Consumer medicine information

Lipigem

Gemfibrozil

BRAND INFORMATION

Brand name

Lipigem

Active ingredient

Gemfibrozil

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Lipigem.

What is in this leaflet

This leaflet answers some common questions about Lipigem.

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

All medicines have benefits and risks. Your doctor has weighed the risks of you taking Lipigem against the benefits expected for you.

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

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

What Lipigem is used for

What Lipigem does

Lipigem helps to lower high triglycerides, cholesterol and other fats. It should be used in conjunction with a low fat diet.

Lipigem is used in patients with pancreatitis (inflammation of the pancreas) to lower very high levels of triglycerides when strict diet control has not been adequate.

Lipigem can also be used to control fats in the blood in diabetic patients, and reduce the risk of heart diseases such as angina and heart attacks in patients with high levels of cholesterol.

What is cholesterol and triglycerides

Everyone has cholesterol in their blood. It is a type of blood fat needed by the body. Cholesterol has many functions; these include building cell membranes, making bile acids (which help digest food) and producing some essential hormones. However, too much cholesterol can be a problem.

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 levels become too high.

High cholesterol is more likely to occur with certain diseases or if you have a family history of high cholesterol.

There are different types of cholesterol. 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.

When you have high levels of 'bad' cholesterol in your blood, it may begin to '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 may become hard deposits, also called plaque, on the lining of your blood vessels, making it more difficult for the blood to flow through the narrowed space. Sometimes, the plaque can detach from the vessel wall and float in the bloodstream; it can then reach a smaller vessel and completely block it. This blocking of your blood vessels can lead to several types of blood vessel diseases, heart attack, angina and stroke.

There is another type of blood fat called triglyceride which is a source of energy. However, high levels of triglyceride can be associated with a low level of "good" cholesterol and may increase your risk of heart disease.

Lipigem does not reduce the cholesterol that comes from fat in food. Therefore, when you are taking Lipigem, you also need to follow a low fat diet and other measures, such as exercise and weight control.

In most people, there are no symptoms of high triglyceride or cholesterol levels. Your doctor can measure your levels with a simple blood test.

How Lipigem works

Lipigem contains the active ingredient, gemfibrozil. It belongs to a group of medicines called fibric acid derivatives or fibrates.

The exact way in which Lipigem works is not known, but it is thought to reduce the amount of triglycerides made in the body. In most patients, Lipigem reduces the 'bad' cholesterol and triglycerides and can actually raise the 'good' cholesterol.

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

Lipigem is not addictive.

Lipigem is available only with a doctor's prescription.

Lipigem is not recommended for use in children, as its safety and effectiveness in children have not been established.

Before you take Lipigem

When you must not take it

Do not take Lipigem if you have an allergy to Lipigem or:

  • any other medicine containing gemfibrozil, or
  • any of the ingredients listed at the end of this leaflet

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin

Do not take this medicine if you:

  • are pregnant, or are thinking of getting pregnant
  • are breast-feeding.
    Your baby may absorb this medicine in the womb or from breast milk and therefore there is a possibility of harm to your baby.
  • are taking medicine to treat diabetes such as repaglinide or rosiglitazone
  • are taking medicines containing simvastatin which is used to control cholesterol
  • have severe liver disease
  • have severe kidney disease
  • have gallstones or gallbladder disease
  • have experienced an increased sensitivity to the sun while taking a medicine called fibrates, a type of medicine used to prevent heart disease.

Symptoms of photosensitivity are sunburn (redness, itching, swelling and blistering of your skin) much quicker than normal.

Do not take Lipigem if the packaging is torn or shows signs of tampering.

If the product is past the expiry date or damaged, return it to your pharmacist.

Talk to your doctor if you are not sure whether you should start taking Lipigem.

Before you start to take it

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

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

  • liver problems
  • kidney problems
  • gall stones or gall bladder problems
  • diabetes
  • a thyroid condition
  • muscle pain, tenderness or weakness from other medicines used to treat triglycerides or cholesterol

If you have not told your doctor about any of the above, tell him/her before you start taking Lipigem.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including:

  • all prescription medicines
  • all medicines, vitamins, herbal supplements or natural therapies you buy without a prescription from a pharmacy, supermarket, naturopath or health food shop.

Some medicines may be affected by Lipigem or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines. Your doctor will advise you.

Tell your doctor or pharmacist if you are taking any of the following:

  • medicines which thin your blood such as warfarin. Your doctor may need to adjust the amount of blood thinning medication.
  • other medicines to treat high triglycerides or cholesterol. Your doctor may choose not to use Lipigem together with other prescription medicines for cholesterol lowering.
  • medicines used to treat diabetes such as repaglinide or rosiglitazones
  • medicines used to treat gout such as colchicine
  • medicines used for cancer treatment such as bexarotene.

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

Tell your doctor about any of the above before you take Lipigem.

How to take Lipigem

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

Ask your doctor or pharmacist for help if you do not understand the instructions on the bottle.

