Consumer medicine information

Fenofibrate RBX

Fenofibrate

BRAND INFORMATION

Brand name

Fenofibrate RBX

Active ingredient

Fenofibrate

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Fenofibrate RBX.

SUMMARY CMI

FENOFIBRATE RBX

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using FENOFIBRATE RBX?

FENOFIBRATE RBX contains the active ingredient fenofibrate. Fenofibrate is used to help regulate cholesterol and triglycerides which are fat-like substances in the blood. For more information, see Section 1. Why am I using FENOFIBRATE RBX? in the full CMI.

2. What should I know before I use FENOFIBRATE RBX?

Do not use if you have ever had an allergic reaction to FENOFIBRATE RBX or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use FENOFIBRATE RBX? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with FENOFIBRATE RBX and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use FENOFIBRATE RBX?

The initial recommended dose is 145 mg daily, taken as 1 x 145 mg tablet. If you have mild to moderate kidney disease, your doctor may tell you to take a lower dose of Fenofibrate.

More instructions can be found in Section 4. How do I use FENOFIBRATE RBX? in the full CMI.

5. What should I know while using FENOFIBRATE RBX?

Things you should do
  • Remind any doctor, dentist, surgeon or pharmacist you visit that you are using FENOFIBRATE RBX.
  • Have your blood fats checked when requested by your doctor to make sure FENOFIBRATE RBX is working.
  • If you become pregnant while you are taking this medicine, tell your doctor or pharmacist immediately.
  • Reduce your saturated fat intake and eat plenty of fruit and vegetables.
  • Be active by maintaining an exercise program that your doctor or other health professional recommends.
Things you should not do
  • Do not use this medicine to treat any other complaints unless your doctor or pharmacist tells you to.
  • Do not give this medicine to anyone else, even if they have same condition as you.
  • Do not stop taking FENOFIBRATE RBX, or change the dosage, without checking with your doctor.
Driving or using machines
  • Be careful before you drive or use any machines or tools until you know how FENOFIBRATE RBX affects you.
Drinking alcohol
  • Drinking large quantities of alcohol may increase your chance of FENOFIBRATE RBX causing liver problems.
Looking after your medicine
  • Keep FENOFIBRATE RBX tablets in the pack until it is time to take them.
  • Store FENOFIBRATE RBX tablets below 25°C.

For more information, see Section 5. What should I know while using FENOFIBRATE RBX? in the full CMI.

6. Are there any side effects?

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

FENOFIBRATE RBX

Active ingredient(s): fenofibrate

Consumer Medicine Information (CMI)

This leaflet provides important information about using FENOFIBRATE RBX. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using FENOFIBRATE RBX.

Where to find information in this leaflet:

1. Why am I using FENOFIBRATE RBX?
2. What should I know before I use FENOFIBRATE RBX?
3. What if I am taking other medicines?
4. How do I use FENOFIBRTE RBX?
5. What should I know while using FENOFIBRATE RBX?
6. Are there any side effects?
7. Product details

1. Why am I using FENOFIBRATE RBX?

FENOFIBRATE RBX contains the active ingredient fenofibrate. FENOFIBRATE RBX belongs to group of class known as fibric acid derivatives.

FENOFIBRATE RBX works through the activation of a cell nuclear receptor called PPARα, which reduces the amount of triglycerides and bad cholesterol made in the body and increases the good cholesterol.

FENOFIBRATE RBX is used to help regulate cholesterol and triglycerides which are fat-like substances in the blood.

Everyone has cholesterol in their blood. It is a type of blood fat needed by the body for many things, such as making bile acids (which help digest food) and some hormones.

Cholesterol is present in many foods and is also made in your body by the liver. If your body does not balance the amount of cholesterol it needs with the amount of cholesterol eaten, then your cholesterol becomes too high. High cholesterol is more likely to occur with certain diseases or if you have a family history of high cholesterol.

When you have high levels of cholesterol it may 'stick' to the inside of your blood vessels instead of being carried to the parts of the body where it is needed.

Having high levels of ‘bad’ cholesterol and triglycerides can be a problem overtime, this can form hard areas called (plague) on the walls of your blood vessels making it more difficult for the blood to flow. This blocking of your blood vessels can lead to heart disease (such as heart attack and angina), and stroke

Cholesterol is carried through the body by different proteins, LDL and HDL. LDL cholesterol is the 'bad' cholesterol that can block your blood vessels. HDL cholesterol is the 'good' cholesterol that is thought to remove the 'bad' cholesterol from the blood vessels. In most patients, FENOFIBRATE RBX reduces the bad cholesterol and can actually raise the good cholesterol.

Patients with type 2 diabetes may have some level of diabetic retinopathy, a complication of diabetes that may lead to vision loss or impairment. FENOFIBRATE RBX has been shown to slow the progression of diabetic retinopathy in patients diagnosed with this condition.

FENOFIBRATE RBX does not reduce the cholesterol that comes from fat in food.

Therefore, when you are taking FENOFIBRATE RBX, you also need to follow a low fat diet and other measures, such as exercise and weight control.

2. What should I know before I use FENOFIBRATE RBX?

Warnings

Do not use FENOFIBRATE RBX if:

  • you are allergic to fenofibrate or any of the ingredients listed at the end of this leaflet.
    Always check the ingredients to make sure you can use this medicine.
  • any medicine containing gemfibrozil
  • it's after the expiry date printed on the pack or if the packaging is damaged or shows signs of tampering.

Some symptoms of an allergic reaction include skin rash, itching, shortness of breath or swelling of the face, lips or tongue, which may cause difficulty in swallowing or breathing.

Check with your doctor if you:

  • have any other medical conditions:
    - liver disease
    - severe kidney disease
    - disease of the gallbladder or pancreas
    - experienced muscular pain, tenderness or weakness from other medicines used to treat high cholesterol or triglycerides.
  • take any medicines for any other condition.
  • have any allergies to any other medicines, foods, preservatives or dyes.
  • experience allergic reaction to sunlight or UV light (photoallergy) during treatment with fibrates or ketoprofen
  • are currently taking another fibrates drug (e.g. gemfibrozil etc)
  • have any other medical conditions: kidney problems muscular aching, tenderness or weakness not caused by exercise. The risk of muscle breakdown is higher in some patients.

Tell your doctor if:

  • you are over 70 years old
  • you have kidney problems
  • you have decreased levels of a certain protein in the blood (hypoalbuminaemia) (seen in a blood test)
  • you have an underactive thyroid
  • you or a close family member has muscle problems which runs in the family
  • you drink large amounts of alcohol
  • you are taking medicines called statins to lower cholesterol such as simvastatin, atorvastatin pravastatin, rosuvastatin or fluvastatin
  • you have ever had muscle problems during treatment with statins or fibrates such as fenofibrate, bezafibrate or gemfibrozil.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Do not take this medicine if you are pregnant.

