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Lovaza

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These highlights do not include all the information needed to use LOVAZA safely and effectively. See full prescribing information for LOVAZA. LOVAZA (omega-3-acid ethyl esters) CapsulesInitial U.S. Approval: 2004

LOVAZA (omega-3-acid ethyl esters) is indicated as an adjunct to diet to reduce triglyceride (TG) levels in adult patients with severe (≥500 mg/dL) hypertriglyceridemia.

Usage Considerations: Patients should be placed on an appropriate lipid-lowering diet before receiving LOVAZA and should continue this diet during treatment with LOVAZA.

Laboratory studies should be done to ascertain that the lipid levels are consistently abnormal before instituting LOVAZA therapy. Every attempt should be made to control serum lipids with appropriate diet, exercise, weight loss in obese patients, and control of any medical problems such as diabetes mellitus and hypothyroidism that are contributing to the lipid abnormalities. Medications known to exacerbate hypertriglyceridemia (such as beta blockers, thiazides, estrogens) should be discontinued or changed if possible prior to consideration of triglyceride-lowering drug therapy.

Limitations of Use: The effect of LOVAZA on cardiovascular mortality and morbidity in patients with elevated triglycerides has not been determined.

The daily dose of LOVAZA is 4 grams per day. The daily dose may be taken as a single 4-gram dose (4 capsules) or as two 2-gram doses (2 capsules given twice daily).

Patients should be advised to swallow LOVAZA capsules whole. Do not break open, crush, dissolve or chew LOVAZA.

LOVAZA (omega-3-acid ethyl esters) capsules are supplied as 1-gram transparent soft-gelatin capsules filled with light-yellow oil and bearing the designation LOVAZA.

LOVAZA is contraindicated in patients with known hypersensitivity (e.g., anaphylactic reaction) to LOVAZA or any of its components.

In patients with hepatic impairment, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels should be monitored periodically during therapy with LOVAZA. In some patients, increases in ALT levels without a concurrent increase in AST levels were observed.

In some patients, LOVAZA increases LDL-C levels. LDL-C levels should be monitored periodically during therapy with LOVAZA.

Laboratory studies should be performed periodically to measure the patient’s TG levels during therapy with LOVAZA.

LOVAZA contains ethyl esters of omega-3 fatty acids (EPA and DHA) obtained from the oil of several fish sources. It is not known whether patients with allergies to fish and/or shellfish, are at increased risk of an allergic reaction to LOVAZA. LOVAZA should be used with caution in patients with known hypersensitivity to fish and/or shellfish.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Adverse reactions reported in at least 3% and at a greater rate than placebo for patients treated with LOVAZA based on pooled data across 23 clinical studies are listed in Table 1.

Studies included subjects with HTG and severe HTG.

Additional adverse reactions from clinical studies are listed below:

Digestive System: Constipation, gastrointestinal disorder and vomiting.

Metabolic and Nutritional Disorders: Increased ALT and increased AST.

Skin: Pruritus and rash.

Table 1. Adverse Reactions Occurring at Incidence ≥3% and Greater than Placebo in Clinical Studies of LOVAZA
BODY SYSTEM Adverse Reaction*	LOVAZA (N = 655)		Placebo (N = 370)
BODY SYSTEM Adverse Reaction*	n	%	n	%
Eructation	29	4	5	1
Dyspepsia	22	3	6	2
Taste perversion	27	4	1	<1

In addition to adverse reactions reported from clinical trials, the events described below have been identified during post-approval use of LOVAZA. Because these events are reported voluntarily from a population of unknown size, it is not possible to reliably estimate their frequency or to always establish a causal relationship to drug exposure.

The following events have been reported: anaphylactic reaction, hemorrhagic diathesis.

Some studies with omega-3-acids demonstrated prolongation of bleeding time. The prolongation of bleeding time reported in these studies has not exceeded normal limits and did not produce clinically significant bleeding episodes. Clinical studies have not been done to thoroughly examine the effect of LOVAZA and concomitant anticoagulants. Patients receiving treatment with LOVAZA and an anticoagulant or other drug affecting coagulation should be monitored periodically (e.g., aspirin, NSAIDS, warfarin, coumarin).

Pregnancy Category C: There are no adequate and well-controlled studies in pregnant women. It is unknown whether LOVAZA can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. LOVAZA should be used during pregnancy only if the potential benefit to the patient justifies the potential risk to the fetus.

Omega-3-acid ethyl esters have been shown to have an embryocidal effect in pregnant rats when given in doses resulting in exposures 7 times the recommended human dose of 4 grams/day based on a body surface area comparison.

