epanova ® - omega-3- carboxylic acids manufacturer: astrazeneca fda approval date: 05/2014

Epanova® - Omega-3-carboxylic acids

Manufacturer:

AstraZeneca

FDA Approval Date: 05/2014


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



• Contraindications:• Known hypersensitivity to Epanova or

any of its components



• 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



• 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


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


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


Drug Facts

• Pharmacokinetics:

ADirectly 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.

DThe 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.

MEPA and DHA are mainly oxidized in the liver.

EEpanova does not undergo renal excretion. EPA half-life is 37 hours, DHA half-life is 46.


Drug Interactions

• Drug Interactions – Object Drugs: • None


Drug Interactions

• Drug Interactions – Precipitant Drugs: • None


Drug Interactions

• Drug Interactions – Pharmacodynamic interactions: • Anticoagulants – may increase bleeding

time


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%


Monitoring Parameters

• Efficacy Monitoring:• Monitor triglycerides

• Toxicity Monitoring:• Monitor for changes in INR as studies

with fish oil have shown an increased bleeding time


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


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.


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


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%)


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



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



Literature Review

• Primary endpoint: TG percentage change

• Secondary endpoint: non-HDL-C and HDL-C percentage change



Literature Review

• Results: (% Δ from baseline, 95% CI)

Significantly different from placebo: † p<0.05, ‡ p<0.01, * p<0.001



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-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)*


Literature Review

• Adverse events:



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%


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



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



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


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.

epanova ® - omega-3- carboxylic acids manufacturer: astrazeneca fda approval date: 05/2014

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