It may affect your developing baby if you take it during pregnancy.

Check with your doctor if you are pregnant or intend to become pregnant.

Do not breastfeed if you are taking this medicine.

It is not known whether the active ingredient in FENOFIBRATE RBX passes into breast milk. FENOFIBRATE RBX should not be administered to breastfeeding women.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

Children under 18

Do not give Fenofibrate RBX to anyone under the age of 18 years

The safety and effectiveness of FENOFIBRATE RBX in children has not been established.

Do not take it after the expiry date printed on the pack or if the packaging is damaged or shows signs of tampering.

If it has expired or is damaged return it to your pharmacist for disposal.

Do not take it if you have been told by your doctor that you have an intolerance to some sugars.

Contact your doctor before taking this medicinal product.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines may interfere with each other. These include:

  • oral anti-coagulants (medicines used to prevent blood clots)
  • other cholesterol regulating medicines including Statins (such as Pravastatin, Atorvastatin and Simvastatin) and fibrates
  • ciclosporin (a medicine which suppresses the immune system)
  • glitazones (medicines to reduce sugar levels)
  • phenylbutazone (a medicine to treat pain and inflammation)
  • oral hormonal contraceptives containing estrogen / ethinyl estradiol and norethindrone (birth control pills)
  • thiazides (fluid or water tablet)
  • beta blockers such as atenolol, carvedilol, timolol, metoprolol (used to treat high blood pressure, heart conditions, glaucoma and migraine)

These medicines may be affected by FENOFIBRATE RBX, or may affect how well it works. You may need to use different amounts of your medicine or take different medicines.

Your doctor has more information on medicines to be careful with or to avoid while taking Fenofibrate RBX.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect FENOFIBRATE RBX.

4. How do I use FENOFIBRATE RBX?

How much to take / use

The initial recommended dose is 145 mg daily, taken as 1 x 145 mg tablet.

If you have mild to moderate kidney disease, your doctor may tell you to take a lower dose of Fenofibrate.

Ask your doctor or pharmacist about properly taking Fenofibrate RBX.

Follow the instructions provided and use FENOFIBRATE RBX until your doctor tells you to stop.

When to take / use FENOFIBRATE RBX

FENOFIBRATE RBX can be taken at any time of the day, with or without food. Any dietary measures started before treatment with Fenofibrate RBX should be continued.

How to use FENOFIBRATE RBX

Swallow the tablet(s) whole with a full glass of water.

How long to take it

Continue taking your medicine for as long as your doctor or pharmacist tells you. FENOFIBRATE RBX helps to regulate your levels of cholesterol (both LDL and HDL) and triglycerides. It does not cure your condition. Therefore you must continue to take it as directed by your doctor if you expect to keep your levels controlled. If you stop taking Fenofibrate RBX, your levels may become abnormal again.

If you forget to use FENOFIBRATE RBX

FENOFIBRATE RBX should be used regularly at the same time each day Taking it at the same time each day will have the best effect. It will also help you remember when to take it.

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

Otherwise take it as soon as you remember and then go back to taking your medicine as you would normally.

Do not take a double dose to make up for the dose you missed.

This may increase the chance of getting an unwanted side effect.

If you use too much FENOFIBRATE RBX

If you think that you have used too much FENOFIBRATE RBX, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

Symptoms of an overdose may include:

  • diarrhoea
  • nausea

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while using FENOFIBRATE RBX?

Things you should do

Have your blood fats checked when requested by your doctor to make sure FENOFIBRATE RBX is working.

Remind any doctor, dentist or pharmacist or surgeons you visit that you are using FENOFIBRATE RBX.

If you become pregnant while you are taking this medicine, tell your doctor or pharmacist immediately.

Reduce your saturated fat intake and eat plenty of fruit and vegetables.

Doing this will help control your cholesterol (and triglyceride) levels, as well as your weight.

Be active by maintaining an exercise program that your doctor or other health professional recommends.

This will also help control your cholesterol levels and weight.

Things that may help you reduce the chance of coronary heart disease

Lowering high cholesterol can help reduce your chances of having Coronary Heart Disease (CHD). However, your chances of having CHD may be increased by several other factors including high blood pressure, cigarette smoking, diabetes, excess weight, family history of CHD, being a male and being a woman who has reached menopause.

Some self-help measures suggested below may help your condition and help reduce your chances of having CHD. Talk to your doctor, pharmacist, or dietician about these measures and for more information.

  • Diet - continue the low fat diet recommended by your doctor, dietician or pharmacist.
  • Weight - your doctor may advise you to lose weight if you are overweight.
  • Exercise - make exercise a part of your routine - walking is good. Ask your doctor for advice before starting exercise.
  • Smoking - your doctor will advise you to stop smoking.

Things you should not do

Do not use this medicine to treat any other complaints unless your doctor or pharmacist tells you to.

Do not give this medicine to anyone else, even if they have same condition as you.

Do not stop taking FENOFIBRATE RBX, or change the dosage, without checking with your doctor.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how FENOFIBRATE RBX affects you.

FENOFIBRATE RBX may cause dizziness in some people.

Drinking alcohol

Tell your doctor if you drink alcohol.

Avoid drinking large quantities of alcohol. Drinking large quantities of alcohol may increase your chance of FENOFIBRATE RBX causing liver problems.

Looking after your medicine

Keep the medicine where temperature stays around 25°C.

Follow the instructions in the carton on how to take care of your medicine properly.

Store it in a cool dry place away from moisture, heat or sunlight; for example, do not store it:

  • in the bathroom or near a sink, or
  • in the car or on window sills.

Keep it where young children cannot reach it.