In female rats given oral gavage doses of 100, 600, and 2,000 mg/kg/day beginning 2 weeks prior to mating and continuing through gestation and lactation, no adverse effects were observed in the high dose group (5 times human systemic exposure following an oral dose of 4 grams/day based on body surface area comparison).

In pregnant rats given oral gavage doses of 1,000, 3,000, and 6,000 mg/kg/day from gestation day 6 through 15, no adverse effects were observed (14 times human systemic exposure following an oral dose of 4 grams/day based on a body surface area comparison).

In pregnant rats given oral gavage doses of 100, 600, and 2,000 mg/kg/day from gestation day 14 through lactation day 21, no adverse effects were seen at 2,000 mg/kg/day (5 times the human systemic exposure following an oral dose of 4 grams/day based on a body surface area comparison). However, decreased live births (20% reduction) and decreased survival to postnatal day 4 (40% reduction) were observed in a dose-ranging study using higher doses of 3,000 mg/kg/day (7 times the human systemic exposure following an oral dose of 4 grams/day based on a body surface area comparison).

In pregnant rabbits given oral gavage doses of 375, 750, and 1,500 mg/kg/day from gestation day 7 through 19, no findings were observed in the fetuses in groups given 375 mg/kg/day (2 times human systemic exposure following an oral dose of 4 grams/day based on a body surface area comparison). However, at higher doses, evidence of maternal toxicity was observed (4 times human systemic exposure following an oral dose of 4 grams/day based on a body surface area comparison).

It is not known whether omega-3-acid ethyl esters are excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when LOVAZA is administered to a nursing woman.

Safety and effectiveness in pediatric patients have not been established.

A limited number of patients older than 65 years were enrolled in the clinical studies of LOVAZA. Safety and efficacy findings in subjects older than 60 years did not appear to differ from those of subjects younger than 60 years.

LOVAZA does not have any known drug abuse or withdrawal effects.

In the event of an overdose, the patient should be treated symptomatically, and general supportive care measures instituted, as required.

LOVAZA, a lipid-regulating agent, is supplied as a liquid-filled gel capsule for oral administration. Each 1-gram capsule of LOVAZA contains at least 900 mg of the ethyl esters of omega-3 fatty acids sourced from fish oils. These are predominantly a combination of ethyl esters of eicosapentaenoic acid (EPA - approximately 465 mg) and docosahexaenoic acid (DHA - approximately 375 mg).

The empirical formula of EPA ethyl ester is CHO, and the molecular weight of EPA ethyl ester is 330.51. The structural formula of EPA ethyl ester is:

The empirical formula of DHA ethyl ester is CHO, and the molecular weight of DHA ethyl ester is 356.55. The structural formula of DHA ethyl ester is:

LOVAZA capsules also contain the following inactive ingredients: 4 mg α-tocopherol (in a carrier of soybean oil), and gelatin, glycerol, and purified water (components of the capsule shell).

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 β-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.

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.

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

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

Pharmacokinetics of LOVAZA in pediatric patients have not been established [see Use in Specific Populations (8.4)].

LOVAZA has not been studied in patients with renal or hepatic impairment.

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 (C) of exposure to simvastatin or the major active metabolite, beta-hydroxy simvastatin at steady state.

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 C of exposure to atorvastatin, 2-hydroxyatorvastatin, or 4-hydroxyatorvastatin at steady state.

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 C 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.

In a rat carcinogenicity study with oral gavage doses of 100, 600, and 2,000 mg/kg/day, males were treated with omega-3-acid ethyl esters for 101 weeks and females for 89 weeks without an increased incidence of tumors (up to 5 times human systemic exposures following an oral dose of 4 grams/day based on a body surface area comparison). Standard lifetime carcinogenicity bioassays were not conducted in mice.

Omega-3-acid ethyl esters were not mutagenic or clastogenic with or without metabolic activation in the bacterial mutagenesis (Ames) test with Salmonella typhimurium and Escherichia coli or in the chromosomal aberration assay in Chinese hamster V79 lung cells or human lymphocytes. Omega-3-acid ethyl esters were negative in the in vivo mouse micronucleus assay.

In a rat fertility study with oral gavage doses of 100, 600, and 2,000 mg/kg/day, males were treated for 10 weeks prior to mating and females were treated for 2 weeks prior to and throughout mating, gestation, and lactation. No adverse effect on fertility was observed at 2,000 mg/kg/day (5 times human systemic exposure following an oral dose of 4 grams/day based on a body surface area comparison).

