Consumer medicine information

Fenofibrate Cipla

Fenofibrate

BRAND INFORMATION

Brand name

Fenofibrate Cipla

Active ingredient

Fenofibrate

Schedule

S4

 

Consumer medicine information (CMI) leaflet

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

What is in this leaflet

This leaflet answers some common questions about Fenofibrate Cipla.

It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor or pharmacist has weighed the risks of you taking this medicine against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What Fenofibrate Cipla is used for

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

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.

Over time, this can form hard areas (called plaque) 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 carriedthrough 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 Cipla reduces the bad cholesterol and can actually raise the good cholesterol.

Fenofibrate Cipla does not reduce the cholesterol that comes from fat in food.

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

How Fenofibrate Cipla works

Fenofibrate Cipla 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 Cipla belongs to a group of medicines known as fibric acid derivatives

Ask your doctor if you have any questions about why it has been prescribed for you. Your doctor may have prescribed it for another purpose.

This medicine is not addictive.

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

Before you take Fenofibrate Cipla

When you must not take it

Do not take Fenofibrate Cipla if you have an allergy to:

  • any medicine containing fenofibrate
  • any fibrates (such as gemfibrozil)
  • ketoprofen
  • any of the ingredients listed at the end of this leaflet

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.

Do not take this medicine if you are pregnant. It may affect your developing baby if you take it during pregnancy.

Do not breastfeed if you are taking this medicine. The active ingredient in Fenofibrate Cipla passes into breast milk and there is a possibility your baby may be affected.

Do not take this medicine if you have:

  • liver disease
  • severe kidney disease.
  • disease of the gallbladder or pancreas
  • experienced muscle pain, tenderness or weakness from other medicines used to treat high cholesterol or triglycerides.

Do not take this medicine if you are taking another fibrate.

Do not take this medicine if you are allergic to peanuts, peanut oil, soy lecithin or related products.

Do not give Fenofibrate Cipla to anyone under the age of 18 years. The safety and effectiveness of Fenofibrate Cipla 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.

Before you start to take it

Tell your doctor if you have any allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor or pharmacist if you have or have had any of the following medical conditions:

  • kidney problems
  • muscular aching, tenderness or weakness not caused by exercise

Tell your doctor if you are pregnant, intend to become pregnant. or are breast-feeding. Your doctor can discuss the risks and benefits involved.

If you have not told your doctor about any of the above, tell them before you take Fenofibrate Cipla.

Taking other medicines

Tell your doctor or pharmacist if you aretaking any other medicines, including any that you buy without a prescription from your pharmacy, supermarket or health food store.

Some medicines may interfere with each other. These include:

  • oral anti-coagulants (medicines used to prevent blood clots)
  • other cholesterol regulating medicines including fibrates
  • ciclosporin (a medicine which suppresses the immune system)
  • glitazones (medicines to reduce sugar levels)

These medicines may be affected by Fenofibrate Cipla 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 Cipla.

How to take Fenofibrate Cipla

Follow all directions given to you by your doctor or pharmacist carefully. They may differ from the information contained in this leaflet.

If you do not understand the instructions on the box, ask your doctor or pharmacist for help.

How much to take

The initial recommended dose is 145 mg daily, taken as 1 x 145 mg or 3 x 48 mg tablets, your doctor may prescribe a lower dose if you have kidney problems.

How to take it

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

When to take it

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

Take Fenofibrate Cipla at about 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.

How long to take it

Continue taking your medicine for as long as your doctor or pharmacist tells you. Fenofibrate Cipla 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 Cipla, your levels may become abnormal again.

If you forget 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 that you missed. This may increase the chance of getting an unwanted side effect.

If you are not sure what to do, ask your doctor or pharmacist.

If you have trouble remembering when to take your medicine, ask your pharmacist for advice.

If you take too much (overdose)

Immediately telephone your doctor, or the Poisons Information Centre (telephone Australia 13 11 26 or New Zealand 0800 764766), or go to Accident and Emergency at your nearest hospital, if you think you or anyone else may have taken too much Fenofibrate Cipla. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

Symptoms of an overdose may include:

  • diarrhoea
  • nausea

Fenofibrate Cipla contains lactose. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product.

While you are using Fenofibrate Cipla

Things you must do

Have your blood fats checked when requested by your doctor to make sure Fenofibrate Cipla is working.

If you are about to be started on any new medicine, remind your doctor and pharmacist thatyou are taking Fenofibrate Cipla.