A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines

When to discard your medicine

If your doctor or pharmacist tells you to stop taking this medicine, or the medicine has passed its expiry date, ask your pharmacist what to do with any that are left over.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effectsWhat to do
  • stomach pain or discomfort
  • backpain
  • headache
  • unusual tiredness or weakness
  • diarrhoea or constipation
  • nausea, vomiting
  • skin reaction, photosensitivity reactions
  • sore throat and discomfort when swallowing (pharyngitis)
  • runny or blocked nose, sneezing or facial pressure or pain (rhinitis)
  • sexual dysfunction
  • muscular pain or spasms
The above list includes the more common side effects of your medicine. They are usually mild and short-lived.
Laboratory abnormalities
  • increase in serum/blood creatinine, increase in creatinine phosphokinase, increase in blood urea.
  • decrease in haemoglobin and haematocrit, decrease in white blood cell (including leukocytes), decrease in platelets (a type of blood cells which help in blood clotting).
  • decrease in HDL-cholesterol levels
  • abnormality/increase in liver enzymes/liver function [elevated levels of serum transaminases (ALT and AST)].
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
  • severe blisters and bleeding in the lips, eyes, mouth, nose and genitals (Stevens Johnson Syndrome).
  • painful red areas, then large blisters and ends with peeling of layers of skin. This is accompanied by fever and chills, aching muscles and generally feeling unwell (Toxic epidermal necrolysis).
  • red, often itchy spots, similar to the rash of measles, which starts on the limbs and sometimes on the face and the rest of the body. The spots may blister or may progress to form raised, red, pale-centred marks you may have fever, sore throat and/or diarrhea(erythema multiforme)
    - difficulty in breathing
    - severe abdominal pain
    - chest pain
    - temporary paralysis of the muscles
    - yellowing of the skin and eyes and dark colored urine
    - blood clot in the leg causing pain, redness or swelling (deep vein thrombosis)
    - you pass little or no urine and experience drowsiness, nausea, vomiting, breathlessness
The above list includes very serious side effects. You may need urgent medical attention. These side effects are rare.		Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What FENOFIBRATE RBX contains

Active ingredient
(main ingredient)		fenofibrate
Other ingredients
(inactive ingredients)
  • sodium lauryl sulfate
  • hypromellose
  • sucrose
  • pregelatinized maize starch
  • microcrystalline cellulose
  • crospovidone
  • silicon dioxide
  • sodium stearyl fumarate opadry AMB OY-B-28920 white
Potential allergensNone

Do not take this medicine if you are allergic to any of these ingredients.

What FENOFIBRATE RBX looks like

FENOFIBRATE RBX comes in two types of tablets:

FENOFIBRATE RBX 48mg tablet (AUST R 233493): white to off-white, oval shaped, biconvex film coated tablets debossed with ‘RH 37’ on one side and plain on the other side.

The 48 mg strength is in blister packs of 60 tablets.

FENOFIBRATE RBX 145mg tablet (AUST R 233492): White to off-white, oval shaped, biconvex film coated tablets debossed with ‘RH 38’ on one side and plain on the other side.

The 145 mg strength is in blister packs of 30 tablets.

Who distributes FENOFIBRATE RBX

Sun Pharma ANZ Pty Ltd
12 Waterloo Road Macquarie Park
NSW 2113 Australia
Email: [email protected]
Tel: 1800 726 229

This leaflet was prepared in June 2024

Published by MIMS August 2024

BRAND INFORMATION

Brand name

Fenofibrate RBX

Active ingredient

Fenofibrate

Schedule

S4

 

1 Name of Medicine

Fenofibrate.

2 Qualitative and Quantitative Composition

Fenofibrate RBX tablets contain 48 mg or 145 mg of fenofibrate nanoparticles.

Excipients with known effect.

Sugars as sucrose.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Tablet.

Fenofibrate RBX 48 mg tablet.

White to off-white, oval shaped, biconvex film coated tablets debossed with 'RH 37' on one side and plain on the other side.

Fenofibrate RBX 145 mg tablet.

White to off-white, oval shaped, biconvex film coated tablets debossed with 'RH 38' on one side and plain on the other side.

4 Clinical Particulars

4.1 Therapeutic Indications

Fenofibrate RBX is indicated as an adjunct to diet in the treatment of:
hypercholesterolaemia;
types II, III, IV and V dyslipidaemia;
dyslipidaemia associated with type 2 diabetes.
Fenofibrate RBX is indicated for the reduction in the progression of diabetic retinopathy in patients with type 2 diabetes and existing diabetic retinopathy. Fenofibrate RBX does not replace the appropriate control of blood pressure, blood glucose and blood lipids in reducing the progression of diabetic retinopathy.

4.2 Dose and Method of Administration

Adults (dyslipidaemia and diabetic retinopathy).

Fenofibrate RBX is presented as a 145 mg tablet and a 48 mg tablet. The usual dose of fenofibrate is 1 x 145 mg tablet. Although 3 x 48 mg tablets are equivalent to 1 x 145 mg tablet, the 48 mg tablets are only recommended when a decreased dosage is required (see Section 4.2 Dose and Method of Administration, Renal impairment).
Patients should never be administered any combination of the 48 mg tablet and the 145 mg tablet of fenofibrate. There is no indication for use of fenofibrate dosages above 145 mg per day.
Fenofibrate RBX 145 mg and 48 mg tablets should be swallowed whole with a glass of water. Fenofibrate RBX 145 mg and 48 mg may be given at any time of the day, with or without food, but it is recommended that they be taken at the same time each day. Dietary measures instituted before therapy should be continued.

Elderly.

In elderly patients without renal impairment, the normal adult dose is recommended.

Renal impairment.

Dosage reduction is required in patients with renal impairment.
In moderate renal dysfunction (eGFR between 30 and 60 mL/min/1.73 m2 or creatinine clearance between 30 and 60 mL/min), start with one fenofibrate 48 mg tablet once daily. The dose may be increased to two fenofibrate 48 mg tablets daily only after evaluation of the effects on renal function and lipid levels at the lower dose.
In patients with severe renal dysfunction (eGFR < 30 mL/min/1.73 m2 or creatinine clearance < 30 mL/min), fenofibrate is contraindicated.

Hepatic disease.

Patients with hepatic disease have not been studied.

4.3 Contraindications

Fenofibrate is contra-indicated in:
children;
patients with liver dysfunction, including primary biliary cirrhosis and unexplained persistent liver function abnormality;
patients with severe renal dysfunction (estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73 m2);
patients with existing gallbladder disease;
co-administration with another fibrate;
patients hypersensitive to fenofibrate or any excipients and in cases of known photoallergy or phototoxic reactions during treatment with fibrates or ketoprofen;
chronic or acute pancreatitis with the exception of acute pancreatitis due to severe hypertriglyceridaemia.

4.4 Special Warnings and Precautions for Use

Initial therapy.

Laboratory analysis should be performed to ascertain that the lipid levels are consistently abnormal before instituting fenofibrate 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 (beta-blockers, thiazides, estrogens) should be discontinued or changed if possible, prior to consideration of triglyceride-lowering drug therapy.

Continued therapy.

