®
Epanova
- Omega-3carboxylic acids
Manufacturer:
AstraZeneca
FDA Approval Date: 05/2014
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
Epanova® - Omega-3-carboxylic acids
Clinical Application
• Contraindications:
• Known hypersensitivity to Epanova or
any of its components
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
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
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
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
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
E
EPA and DHA are mainly oxidized in the liver.
Epanova does not undergo renal excretion. EPA half-life is
37 hours, DHA half-life is 46.
Epanova® - Omega-3-carboxylic acids
Drug Interactions
• Drug Interactions – Object Drugs:
• None
Epanova® - Omega-3-carboxylic acids
Drug Interactions
• Drug Interactions – Precipitant Drugs:
• None
Epanova® - Omega-3-carboxylic acids
Drug Interactions
• Drug Interactions – Pharmacodynamic
interactions:
• Anticoagulants – may increase bleeding
time
Epanova® - Omega-3-carboxylic acids
Adverse Effects
• Common Adverse Effects:
Placebo
Epanova 2g
Epanova 4g
Diarrhea
2%
7%
15%
Nausea
1%
4%
6%
Abdominal
pain or
discomfort
2%
3%
5%
Eructation
<1%
3%
3%
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
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
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.
Epanova® - Omega-3-carboxylic acids
Literature Review
Inclusion criteria
Exclusion criteria
≥ 18 years old
Known lipoprotein lipase impairment
Not pregnant or lactating
Hx of pancreatitis, symptomatic
gallstone disease
BMI ≥ 20
Uncontrolled 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
Kastelein, J., et al. Journal of Clinical Lipidology. 2014(8)94-106.
Epanova® - Omega-3-carboxylic acids
Literature Review
• Baseline characteristics:
Placebo (OO)
Epanova 2 g
Epanova 3 g
Epanova 4 g
Number
99
100
101
99
Men
77 (78%)
80 (80%)
79 (78%)
71 (72%)
Mean age
51 ± 11
51 ± 10
51 ± 9
53 ± 11
White race
95 (96%)
93 (93%)
92 (91%)
88 (89%)
Diabetes
30 (30%)
39 (39%)
45 (45%)
36 (36%)
HTN
64 (65%)
69 (69%)
69 (68%)
67 (68%)
Statin/CAI
users
34 (34%)
35 (35%)
35 (35%)
34 (34%)
Kastelein, J., et al. Journal of Clinical Lipidology. 2014(8)94-106.
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.
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.
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.
Epanova® - Omega-3-carboxylic acids
Literature Review
• Results: (% Δ from baseline, 95% CI)
Placebo (OO)
Epanova 2 g
Epanova 3 g
-25.9%
-25.5%
(-32.8 to -18.3)‡ (-32.4 to -17.8)‡
Epanova 4 g
TG
-4.3%
(-13.1 to 5.4)
-30.9%
(-37.3 to -23.7)*
NonHDL-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-C
1.9%
(-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-C
3.2%
(-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-C
3.0%
(-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)*
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.
Epanova® - Omega-3-carboxylic acids
Literature Review
• Adverse events:
Placebo (OO) Epanova 2 g Epanova 3 g Epanova 4 g
Diarrhea
2.0%
10.0%
5.9%
10.1%
Nausea
1.0%
6.0%
8.9%
5.1%
Abdominal
pain/discomfort
1.0%
4.0%
1.0%
1.0%
Eructation
1.0%
3.0%
4.0%
4.0%
Infections (all)
11.1%
14.0%
6.9%
12.1%
Kastelein, J., et al. Journal of Clinical Lipidology. 2014(8)94-106.
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 57% for Epanova and 0% for placebo
Kastelein, J., et al. Journal of Clinical Lipidology. 2014(8)94-106.
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.
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
Epanova® - Omega-3-carboxylic acids
References
1. http://www.epanovahcp.com. 06/14.
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.