Lovaza

Lovaza

CLINICAL PHARMACOLOGY

Mechanism of Action

The mechanism of action of LOVAZA is not completely understood. Potential mechanisms of action include inhibition of acyl-CoA:1,2-diacylglycerol acyltransferase, increased mitochondrial and peroxisomal P-oxidation in the liver, decreased lipogenesis in the liver, and increased plasma lipoprotein lipase activity. LOVAZA may reduce the synthesis of triglycerides in the liver because EPA and DHA are poor substrates for the enzymes responsible for TG synthesis, and EPA and DHA inhibit esterification of other fatty acids.

Pharmacokinetics

In healthy volunteers and in patients with hypertriglyceridemia, EPA and DHA were absorbed when administered as ethyl esters orally. Omega-3-acids administered as ethyl esters (LOVAZA) induced significant, dose-dependent increases in serum phospholipid EPA content, though increases in DHA content were less marked and not dose-dependent when administered as ethyl esters.

Specific Populations

Age: Uptake of EPA and DHA into serum phospholipids in subjects treated with LOVAZA was independent of age ( < 49 years versus > 49 years).

Gender: Females tended to have more uptake of EPA into serum phospholipids than males. The clinical significance of this is unknown.

Pediatric: Pharmacokinetics of LOVAZA have not been studied.

Renal or Hepatic Impairment: LOVAZA has not been studied in patients with renal or hepatic impairment.

Drug-Drug Interactions

Simvastatin: In a 14-day study of 24 healthy adult subjects, daily co-administration of simvastatin 80 mg with LOVAZA 4 grams did not affect the extent (AUC) or rate (Cmax) of exposure to simvastatin or the major active metabolite, beta-hydroxy simvastatin at steady state.

Atorvastatin: In a 14-day study of 50 healthy adult subjects, daily co-administration of atorvastatin 80 mg with LOVAZA 4 grams did not affect AUC or Cmax of exposure to atorvastatin, 2-hydroxyatorvastatin, or 4-hydroxyatorvastatin at steady state.

Rosuvastatin: In a 14-day study of 48 healthy adult subjects, daily co-administration of rosuvastatin 40 mg with LOVAZA 4 grams did not affect AUC or Cmax of exposure to rosuvastatin at steady state.

In vitro studies using human liver microsomes indicated that clinically significant cytochrome P450 mediated inhibition by EPA/DHA combinations are not expected in humans.

Clinical Studies

Severe Hypertriglyceridemia

The effects of LOVAZA 4 grams per day were assessed in 2 randomized, placebocontrolled, double-blind, parallel-group studies of 84 adult patients (42 on LOVAZA, 42 on placebo) with very high triglyceride levels. Patients whose baseline triglyceride levels were between 500 and 2,000 mg/dL were enrolled in these 2 studies of 6 and 16 weeks duration. The median triglyceride and LDL-C levels in these patients were 792 mg/dL and 100 mg/dL, respectively. Median HDL-C level was 23.0 mg/dL.

The changes in the major lipoprotein lipid parameters for the groups receiving LOVAZA or placebo are shown in Table 2.

Table 2: Median Baseline and Percent Change From Baseline in Lipid Parameters in Patients with Severe Hypertriglyceridemia ( ≥ 500 mg/dL)

Parameter LOVAZA
N= 42
Placebo
N =42
Difference
BL % Change BL % Change
TG 816 -44.9 788 +6.7 -51.6
Non-HDL-C 271 -13.8 292 -3.6 -10.2
TC 296 -9.7 314 -1.7 -8.0
VLDL-C 175 -41.7 175 -0.9 -40.8
HDL-C 22 +9.1 24 0.0 +9.1
LDL-C 89 +44.5 108 -4.8 +49.3
BL = Baseline (mg/dL); % Change = Median Percent Change from Baseline; Difference = LOVAZA Median % Change - Placebo Median % Change

LOVAZA 4 grams per day reduced median TG, VLDL-C, and non-HDL-C levels and increased median HDL-C from baseline relative to placebo. Treatment with LOVAZA to reduce very high TG levels may result in elevations in LDL-C and non-HDL-C in some individuals. Patients should be monitored to ensure that the LDL-C level does not increase excessively.

The effect of LOVAZA on the risk of pancreatitis in patients with severe hypertriglyceridemia has not been determined.

The effect of LOVAZA on cardiovascular mortality and morbidity in patients with severe hypertriglyceridemia has not been determined.

Other Clinical Experience

The effects of LOVAZA 4 grams per day as add-on therapy to treatment with simvastatin were evaluated in a randomized, placebo-controlled, double-blind, parallel-group study of 254 adult patients (122 on LOVAZA and 132 on placebo) with persistent high triglycerides (200 to 499 mg/dL) despite simvastatin therapy. Patients were treated with open-label simvastatin 40 mg per day for 8 weeks prior to randomization to control their LDL-C to no greater than 10% above NCEP ATP III goal and remained on this dose throughout the study. Following 8 weeks of openlabel treatment with simvastatin, patients were randomized to either LOVAZA 4 grams per day or placebo for an additional 8 weeks with simvastatin co-therapy. The median baseline triglyceride and LDL-C levels in these patients were 268 mg/dL and 89 mg/dL, respectively. Median baseline non-HDL-C and HDL-C levels were 138 mg/dL and 45 mg/dL, respectively.

The changes in the major lipoprotein lipid parameters for the groups receiving LOVAZA plus simvastatin or placebo plus simvastatin are shown in Table 3.

Table 3: Response to the Addition of LOVAZA 4 grams per day to Ongoing Simvastatin 40 mg per day Therapy in Patients with High Triglycerides (200 to 499 mg/dL)

Parameter LOVAZA + Simvastatin N = 122 Placebo + Simvastatin N = 132 Difference P-Value
BL EOT Median % Change BL EOT Median % Change
Non-HDL-C 137 123 -9.0 141 134 -2.2 -6.8 < 0.0001
TG 268 182 -29.5 271 260 -6.3 -23.2 < 0.0001
TC 184 172 -4.8 184 178 -1.7 -3.1 < 0.05
VLDL-C 52 37 -27.5 52 49 -7.2 -20.3 < 0.05
Apo-B 86 80 -4.2 87 85 -1.9 -2.3 < 0.05
HDL-C 46 48 +3.4 43 44 -1.2 +4.6 < 0.05
LDL-C 91 88 +0.7 88 85 -2.8 +3.5 =0.05
BL = Baseline (mg/dL); EOT = End of Treatment (mg/dL); Median % Change = Median Percent Change from Baseline; Difference = LOVAZA Median % Change - Placebo Median % Change

LOVAZA 4 grams per day significantly reduced non-HDL-C, TG, TC, VLDL-C, and Apo-B levels and increased HDL-C and LDL-C from baseline relative to placebo.

Last reviewed on RxList: 9/26/2013
This monograph has been modified to include the generic and brand name in many instances.

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