Periodic determinations of serum lipids should be obtained during initial therapy in order to establish the lowest effective dose of fenofibrate. If an adequate response has not been achieved after three months of treatment with the maximum recommended dose of one 145 mg tablet per day, complementary or different therapeutic measures should be considered.

Mortality and coronary heart disease morbidity.

The effects of fenofibrate on coronary heart disease morbidity and mortality and non-cardiovascular mortality have not been established (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
Fenofibrate was not shown to reduce coronary heart disease morbidity and mortality in patients with type 2 diabetes mellitus overall.

Use in renal impairment.

Fenofibrate is contraindicated in patients with severe renal dysfunction (eGFR < 30 mL/min/1.73 m2) (see Section 4.3 Contraindications). In renal dysfunction (eGFR < 60 mL/min/1.73 m2 or CrCl < 60 mL/min) the dose of fenofibrate may need to be reduced (see Section 4.2 Dose and Method of Administration). This should also be considered in elderly patients with impaired renal function.

Serum creatinine.

Elevations in serum creatinine have been reported in patients on fenofibrate. These elevations tend to return to baseline following discontinuation of fenofibrate. The clinical significance of these observations is unknown. In the FIELD study, plasma creatinine remained on average 10-12 micromol/L higher on fenofibrate than in the placebo group from 4 months after randomisation until the end of the study. It is recommended that creatinine is measured during the first 3 months after initiation of treatment and thereafter periodically. Monitoring of creatinine should also be considered for patients taking fenofibrate at risk for renal insufficiency such as the elderly and patients with diabetes. Treatment should be interrupted in case of an increase in creatinine levels > 50% of upper limit of normal).

Use in hepatic impairment.

Increased liver function test abnormalities have been observed during fenofibrate therapy (see Section 4.8 Adverse Effects (Undesirable Effects)). Clinically significant liver injury has been reported rarely. Hepatocellular, chronic active and cholestatic hepatitis associated with fenofibrate therapy have been reported after exposures of weeks to several years. In extremely rare cases, cirrhosis has been reported in association with chronic active hepatitis. The incidence of liver function test abnormalities or hepatic injury when fenofibrate is administered in combination with other potentially hepatotoxic agents has not been studied.

Transaminases.

Fenofibrate at doses equivalent to 145 mg per day has been associated with increases in serum transaminases [AST (SGOT) or ALT (SGPT)]. When transaminase determinations were followed either after discontinuation of treatment or during continued treatment, a return to normal limits was usually observed. The incidence of increases in transaminases related to fenofibrate therapy appears to be dose related. Baseline and ongoing monitoring (every 3 months during the first 12 months of treatment and thereafter periodically) of liver function should be performed for the duration of fenofibrate therapy. Therapy should be discontinued if AST (SGOT) and ALT (SGPT) levels increase to more than 3 times the upper limit of the normal range. Also, if symptoms indicative of hepatitis occur (e.g. jaundice, pruritus), and diagnosis is confirmed by laboratory testing, fenofibrate therapy should be discontinued.

Cholelithiasis.

Fenofibrate, like clofibrate and gemfibrozil, may increase cholesterol excretion into the bile, leading to cholelithiasis. If cholelithiasis is suspected, gallbladder studies are indicated. Fenofibrate therapy should be discontinued if gallstones are found.

Myopathy.

There have been reports of elevations (sometimes marked) of creatine phosphokinase (CPK), myositis and myopathy associated with fibrates as well as other systemically absorbed lipid modifying drugs. Rhabdomyolysis has also been reported rarely. Patients receiving fenofibrate and complaining of muscle pain, tenderness or weakness should have prompt medical evaluation for myositis, including serum creatinine level determination. If myositis is suspected or if CPK rises to ≥ 5 times the upper limit of normal, fenofibrate therapy should be withdrawn. Patients with pre-disposing factors for myopathy and/or rhabdomyolysis, including age above 70 years old, personal or familial history of hereditary muscular disorders, renal impairment, hypoalbuminaemia, hypothyroidism and high alcohol intake, may be at an increased risk of developing rhabdomyolysis. For these patients, the putative benefits and risks of fenofibrate therapy should be carefully weighed up. The risk of serious muscle toxicity is increased if fenofibrate is used concomitantly with HMG-CoA reductase inhibitors or other fibrates (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Pancreatitis.

Pancreatitis has been reported in patients taking fenofibrate, gemfibrozil, and clofibrate. This occurrence may represent a failure of efficacy in patients with severe hypertriglyceridemia, a direct drug effect, or a secondary phenomenon mediated through biliary tract stone or sludge formation with obstruction of the common bile duct (see Section 4.8 Adverse Effects (Undesirable Effects)).

Estrogens.

For hyperlipidaemic patients taking estrogens or contraceptives containing estrogen it should be ascertained whether the hyperlipidaemia is of primary or secondary nature (possible elevation of lipid values caused by oral estrogen).
Patients with rare hereditary problems of fructose and galactose intolerance, the Lapp lactase deficiency, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.
Fenofibrate should not be taken in patients allergic to lecithin or related products due to the risk of hypersensitivity reactions.

Venothromboembolic disease.

In the FIELD trial, pulmonary embolus (PE) and deep vein thrombosis (DVT) were observed at higher rates in the fenofibrate- than the placebo-treated group. Of 9,795 patients enrolled in FIELD, there were 4,900 in the placebo group and 4,895 in the fenofibrate group. For DVT, there were 48 events (1%) in the placebo group and 67 (1.4%) in the fenofibrate group (p = 0.074); and for PE, there were 32 (0.7%) events in the placebo group and 53 (1.1%) in the fenofibrate group (p = 0.022).

Haematologic changes.

Mild to moderate haemoglobin, haematocrit, and white blood cell decreases have been observed in patients following initiation of fenofibrate therapy. However, these levels stabilise during long-term administration. Thrombocytopenia and agranulocytosis have been reported in individuals treated with fenofibrate. Periodic monitoring of red and white blood cell counts are recommended during the first 12 months of treatment.

Hypersensitivity reactions.

Acute hypersensitivity reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis requiring patient hospitalisation and treatment with steroids have been reported in individuals treated with fenofibrates. Urticaria was seen in 1.3 vs. 0%, and rash in 1.5 vs. 0.8% of fenofibrate and placebo patients respectively in controlled trials.

Paradoxical decreases in HDL cholesterol (HDL-C) levels.