The effects of LOVAZA 4 grams per day were assessed in 2 randomized, placebo-controlled, 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.

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 very high TG levels has not been eva luated.

The effect of LOVAZA on cardiovascular mortality and morbidity in patients with elevated TG levels has not been determined.

Table 2. Median Baseline and Percent Change From Baseline in Lipid Parameters in Patients with Very High TG Levels (≥500 mg/dL)
Parameter	LOVAZA N = 42		Placebo N = 42		Difference
Parameter	BL	% Change	BL	% Change	Difference
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

The effects of LOVAZA 4 grams per day as add-on therapy to treatment with simvastatin were eva luated 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 open-label 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.

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.

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
Parameter	BL	EOT	Median % Change	BL	EOT	Median % Change	Difference	P-Value
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

LOVAZA (omega-3-acid ethyl esters) capsules are supplied as 1-gram transparent soft-gelatin capsules filled with light-yellow oil and bearing the designation LOVAZA.

Bottles of 60: NDC 0173-0783-01

Bottles of 120: NDC 0173-0783-02

Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Do not freeze. Keep out of reach of children.

See FDA-approved patient labeling (17.2).

Patient labeling is provided as a tear-off leaflet at the end of this full prescribing information.

Manufactured for GlaxoSmithKline by:

Catalent Pharma Solutions

2725 Scherer Drive

St. Petersburg, FL 33716-1016

Accucaps Industries Limited

2125 Ambassador Drive

Windsor, Ontario, Canada N9B 3R5

Banner Pharmaceuticals Inc.

4125 Premier Drive

High Point, NC 27265

Distributed by:

GlaxoSmithKline

Research Triangle Park, NC 27709

LOVAZA is a registered trademark of the GlaxoSmithKline group of companies.

December 2010

LVZ:6PI

PHARMACIST-DETACH HERE AND GIVE INSTRUCTIONS TO PATIENT

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PATIENT INFORMATION

LOVAZA (lō-vā-ză)

(omega-3-acid ethyl esters) Capsules

Read the Patient Information that comes with LOVAZA before you start taking it, and each time you get a refill. There may be new information. This leaflet does not take the place of talking with your doctor about your condition or treatment.

What is LOVAZA?

LOVAZA is a prescription medicine, called a lipid-regulating medicine, for adults. LOVAZA is made of omega-3 fatty acids from oils of fish, such as salmon and mackerel. Omega-3 fatty acids are substances that your body needs but cannot produce itself.

LOVAZA is used along with a low-fat and low-cholesterol diet to lower very high triglycerides (fats) in your blood. Before taking LOVAZA, talk to your healthcare provider about how you can lower high blood fats by:

Treatment with LOVAZA has not been shown to prevent heart attacks or strokes.

LOVAZA has not been studied in children under the age of 18 years.

Who should not take LOVAZA?

Do not take LOVAZA if you:

What should I tell my doctor before taking LOVAZA?

Tell your doctor about all of your medical conditions, including if you:

Tell your doctor about all the medicines you take, including prescription and non-prescription medicine, vitamins, and herbal supplements. LOVAZA and certain other medicines can interact. Especially tell your doctor if you take medicines that affect clotting such as anticoagulants or blood thinners. Examples of these medicines include aspirin, nonsteroidal anti-inflammatory agents (NSAIDS), warfarin, coumarin, and clopidogrel (PLAVIX).

Know all the medicines you take. Keep a list of them with you to show your doctor and pharmacist.

How should I take LOVAZA?

What are the possible side effects of LOVAZA?

The most common side effects with LOVAZA are burping, upset stomach, and a change in your sense of taste.

LOVAZA may affect certain blood tests. It may change:

Talk to your doctor if you have side effects that bother you or that will not go away. You may report side effects to FDA at 1-800-FDA-1088.

These are not all the side effects with LOVAZA. For more information, ask your doctor or pharmacist.

How should I store LOVAZA?

General information about LOVAZA

Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use LOVAZA for a condition for which it was not prescribed. Do not give LOVAZA to other people, even if they have the same problem you have. It may harm them.

This leaflet summarizes the most important information about LOVAZA. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about LOVAZA that is written for health professionals or go to www.LOVAZA.com.

What are the ingredients in LOVAZA?

Active Ingredient: Omega-3-acid ethyl esters

Inactive Ingredients: Gelatin, glycerol, purified water, alpha-tocopherol (in soybean oil)