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1. Nebbaro 1000mg Soft Capsules
2. Nebbaro 1000mg Soft Capsules

SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Nebbaro 1000mg soft Capsules

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each soft capsule contains 1000 mg omega-3-acid ethyl esters 90, comprising principally 840 mg ethyl esters of eicosapentaenoic acid (EPA) (460 mg) and docosahexaenoic acid (DHA) ethyl esters (380 mg).

Excipient with known effect: This medicinal product contains soya oil.

For the full list of excipients see section 6.1.

3 PHARMACEUTICAL FORM

Capsule, soft

Soft, transparent gelatine capsules containing pale yellow oil

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Post Myocardial Infarction

Adjuvant treatment in secondary prevention after myocardial infarction, in addition to other standard therapy (e.g. statins, anti-platelet medicinal products, beta-blockers, ACE inhibitors).

Hypertriglyceridaemia

Endogenous hypertriglyceridaemia as a supplement to diet when dietary measures alone are insufficient to produce an adequate response: type IV hypertriglyceridaemia in monotherapy

type IIb/III hypertriglyceridaemia in combination with statins, when control of triglycerides through statins alone is not sufficient

4.2 Posology and method of administration

Post Myocardial Infarction

The recommended dose is one capsule daily.

Hypertriglyceridaemia

Initial treatment two capsules daily. If adequate response is not obtained, the dose may be increased to four capsules daily.

The soft capsules should be taken with food to avoid gastrointestinal disturbances.

There is no information regarding the use of Nebbaro in children and adolescents, in elderly patients over 70 years of age, or in patients with hepatic impairment (see section 4.4), and only limited information regarding the use in patients with renal impairment.

4.3 Contraindications

Hypersensitivity to the active substance, to soya, peanut or to any of the other excipients listed in section 6.1.

4.4 Special warnings and precautions for use

Warnings

Because of the moderate increase in bleeding time (with the high dosage, i.e. 4 capsules per day), patients receiving anticoagulant therapy must be monitored and the dosage of anticoagulant adjusted if necessary (see section 4.5). Use of Nebbaro does not eliminate the need for the surveillance usually required for patients of this type.

Make allowance for the increased bleeding time in patients at high risk of haemorrhage (because of severe trauma, surgery, etc).

In the absence of efficacy and safety data, Nebbaro should not be used in children and adolescents.

Nebbaro is not indicated in exogenous hypertriglyceridaemia (type 1 hyperchylomicronaemia).

There is only limited experience in secondary endogenous hypertriglyceridaemia (especially uncontrolled diabetes).

There is no experience regarding the treatment of hypertriglyceridaemia in combination with fibrates.

Special precaution

Regular monitoring of hepatic function (ASAT and ALAT) is required in patients with hepatic impairment, in particular with the high dosage (4 soft capsules per day).

Soya oil

This medicinal product contains soya oil. If the patient is allergic to peanut or soya, do not take this medicinal product (see section 4.3).

4.5 Interaction with other medicinal products and other forms of interaction

Oral anticoagulants: See also section 4.4.

Nebbaro has been given in conjunction with warfarin without haemorrhagic complications. However, the prothrombin time must be checked when Nebbaro is combined with warfarin or when treatment with Nebbaro is stopped.

4.6 Fertility, Pregnancy and lactation

Pregnancy

There are no adequate data from the use of Nebbaro in pregnant women. Studies in animals have not shown reproductive toxicity. The potential risk for humans is unknown and therefore Nebbaro should not be used during pregnancy unless clearly necessary.

Lactation

There are no data on the excretion of Nebbaro in animal and human milk. Therefore, Nebbaro should not be used during lactation.

4.7 Effects on ability to drive and use machines

Not relevant

Rare	acne, rash pruritic
Very rare	urticaria
General disorders and administration site conditions:
Rare	Ill-defined disorders
Investigations:
Very rare	white blood count increased, blood lactate dehydrogenase increased; Moderate elevation of transaminases has been reported in patients with hypertriglyceridaemia

4.9 Overdose

There are no special recommendations for overdose. Administer symptomatic treatment.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: omega-3-triglycerides, incl. other esters and acids ATC code: C10AX06

The omega-3 series polyunsaturated fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are essential fatty acids.

Nebbaro is active on the plasma lipids by lowering triglyceride levels as a result of a fall in VLDL (very low density lipoprotein). Nebbaro is also active on haemostasis and blood pressure.

Nebbaro reduces the synthesis of triglycerides in the liver because EPA and DHA are poor substrates for the enzymes responsible for triglyceride synthesis and they inhibit esterification of other fatty acids.

The increase in peroxisomes of P-oxidation of fatty acids in the liver also contributes to the fall in triglycerides, by reducing the quantity of free fatty acids available for their synthesis. The inhibition of this synthesis lowers VLDL.