There have been postmarketing and clinical trial reports of severe decreases in HDL-C levels (as low as 2 mg/dL) occurring in diabetic and non-diabetic patients initiated on fibrate therapy. The decrease in HDL-C is mirrored by a decrease in Apolipoprotein A1. This decrease has been reported to occur within 2 weeks to years after initiation of fibrate therapy. The HDL-C levels remain depressed until fibrate therapy has been withdrawn; the response to withdrawal of fibrate therapy is rapid and sustained. The clinical significance of this decrease in HDL-C is unknown. It is recommended that HDL-C levels be checked within the first few months after initiation of fibrate therapy. If a severely depressed HDL-C level is detected, fibrate therapy should be withdrawn, and the HDL-C level monitored until it has returned to baseline, and fibrate therapy should not be re-initiated.

Use in the elderly.

No data available.

Paediatric use.

No data available.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Oral anticoagulants.

Fenofibrate enhances oral anticoagulant effect and may increase risk of bleeding. It is recommended that the dose of anticoagulants is reduced by about one third at the start of treatment and then gradually adjusted if necessary according to INR (International Normalised Ratio) monitoring.

HMG-CoA reductase inhibitors.

There have been reports of severe myositis and myoglobinuria (rhabdomyolysis) when fenofibrate and HMG-CoA reductase inhibitors were used concurrently. The risk of serious muscle toxicity is increased if fenofibrate is used concomitantly with HMG-CoA reductase inhibitors. This reaction may occur at any point throughout therapy. Such combination therapy should be used with caution in patients with severe combined dyslipidaemia and high cardiovascular risk without any history of muscular disease and patients monitored closely for chronic signs of muscle toxicity although toxicity may occur even in the presence of such monitoring. However, data from fenofibrate HMG-CoA reductase inhibitors interaction studies have shown that, contrary to gemfibrozil, the coadministration of fenofibrate with pravastatin, atorvastatin and simvastatin is associated with moderate pharmacokinetic interactions.

Pravastatin.

Concomitant administration of fenofibrate (dose equivalent to fenofibrate 145 mg tablet once daily over 10 days) and pravastatin (40 mg once daily for 15 days) resulted in an increase of the mean AUC and Cmax for pravastatin by 27 and 36%, respectively and its metabolite 3-hydroxy-iso-pravastatin (which activity represents only 2.5 to 10% of the activity of pravastatin) by 39 and 55%, respectively. The clinical significance of this finding has not been studied. A previous single dose study showed that pravastatin had no effect on the pharmacokinetics of fenofibric acid.

Atorvastatin.

Concomitant administration over 10 days of fenofibrate (dose equivalent to fenofibrate 145 mg tablet once daily) and atorvastatin (20 mg once daily) resulted in a slight decrease in the mean atorvastatin AUC (14%). Atorvastatin Cmax was not affected by fenofibrate. The pharmacokinetics of fenofibric acid was not significantly modified by atorvastatin (-3% and 4% for AUC and Cmax, respectively).

Simvastatin.

Concomitant administration of fenofibrate (160 mg tablet once daily for 10 days) and simvastatin (single dose of 40 mg taken simultaneously with the last dose of fenofibrate) resulted in no significant change in simvastatin AUC (-8%), but in significant decrease in simvastatin acid AUC (-42%) the main active metabolite. However, recently published data, while showing similar PK results, provide data on HMG-CoA reductase inhibition, and show that despite the significant reduction in exposure to simvastatin acid, the pharmacological activity of simvastatin measured by active HMG-CoA reductase inhibitors, is not significantly impacted by concomitant treatment with fenofibrate. No significant effect was observed on Cmax. The pharmacokinetics of fenofibric acid was not significantly modified by simvastatin (+ 14% for Cmin).
Patients receiving fenofibrate and complaining of muscle pain, tenderness or weakness should have prompt medical evaluation for myositis, including serum creatinine level determination. If myositis is suspected or diagnosed, fenofibrate therapy should be withdrawn.

Fibrates.

The risk of serious toxicity is increased if fibrates are used concomitantly. Such combination therapy is contraindicated (see Section 4.3 Contraindications).

Ciclosporin.

Some severe cases of reversible renal function impairment have been reported during concomitant administration of fenofibrate and ciclosporin. The renal function of these patients must therefore be closely monitored and treatment with fenofibrate stopped in the case of a severe alteration of laboratory parameters.

Glitazones.

Some cases of reversible paradoxical reduction of HDL-cholesterol have been reported during concomitant administration of fenofibrate and glitazones. Therefore, it is recommended to monitor HDL-cholesterol if one of these components is added to the other and stopping of either therapy if HDL-cholesterol is too low.

Other concomitant therapy.

The potential for fenofibrate/fenofibric acid to affect the metabolism of other drugs has not been fully investigated in vitro or in vivo. Interactions cannot be predicted, and therefore, caution is therefore recommended if fenofibrate is combined with other drugs. In vitro studies using human liver microsomes indicate that fenofibrate and fenofibric acid are not inhibitors of cytochrome (CYP) P450 isoforms CYP3A4, CYP2D6, CYP2E1, or CYP1A2 dependent metabolism, weakly inhibits CYP2C19 and CYP2A6 dependent metabolism, and exhibits a mild-to-moderate inhibition of CYP2C9 dependent metabolism at therapeutic concentrations. In vitro interaction studies suggest displacement of phenylbutazone from plasma protein binding sites.
Patients coadministered fenofibrate and CYP2C19, CYP2A6, and especially CYP2C9 metabolised drugs with a narrow therapeutic index should be carefully monitored and, if necessary, dose adjustment of these drugs is recommended.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Fertility was not affected in rats at oral doses up to 300 mg/kg/day. Based on AUC after single PO dose in rats, the exposure at 300 mg/kg/day is approximately 16x the clinical exposure at steady state.
(Category B3)
There are no adequate and well-controlled studies in pregnant women. Embryofetal toxicity was observed in animals (see below). It is recommended that fenofibrate should not be administered to pregnant women.
In rats, fenofibrate treatment during organogenesis (gestation days 6-15) caused an increase in fetal abnormalities (domed head, rounded body, hunched shoulders, supernumerary ribs and misshapen vertebrae) at 300 mg/kg/day and stunting at 150 and 300 mg/kg/day (approximately 10x and 16x the clinical exposure based on AUC, respectively). When administered to rats during gestation and lactation, fenofibrate prolonged gestation, increased stillbirths and reduced birth weight, pup weight gain and survival at 300 mg/kg/day PO, and decreased birth weight, pup survival and pup weight gain at 75 mg/kg/day PO (approximately 6x the clinical exposure based on AUC). The above findings were associated with maternal toxicity (decreased body weight gain). In rabbits, fenofibrate caused abortion at 150 and 300 mg/kg/day and increased fetal deaths at 300 mg/kg/day, associated with maternal body weight loss at 300 mg/kg/day (not at 150 mg/kg/day). The oral doses of 150 and 300 mg/kg/day in rabbits were 12.5x and 25x the MRCD, based on BSA.
 It is not known whether fenofibrate is excreted into human milk. Fenofibrate should not be administrated to breastfeeding women.
As described above (see Use in pregnancy), fenofibrate treatment during gestation and lactation in rats at oral doses of 75 and 300 mg/kg/day decreased pup survival and pup weight gain.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.