Tell any other doctors, dentists and pharmacists who treat you that you are taking this medicine.

If you are going to have surgery, tell the surgeon that you are taking this medicine.

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

Things you must 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 the same condition as you.

Do not stop taking Fenofibrate Cipla, or change the dosage, without checking with your doctor.

Things to be careful of

Be careful driving or operating machinery until you know how Fenofibrate Cipla affects you. This medicine may cause dizziness in some people.

Avoid drinking large quantities of alcohol while you are taking this medicine. Drinking large quantities of alcohol may increase your chance of Fenofibrate Cipla causing liver problems.

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 ofCHD, 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 healthy 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.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking Fenofibrate Cipla. It helps most people with high cholesterol, but it may have unwanted side effects in a few people. All medicines have some unwanted side effects.Sometimes they are serious, but most of the time they are not. You may need medical attention if you get some of the side-effects.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor or pharmacist if you notice any of the following and they worry you:

  • stomach pain or discomfort
  • back pain
  • headache
  • muscular pain or spasms
  • unusual tiredness or weakness
  • diarrhoea or constipation
  • nausea
  • skin reactions, photosensitivity reactions
  • sexual dysfunction

The above list includes the more common side effects of your medicine. They are usually mild and short-lived.

If any of the following happen, tell your doctor immediately or go to Accident and Emergency at your nearest hospital:

  • difficulty in breathing
  • severe abdominal pain
  • chest pain
  • temporary paralysis of the muscles
  • yellowing of the skin and eyes and dark coloured urine

The above list includes very serious side effects. You may need urgent medical attention. These side effects are rare.

Tell your doctor or pharmacist if you notice anything else that is making you feel unwell. Other side effects not listed above may occur in some people.

After using Fenofibrate Cipla

Storage

Keep your tablets in the pack until it is time to take them. If you take the tablets out of the box or the blister pack they may not keep well.

Keep the medicine in a cool, dry place where the temperature stays below 30°C

Do not store it or any other medicine in the bathroom, near a sink, or on a windowsill. Do not leave it in the car. Heat and dampness can destroy some medicines.

Keep it where children cannot reach it. A locked cupboard at least one-and-a- half metres above the ground is a good place to store medicines.

Disposal

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.

Product description

What it looks like

Fenofibrate Cipla 48 mg film-coated tablet

Fenofibrate Cipla 48 mg film-coated tablets are yellow coloured, oval shaped, biconvex film-coated tablet debossed with ‘cipla’ on one side and code '459' on other side.

The 48 mg strength is available in packs of 60 in blister strip (PVC/PE/PVDC/Aluminium).

Fenofibrate Cipla 145 mg film-coated tablet

Fenofibrate Cipla 145 mg film-coated tablets are white to off white coloured, oval shaped, biconvex film coated tablet, debrosed with 'cipla' on one side and code '458' on other side.

The 145 mg strength is available in boxes of 10 and 30 tablets.

Ingredients

Fenofibrate Cipla 48 mg and 145 mg contains fenofibrate as the active ingredient:

The tablets also contain the following inactive ingredients:

  • sucrose
  • hypromellose
  • sodium lauryl sulfate
  • lactose monohydrate
  • crospovidone
  • silicified microcrystalline cellulose
  • docusate sodium
  • magnesium stearate-part hydrolyzed
  • polyvinyl alcohol
  • titanium dioxide
  • talc
  • lecithin
  • xanthan gum

Fenofibrate Cipla 48 mg filmcoated tablets also contains the following inactive ingredients in tablet coat

  • indigo carmine (aluminium lake)
  • D&C yellow #10 aluminium lake
  • sunset yellow FCF (aluminium lake)

Manufacturer/Distributor/Supplier

Fenofibrate Cipla is supplied in Australia by:

Cipla Australia Pty Ltd.,
Level 1 / 132-136 Albert Road,
SOUTH MELBOURNE VIC 3205
[email protected]
Phone: 1800 569 074

Australian Registration Number

Fenofibrate Cipla 48 mg film-coated tablets [AUST R 323817]

Fenofibrate Cipla 145 mg film-coated tablets [AUST R 288059]

Date of preparation

This leaflet was last revised on September 2020.

Published by MIMS November 2020

BRAND INFORMATION

Brand name

Fenofibrate Cipla

Active ingredient

Fenofibrate

Schedule

S4

 

1 Name of Medicine

Fenofibrate.