Nebbaro increases LDL-cholesterol in some patients with hypertriglyceridaemia. A rise in HDL-cholesterol is only small, significantly smaller than seen after administration of fibrates, and not consistent.

The long-term lipid-lowering effect (after more than one year) is not known. Otherwise there is no strong evidence that lowering triglycerides reduces the risk of ischaemic heart disease.

During treatment with Nebbaro, there is a fall in thromboxane A2 production and a slight increase in bleeding time. No significant effect has been observed on the other coagulation factors.

11324 patients, with recent myocardial infarction MI (<3 months) and receiving a recommended preventative treatment associated with a Mediterranean diet, were randomised in the GISSI-Prevenzione study in order to receive omega-3-acid ethyl esters 90 (n=2836), vitamin E (n=2830), omega-3-acid ethyl esters 90 + vitamin E (n=2830) or no treatment (n=2828). GISSI-P was a multicentre, randomised, open-label study performed in Italy.

The results observed over 3.5 years, with omega-3-acid ethyl esters 90 1g/day, have shown a significant reduction of a combined endpoint including all-cause death, non fatal MI and non fatal stroke (decrease in relative risk of 15% [226] p=0.0226 in patients taking omega-3-acid ethyl esters 90 alone compared to control, and of 10% [1-18] p=0.0482 in patients taking omega-3-acid ethyl esters 90 with or without vitamin E). A reduction of the second pre-specified endpoint criteria including cardiovascular deaths, non fatal MI and non-fatal stroke has been shown (decrease in relative risk of 20% [5-32] p=0.0082 in patients taking omega-3-acid ethyl esters 90 alone compared to control, decrease in relative risk of 11% [1-20] p= 0.0526 in patients taking omega-3-acid ethyl esters 90 with or without vitamin E). The secondary analysis for each component of the primary endpoints has shown a significant reduction of all cause deaths and cardiovascular deaths, but no reduction of non fatal cardiovascular events or fatal and non fatal strokes.

5.2 Pharmacokinetic properties

During and after absorption, there are three main pathways for the metabolism of the omega-3 fatty acids:

The fatty acids are first transported to the liver where they are incorporated into various categories of lipoproteins and then channelled to the peripheral lipid stores;

The cell membrane phospholipids are replaced by lipoprotein phospholipids and the fatty acids can then act as precursors for various eicosanoids;

The majority is oxidised to meet energy requirements.

The concentration of the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in the plasma phospholipids corresponds to the EPA and DHA incorporated into the cell membranes.

Animal pharmacokinetic studies have shown that there is a complete hydrolysis of the ethyl ester accompanied by satisfactory absorption and incorporation of EPA and DHA into the plasma phospholipids and cholesterol esters.

5.3 Preclinical safety data

No safety issues have been identified relevant to human use at the recommended daily intake.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Capsule core: alpha-tocopherol (Ph. Eur.)

Capsule shell: gelatine, glycerol, purified water, medium-chain triglycerides, sunflower lecithin

6.2 Incompatibilities

Not applicable

6.3 Shelf life

3 years

6.4 Special precautions for storage

Do not store above 25°C. Do not freeze.

After first opening:

20caps-75ml: 20 days 28caps-75ml: 28 days 30caps-75ml: 30 days (20 oblong) 60caps-150ml 60 days (20 oblong) 60caps-150ml: 105 days 98caps-250ml: 98 days 100caps-250ml: 100 days 100caps-275ml: 100 days (20 oblong)

20 caps x 10 bottles-75ml: each bottle 20 days

6.5 Nature and contents of container

Bottles:

White (HDPE) bottles of 75 ml 150 ml or 275 ml with a LDPE push-fit tamper-evident cap or white (HDPE) bottles of 250 ml with a PE white flip-top cap.

Containing :

HDPE-bottles 75 ml

20 capsules

28 capsules

30 capsules

200 capsules (10 bottles x 20 capsules)

HDPE-bottles 150 ml 60 capsules

HDPE-bottles 250 ml 98 capsules 100 capsules

HDPE-bottles 275ml 100 capsules

Blister:

White, opaque PVC/PVDC/AL blister containing 20 capsules (10 capsules x 2 blisters).

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7 MARKETING AUTHORISATION HOLDER

Winthrop Pharmaceuticals UK Limited

One Onslow Street

Guildford

Surrey

GU1 4YS, UK

Trading as: Zentiva, One Onslow Street, Guildford, Surrey, GU1 4YS, UK

8    MARKETING AUTHORISATION NUMBER(S)

PL 17780/0658

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

21/01/2013

10 DATE OF REVISION OF THE TEXT

19/09/2014