4.8 Adverse Effects (Undesirable Effects)

The frequencies of adverse events are ranked according to the following: very common (> 1/10); common (> 1/100, < 1/10); uncommon (> 1/1,000, < 1/100); rare (> 1/10,000, < 1/1,000); very rare (< 1/10,000), including isolated reports and during post marketing experience+.

Gastrointestinal disorders.

Common: digestive, gastric or intestinal disorders (abdominal pain, nausea, vomiting, diarrhoea, and flatulence) moderate in severity.
Uncommon: pancreatitis*.
Post-marketing+: pancreatitis.

Hepato-biliary disorders.

Common: moderately elevated levels of serum transaminases.
Uncommon: development of gallstones.
Rare: episodes of hepatitis. When symptoms (e.g. jaundice, pruritus) indicative of hepatitis occur, laboratory tests are to be conducted for verification and fenofibrate discontinued, if applicable.
Post-marketing+: jaundice, complications of cholelithiasis (e.g. cholecystitis, cholangitis, biliary colic), hepatitis, cirrhosis.

Skin and subcutaneous tissue disorders.

Uncommon: rashes, pruritus, urticaria or photosensitivity reactions.
Rare: alopecia.
Very rare: cutaneous photosensitivity with erythema, vesiculation or nodulation on parts of the skin exposed to sunlight or artificial UV light (e.g. sunlamp) in individual cases (even after many months of uncomplicated use).
Post-marketing+: severe cutaneous reactions (e.g. erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis).

Musculoskeletal, connective tissue and bone disorders.

Uncommon: diffuse myalgia, myositis, muscular cramps and weakness.
Very rare: rhabdomyolysis.
Post-marketing+: muscle spasm, myalgia, rhabdomyolysis, arthralgia, asthenia.

Cardiovascular system.

Uncommon: thromboembolism (pulmonary embolism, deep vein thrombosis).

Blood and lymphatic system disorders.

Rare: decrease in haemoglobin and leukocytes.
Post-marketing+: anaemia, decreases in haemoglobin, decreases in haematocrit, white blood cell decreases.

Immune system disorders.

Rare: hypersensitivity.

Nervous system disorders.

Uncommon: headache.
Post-marketing+: fatigue.

Reproductive system and breast disorders.

Uncommon: sexual dysfunction.
Rare: sexual asthenia.

Respiratory, thoracic and mediastinal disorders.

Very rare: interstitial pneumopathies.
Post-marketing+: interstitial lung disease.

Renal disorders.

Post-marketing+: acute renal failure.

Investigations.

Common: increases in serum homocysteine level**.
Uncommon: increases in serum creatinine and urea.
Post-marketing+: severely depressed HDL-cholesterol levels.

Notes.

+ Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
* In the FIELD-study, a randomised placebo-controlled trial performed in 9795 patients with type 2 diabetes mellitus, a statistically significant increase in pancreatitis cases was observed in patients receiving fenofibrate versus patients receiving placebo (0.8% versus 0.5%; p = 0.031).
** In the FIELD study, the average increase in serum homocysteine level in patients treated with fenofibrate was 6.5 micromol/L and was reversible on discontinuation of fenofibrate treatment. The increased risk of venous thrombotic events may be related to the increased homocysteine level.
Adverse events reported by 1% or more of patients with dyslipidaemia or type 2 diabetes treated with fenofibrate during double blind, placebo-controlled trials, regardless of causality, at the time of registration are listed in Table 1.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

There is no specific treatment for overdose with fenofibrate. General supportive care of the patient is indicated, including monitoring of vital signs and observation of clinical status, should an overdose occur. Because fenofibrate is highly bound to plasma proteins, haemodialysis should not be considered.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

The majority of clinical trials have been conducted with a micronised fenofibrate 200 mg capsule formulation. The micronised fenofibrate 200 mg capsule, 3 tablets of 48 mg and the 145 mg tablet have been demonstrated to be bioequivalent in a bioequivalence study carried out under fed conditions.

5.1 Pharmacodynamic Properties

Mechanism of action.

The lipid-lowering properties of fenofibrate seen in clinical practice have been explained in vivo in transgenic mice and in human hepatocyte cultures by the activation of peroxisome proliferator activated receptor type α (PPARα). Through this mechanism, fenofibrate increases lipolysis and elimination of triglyceride-rich particles from plasma by activating lipoprotein lipase and reducing production of Apoprotein C-III. Activation of PPARα also induces an increase in the synthesis of Apoproteins A-I, A-II and of HDL cholesterol.
The above stated effects of fenofibrate on lipoproteins lead to a reduction in the very low- and low-density (VLDL and LDL) fractions containing Apoprotein B and to an increase in the high density lipoprotein (HDL) fraction containing Apoprotein AI and AII.
In addition, through modulation of the synthesis and the catabolism of VLDL fractions fenofibrate increases the LDL clearance and reduces small dense LDL, the levels of which are elevated in the atherogenic lipoprotein phenotype, a common disorder in patients at risk of coronary heart disease. Extravascular deposits of cholesterol (tendinous and tuberous xanthoma) may be markedly reduced or even entirely eliminated during fenofibrate therapy. The uricosuric effect of fenofibrate leading to reduction in uric acid levels of approximately 25% should be of additional benefit in those dyslipidaemic patients with hyperuricaemia.

Clinical trials.

Dyslipidaemia. During clinical trials with fenofibrate total cholesterol was reduced by 20 to 25%, triglycerides by 40-50% and HDL cholesterol was increased by 10 to 30%. In hypercholesterolaemic patients, where LDL cholesterol levels were reduced by 20 to 30%, the overall effect on cholesterol resulted in a decrease in the ratios of total cholesterol to HDL cholesterol, LDL cholesterol to HDL cholesterol, and Apo B to Apo AI, all of which are markers of atherogenic risk. Patients with raised levels of fibrinogen treated with fenofibrate have shown significant reductions in this parameter, as have those with raised levels of Lp(a). Other inflammatory markers such as C Reactive Protein are reduced with fenofibrate treatment.
The long-term effects of fenofibrate were assessed in an open-label, prospective six month trial that examined the efficacy of fenofibrate 145 mg/day equivalent (see Section 5 Pharmacological Properties) in 1334 patients with type IIa, IIb or IV dyslipidaemia. The results of the trial are summarized in Table 2.