2 Qualitative and Quantitative Composition

Fenofibrate Cipla 48 mg film-coated tablet.

Each tablet of Fenofibrate Cipla for oral administration contains 48 mg of fenofibrate.

Excipients with known effect.

Contains sugar (as lactose monohydrate).

Fenofibrate Cipla 145 mg film-coated tablet.

Each tablet of Fenofibrate Cipla for oral administration contains 145 mg of fenofibrate.

Excipients with known effect.

Contains sugars (as lactose and sucrose).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Fenofibrate Cipla 48 mg film-coated tablet.

Fenofibrate Cipla 48 mg film-coated tablets are yellow coloured, oval shaped, biconvex film-coated tablet, debossed with 'cipla' on one side and code '459' on other side.

Fenofibrate Cipla 145 mg film-coated tablet.

Fenofibrate Cipla 145 mg film-coated tablets are white to off white coloured, oval shaped, biconvex film coated tablet, debossed with 'cipla' on one side and code '458' on other side.

4 Clinical Particulars

4.1 Therapeutic Indications

Fenofibrate Cipla 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.

4.2 Dose and Method of Administration

Adults (dyslipidaemia).

Fenofibrate Cipla is presented as a 145 mg and 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 Cipla 145 mg and 48 mg tablets should be swallowed whole with a glass of water. Fenofibrate Cipla 145 mg and 48 mg tablets 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 Cipla 48 mg tablet once daily. The dose may be increased to two Fenofibrate Cipla 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 impairment.

Patients with hepatic disease have not been studied.

4.3 Contraindications

Fenofibrate Cipla is contraindicated 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;
patients allergic to peanuts or arachis oil or soya lecithin or related products due to risk of hypersensitivity reactions.

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, FIELD, ACCORD-Lipid). Fenofibrate was not shown to reduce coronary heart disease morbidity and mortality in patients with type 2 diabetes mellitus overall.

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).

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 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.

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.

Use in the elderly.

No data available.

Paediatric use.

No data available.

Effects on laboratory tests.

No data available.

Lactose intolerance.

Fenofibrate Cipla contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactose deficiency or glucose-galactose malabsorption should not take this medicinal product.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Oral anti-coagulants.

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 co-administration 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 co-administered 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 in the 'Use in pregnancy' section, 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.

Investigation.

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 Poison Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

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.

Pharmacodynamics.

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 5.1 Pharmacodynamic 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 5.1 Pharmacodynamic 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% Cl 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.

5.2 Pharmacokinetic Properties

Absorption and bioavailability.

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 is not significantly affected by food. A food-effect study involving administration of the new 145 mg tablet formulation of fenofibrate 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 and fenofibrate 160 mg are bioequivalent in respect of AUC and Cmax under low fat fed conditions. The average Cmax of fenofibrate 145 mg 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).

Distribution.

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 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

Tablets core.

Sucrose, hypromellose, sodium lauryl sulfate, lactose monohydrate, silicified microcrystalline cellulose, crospovidone, docusate sodium, magnesium stearate.

Tablets coating.

Fenofibrate Cipla 48 mg film-coated tablet.

Polyvinyl alcohol-part hydrolyzed, titanium dioxide, talc, lecithin, xanthan gum, indigo carmine (aluminium lake), D and C yellow #10 (aluminium lake), Sunset yellow FCF (aluminium lake).

Fenofibrate Cipla 145 mg film-coated tablet.

Polyvinyl alcohol-part hydrolyzed, titanium dioxide, talc, lecithin (soya), xanthan gum.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In 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 30°C.

6.5 Nature and Contents of Container

Fenofibrate Cipla 48 mg film-coated tablet.

Packs of 60 in blister strip (PVC/PE/PVDC/Aluminium).

Fenofibrate Cipla 145 mg film-coated tablet.

Packs of 10 and 30 tablets in blister strip (PVC/PE/PVDC/Aluminium).

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Fenofibrate is white or almost white crystalline powder. Practically insoluble in water, very soluble in methylene chloride, slightly soluble in alcohol. The melting point is 79-82°C.
Fenofibrate is a fibric acid derivative.
The chemical name for fenofibrate is 2-[4-(4-chlorobenzoyl) phenoxy]-2-methyl-propanoic acid, 1-methylethyl ester.

Chemical structure.


Molecular formula: C20H21O4Cl.
Molecular weight: 360.83.

CAS number.

49562-28-9.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription Only Medicine.

Summary Table of Changes