO) 4 g/day x 12 weeks Epanova 2 g/day + OO 2 g/day x 12 weeks Epanova 3 g/day + OO 1 g/day x 12 weeks Epanova 4 g/day x 12 weeks Efficacy monitoring: Lipid panel Kastelein, J., et al. Journal of Clinical Lipidology. 2014(8)94-106.

19. Epanova ® - Omega-3-carboxylic acids Literature Review Statistical analysis: 332 patients needed for 80% power to detect at least 20% difference in TG levels Intention-to-treat analysis, included participants with 1+ doses and 1+ efficacy assessments Kastelein, J., et al. Journal of Clinical Lipidology. 2014(8)94-106.

20. Epanova ® - Omega-3-carboxylic acids Literature Review Primary endpoint: TG percentage change Secondary endpoint: non-HDL-C and HDL-C percentage change Kastelein, J., et al. Journal of Clinical Lipidology. 2014(8)94-106.

21. Epanova ® - Omega-3-carboxylic acids Literature Review Results: (% Δ from baseline, 95% CI) Significantly different from placebo: † p<0.05, ‡ p<0.01, * p<0.001 Kastelein, J., et al. Journal of Clinical Lipidology. 2014(8)94-106. Placebo (OO)Epanova 2 gEpanova 3 gEpanova 4 g TG-4.3% (-13.1 to 5.4) -25.9% (-32.8 to -18.3) ‡ -25.5% (-32.4 to -17.8) ‡ -30.9% (-37.3 to -23.7)* Non- HDL-C 2.5% (-2.3 to 7.6) -7.6% (-12.0 to -3.0) † -6.9% (-11.4 to -2.2) † -9.6% (-14.0 to -5.1) ‡ HDL-C1.9% (-2.0 to 6.0) 7.4% (3.2 to 11.7) 3.8% (-0.3 to 8.0) 5.8% (1.7 to 10.1) Total-C3.2% (-1.0 to 7.5) -5.4% (-9.3 to -1.4) † -4.9% (-8.7 to -0.8) -7.5% (-11.2 to -3.5) ‡ LDL-C3.0% (-2.9 to 9.3) 19.2% ( 12.3 to 26.6) ‡ 14.3% (7.6 to 21.4) 19.4% (12.4 to 26.8)*

22. Epanova ® - Omega-3-carboxylic acids Literature Review Adverse events: Kastelein, J., et al. Journal of Clinical Lipidology. 2014(8)94-106. Placebo (OO)Epanova 2 gEpanova 3 gEpanova 4 g Diarrhea2.0%10.0%5.9%10.1% Nausea1.0%6.0%8.9%5.1% Abdominal pain/discomfort 1.0%4.0%1.0% Eructation1.0%3.0%4.0% Infections (all)11.1%14.0%6.9%12.1%

23. Epanova ® - Omega-3-carboxylic acids Literature Review Discussion: Total N = 364 No significant difference between treatment groups for those who discontinued Discontinuation due to GI upset was 5- 7% for Epanova and 0% for placebo Kastelein, J., et al. Journal of Clinical Lipidology. 2014(8)94-106.

24. Epanova ® - Omega-3-carboxylic acids Literature Review Discussion: Epanova reduced TG levels by at least 25% The degree of TG lowering was less with 3 g/day than the 2 or 4 g/day Non-HDL-C was also significantly lowered in each Epanova group LDL was significantly increased in Epanova groups Kastelein, J., et al. Journal of Clinical Lipidology. 2014(8)94-106.

25. Epanova ® - Omega-3-carboxylic acids Summary Epanova is indicated for the treatment of severe hypertriglyceridemia (≥ 500 mg/dL) as an adjunct to diet. Epanova should be used after diet changes have failed to lower triglycerides. Epanova ® has no pharmacokinetic interactions but a pharmacodynamic interaction occurs between Epanova ® and anticoagulants - increased bleeding time Epanova is commonly dosed between 2 and 4 grams daily but dosing is individualized

26. Epanova ® - Omega-3-carboxylic acids References 1. http://www.epanovahcp.com. 06/14. http://www.epanovahcp.com 2. Epanova package insert. AstraZeneca. May 2014. 3. Kastelein, J.J.P., Maki, K.C., et al. Omega-3 free fatty acids for the treatment of severe hypertriglyceridemia: The EpanoVa fOr Lowering Very high triglyceridEs (EVOLVE) trial. Journal of Clinical Lipidology (2014)8;94-106.