DAIS study.

The Diabetes Atherosclerosis Intervention Study (DAIS) was a double-blind, randomised, placebo-controlled study in 418 patients with type 2 diabetes and hyperlipoproteinaemia. Patients were randomised to fenofibrate 145 mg/day equivalent (see Section 5 Pharmacological Properties) or placebo for at least 3 years. Patients had stable glycaemic control, (mean HbA1c 7.5%), mild lipoprotein abnormalities typical of type 2 diabetes and at least one visible coronary lesion.
The primary efficacy criterion was the mean segment diameter averaged per patient across all pairs of analysable coronary segments, a criterion believed to reflect diffuse coronary artery disease. Among the secondary criteria were other angiographic parameters (mean diameter averaged per segment and minimum segment diameter averaged per patient and per segment).
Results (see Table 3) showed that fenofibrate significantly reduces the angiographic progression of focal coronary atherosclerosis characterized by minimum segment diameter and percent diameter stenosis in patients with type 2 diabetes and hyperlipoproteinaemia (mean total cholesterol 5.57 mmol/L, triglycerides 2.54 mmol/L, LDL cholesterol 3.37 mmol/L and HDL-cholesterol 1.03 mmol/L).
The reduction in the progression of angiographic coronary disease was associated with a reduction in lipid parameters (total cholesterol, LDL-cholesterol, triglycerides, TC/HDL-C), and an increase in HDL-cholesterol and therefore results apply to patients who respond to treatment. This trial did not assess whether the observed change in angiographic endpoints, particularly in asymptomatic patients, had any effect on cardiovascular events or mortality.

FIELD.

The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study was a 5-year randomised, placebo-controlled study of 9795 patients with type 2 diabetes mellitus treated with fenofibrate.
Fenofibrate demonstrated a non-significant 11% relative reduction in the primary outcome of coronary heart disease events (hazard ratio [HR] 0.89, 95% CI 0.75-1.05, p=0.16) and a significant 11% relative reduction in the secondary outcome of total cardiovascular disease events (HR 0.89 [0.80-0.99], p = 0.04). There was a non-significant 11% (HR 1.11 [0.95-1.29], p = 0.18) and 19% (HR 1.19, [0.90-1.57]; p = 0.22) relative increase in total and coronary heart disease mortality, respectively, with fenofibrate as compared with placebo.

ACCORD-Lipid.

The Action to Control Cardiovascular Risk in Diabetes Lipid (ACCORD Lipid) trial was a randomised placebo-controlled study of 5518 patients with type 2 diabetes mellitus on background statin therapy treated with fenofibrate.
Fenofibrate plus simvastatin therapy did not show any significant differences compared to simvastatin monotherapy in the composite primary outcome of non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death (hazard ratio [HR] 0.92, 95% CI: 0.79-1.08, p = 0.32; absolute risk reduction: 0.74%). In the pre-specified subgroup of dyslipidaemic patients, defined as those in the lowest tertile of HDL-C (≤ 0.88 mmol/L) and highest tertile of TG (≥ 2.3 mmol/L) at baseline, fenofibrate plus simvastatin therapy demonstrated a 31% relative reduction compared to simvastatin monotherapy for the composite primary outcome (hazard ratio [HR] 0.69, 95% CI: 0.49-0.97, p = 0.03; absolute risk reduction: 4.95%). Another pre-specified subgroup analysis identified a statistically significant treatment-by-gender interaction (p = 0.01) indicating a possible treatment benefit of combination therapy in men (p = 0.037) but a potentially higher risk for the primary outcome in women treated with combination therapy compared to simvastatin monotherapy (p = 0.069). This was not observed in the aforementioned subgroup of patients with dyslipidaemia but there was also no clear evidence of benefit in dyslipidaemic women treated with fenofibrate plus simvastatin, and a possible harmful effect in this subgroup could not be excluded.
Epidemiological studies have demonstrated a positive correlation between increased serum lipid levels and an increased risk of coronary heart disease. The control of such dyslipidaemias forms the rationale for treatment with fenofibrate. There is evidence that treatment with fibrates may reduce coronary heart disease events but fenofibrate has not been shown to decrease all-cause mortality in the primary or secondary prevention of cardiovascular disease. Fenofibrate was not shown to reduce coronary heart disease morbidity and mortality in patients with type 2 diabetes mellitus overall.
Diabetic retinopathy.

FIELD-PSP-DR.

In the (FIELD) study information on laser treatment for diabetic retinopathy - a pre-specified tertiary endpoint of the main study - was collected at each study visit for all study patients. The requirement for first laser treatment for all retinopathy was significantly lower in the fenofibrate group than in the placebo group (164 [3.4%] vs. 238 [4.9%]; hazard ratio [HR] 0.69, 95% CI 0.56-0.84; p=0.0002; absolute risk reduction [ARR] 1.5% [0.7-2.3]). The reduction in the need for laser in the fenofibrate treatment group was not related to baseline plasma lipid concentrations.
In the FIELD sub-study of 1012 patients (FIELD-PSP-DR), standardised retinal photographs were taken and graded according to the Early Treatment Diabetic Retinopathy Study (ETDRS) criteria to determine the cumulative incidence of diabetic retinopathy and its component lesions. Analyses were by intention to treat. The primary endpoint of 2-step progression of EDTRS grade did not differ significantly between the two groups overall (46 [9.6%] patients on fenofibrate vs. 57 [12.3%] on placebo; p=0.19) or in the subset of patients without pre-existing retinopathy (43 [11.4%] vs. 43 [11.7%]; p=0.87). By contrast, in patients with pre-existing retinopathy, significantly fewer patients on fenofibrate had a 2-step progression than did those on placebo (three [3.1%] patients vs. 14 [14.6%]; p=0.004). The composite endpoint of 2-step progression of EDTRS grade, macular oedema, or laser treatments was significantly lower in fenofibrate treated group (HR 0.66, 95% CI 0.47-0.94; p=0.022).

ACCORD-Eye.

A subgroup of 1593 participants of the ACCORD-Lipid trial (ACCORD-Eye) was evaluated for the effects of treatment with fenofibrate and simvastatin compared to treatment with simvastatin plus a placebo at 4 years on the progression of diabetic retinopathy by 3 or more steps on the Early Treatment Diabetic Retinopathy Study (ETDRS) Severity Scale (as assessed from seven-field stereoscopic fundus photographs, with 17 possible steps and a higher number of steps indicating greater severity) or the development of diabetic retinopathy necessitating laser photocoagulation or vitrectomy. The progression of diabetic retinopathy was 6.5% with fenofibrate for intensive dyslipidaemia therapy, versus 10.2% with placebo for standard dyslipidaemia therapy (adjusted odds ratio, 0.60; 95% CI, 0.42 to 0.87; P = 0.006). It was concluded that intensive combination treatment of dyslipidaemia reduced the rate of progression of diabetic retinopathy.
An integrated analysis was performed from patient individual data from the FIELD study and the published information from ACCORD-Eye publications. The combined primary endpoint of ACCORD-Eye was applied to FIELD i.e. 3-step ETDRS severity scale, photocoagulation or vitrectomy for proliferative diabetic retinopathy. The two studies were homogeneous (fixed effect model applicable) and showed an overall 60% reduction in the progression of diabetic retinopathy, OR: 0.40; 95% CI (0.26-0.61) for the subjects with existing DR at baseline.
Neither FIELD nor ACCORD-Eye showed an improvement in visual acuity.
FIELD and ACCORD excluded patients with severe non-proliferative and proliferative diabetic retinopathy at baseline.

5.2 Pharmacokinetic Properties

Absorption.

Unlike that observed for fenofibrate 160 mg tablets and 67 mg and 200 mg capsules, in which the absorption of fenofibrate is increased significantly when administered with food, the rate and extent of absorption of fenofibrate from fenofibrate 48 mg and 145 mg tablets (Lipidil) is reported to be not significantly affected by food. A food-effect study involving administration of the new 145 mg tablet formulation of fenofibrate (Lipidil) to healthy male and female subjects under fasting conditions and with a high fat meal indicated that exposure (AUC and Cmax) to fenofibric acid is not affected by food. Therefore, fenofibrate 145 mg and 48 mg tablets may be taken without regard to meals.
The nanosized formulation of fenofibrate 145 mg (Lipidil) and fenofibrate 160 mg are bioequivalent in respect of AUC and Cmax under low fat fed conditions. The average Cmax of fenofibrate 145 mg (Lipidil) is 15.5% higher than that from 160 mg tablets and its median Tmax significantly shorter (2.9 and 3.7 hours for fenofibrate 145 mg and 160 mg, respectively).
Fenofibrate RBX 145 mg has been shown to be bioequivalent to the nanosized formulation of Lipidil 145 mg in respect of AUC and Cmax under fasted conditions.

Distribution and metabolism.

After oral administration, fenofibrate is rapidly hydrolysed by esterases to the active metabolite fenofibric acid. Unchanged fenofibrate is not recovered in the plasma. Fenofibric acid, the major plasma metabolite, is highly bound to plasma albumin (more than 99%).
Peak plasma concentration occurs after a mean period of 2 to 4 hours following administration of Fenofibrate RBX 145 mg fenofibrate tablets. Kinetic studies after administration of repeated doses show the absence of accumulation of the product. The plasma half-life of elimination of fenofibric acid is approximately 20 hours.

Excretion.

The product is mainly excreted in the urine: 70% in 24 hours and 88% in 6 days, at which time total excretion in urine and faeces reaches 93%. Fenofibrate is mainly excreted as fenofibric acid and its derived glucuronoconjugate. Fenofibric acid is not eliminated during haemodialysis.

5.3 Preclinical Safety Data

Genotoxicity.

Fenofibrate did not induce gene mutation in bacteria or mouse lymphoma cells in vitro, or chromosome aberration in CHO cells in vitro or rat bone marrow cells in vivo. Nor did it cause DNA damage in rat hepatocytes in vitro.

Carcinogenicity.

The carcinogenic potential of fenofibrate was investigated in mice and rats. In two carcinogenicity studies in rats at dietary doses of 10, 45 and 200 mg/kg/day (24-month study) or 10 and 60 mg/kg/day (27-month study), the incidence of liver carcinomas and/or adenomas was increased at ≥ 45 mg/kg/day (≥ 4x the clinical exposure, based on AUC) in the 24-month study. Increased incidence of pancreatic acinar cell tumours (carcinomas and/or adenomas) occurred in males in both studies at ≥ 45 mg/kg/day and increased testicular Leydig cell tumours in both studies at ≥ 60 mg/kg/day (≥ 5x the clinical exposure, based on AUC). In two mouse studies at fenofibrate doses 10, 45 and 200 mg/kg/day (18-month study) or 10, 60 and 200 mg/kg/day (21-month study), the incidence of liver tumours (hepatocellular adenomas and/or carcinomas) was increased in the 18-month study at all doses (0.2x to 4.5x the maximum recommended clinical dose (MRCD) adjusted for body surface area (BSA)), and in the 21-month study at ≥ 60 mg/kg/day (1.4x the MRCD adjusted for BSA). Electron microscopy studies have demonstrated peroxisomal proliferation following fenofibrate administration to the rat. These changes are specific to small rodents and have not been observed in other animal species. This is of no relevance to therapeutic use in man.

6 Pharmaceutical Particulars

6.1 List of Excipients

Sodium lauryl sulfate, hypromellose, sucrose, pregelatinised maize starch, microcrystalline cellulose, crospovidone, silicon dioxide, sodium stearyl fumarate and Opadry AMB OY-B-28920 White (Proprietary Ingredient No. 10274).

6.2 Incompatibilities

See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

6.3 Shelf Life

Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C. Protect from moisture.

6.5 Nature and Contents of Container

Fenofibrate RBX 48 mg tablets are supplied in PVdc/PE/PVC blister packs containing 60 tablets and HDPE bottle packs containing 30 and 60 tablets.
Fenofibrate RBX 145 mg tablets are supplied in PVdc/PE/PVC blister packs containing 30 tablets and HDPE bottle packs containing 30 tablets.
Not all pack sizes and presentations are marketed in Australia.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Chemical structure.

Fenofibrate is a fibric acid derivative. Fenofibrate is a white or almost white crystalline powder, stable under ordinary conditions and practically insoluble in water. The melting point is 79-82°C. The partition-coefficient is log POW = 5.2.
Chemical Name: 2-[4-(4-chlorobenzoyl) phenoxy]-2-methyl- propanoic acid, 1-methylethyl ester.
Empirical Formula: C20H21O4Cl.
Molecular Weight: 360.83.

CAS number.

49562-28-9.

7 Medicine Schedule (Poisons Standard)

Schedule 4.

Summary Table of Changes