How much to take

Your doctor will tell you how many tablets you need to take each day. This may depend on your condition and whether or not you are taking any other medicines.

The normal dose of Lipigem is one 600 mg tablet twice a day.

How to take it

Swallow Lipigem whole with a glass of water or other liquid. Do not crush or chew the tablets.

When to take it

Take one tablet in the morning and one in the evening. The tablets are best taken on an empty stomach, half an hour before food. Taking the tablets half an hour before food means the medicine is absorbed faster into your body. If taking the tablets on an empty stomach makes you feel unwell, you may take them with food.

How long to take it

You may have to take this kind of medicine for the rest of your life.

Lipigem helps to regulate your levels of cholesterol 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 Lipigem, your levels may become abnormal again.

If you forget to take it

If you forget to take a dose, take it as soon as you remember, as long as it is more than 6 hours before your next dose.

If it is less than 6 hours before your next dose, skip the dose you missed. Take your following dose at the normal time.

Talk to your doctor or pharmacist if you are not sure whether to skip the dose or if you have trouble remembering when to take your medicine.

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

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice, or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have taken too much Lipigem. Do this even if there are no signs of discomfort or poisoning.

You may need urgent medical attention. Keep telephone numbers of these places handy.

While you are taking Lipigem

Things you must do

Keep all of your doctor's appointments so that your progress can be checked.

Your doctor will ask you to have regular blood tests. Your cholesterol and triglyceride levels need to be checked regularly while you are taking this medicine to make sure the medicine is working. Your liver function will also be tested from time to time while you are taking Lipigem to prevent unwanted side effects.

Tell your doctor and pharmacist that you are taking Lipigem if you are about to start on any new medicine.

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

Tell your doctor if you are pregnant, breast-feeding, or are thinking about becoming pregnant. If you become pregnant while taking Lipigem, stop taking Lipigem and contact your doctor immediately.

Things you must not do

Do not take Lipigem to treat any other complaints unless your doctor tells you to.

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

Things to be careful of

Be careful driving or operating machinery until you know how Lipigem affects you. Lipigem generally does not cause any problems with your ability to drive a car or operate machinery. However, as with many other medicines, Lipigem may cause dizziness in some people.

If you feel dizzy, do not drive, operate machinery, or do anything else that could be dangerous.

Things that would be helpful for your condition

Some self-help measures suggested below may assist your condition. Your doctor or pharmacist can give you more information about these measures.

  • Weight: While you are taking Lipigem, you need to follow a diet plan agreed to with your doctor. This may include measures to lose some weight.
  • Exercise: Regular exercise can help lower your cholesterol levels. It is important not to overdo it. Before commencing regular exercise you should consult your doctor who will suggest the most suitable exercise for you. If you experience any discomfort when exercising, see your doctor.
  • Alcohol: Excessive alcohol intake can raise your cholesterol levels or affect your liver function, which could increase the chance of you getting unwanted side effects. Your doctor may discuss with you whether you should reduce the amount of alcohol you drink.
  • Smoking: Smoking increases the risk of you suffering from heart problems. Your doctor may 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 Lipigem.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

Do not be alarmed by the 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 if...

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

  • heartburn
  • pain in the stomach
  • feeling sick (nausea)
  • vomiting
  • skin rash
  • constipation
  • change in taste
  • diarrhoea
  • tiredness
  • dizziness
  • headache
  • depression
  • decreased libido
  • tingling in the hands or feet

These are mild but more frequent side effects of Lipigem.

Tell your doctor as soon as possible if...

Tell your doctor as soon as possible if you notice any of the following:

  • painful, weak or tender muscles
  • signs of kidney disease such as passing little or no urine
  • signs of anaemia, such as tiredness, being short of breath and looking pale
  • signs of frequent infections such as fever, chills, sore throat or mouth ulcers
  • signs of liver disease such as yellowing of the skin and eyes and dark coloured urine.

These are serious but rare side effects. You may need urgent medical attention.

Go to hospital if...

Tell your doctor immediately or go to Accident and Emergency at your nearest hospital if you notice any of the following:

  • swelling of the face, lips, mouth, throat or neck which may cause difficulty in swallowing and breathing
  • temporary paralysis or weakness of muscles
  • very strong and sudden pain in the upper right part of the abdomen, recurrent painful attacks for several hours after meals, abdominal bloating (inflammation of the gall bladder).

The above list includes very serious side effects. You may need urgent medical attention or hospitalisation.

Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

Other side effects not listed above may also occur in some people.

Some of these side effects (for example, changes in white blood cells, low blood platelet count) can only be found when your doctor does tests from time to time to check your progress.

After taking Lipigem

Storage

Keep your Lipigem in the bottle until it is time to take them. If you take the tablets out of the bottle they may not keep well.

Keep your tablets in a cool dry place where the temperature stays below 25°C.

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

Keep your tablets where young children cannot reach them. A locked cupboard at least one-and-a-half metres off the ground is a good place to store medicines.

Disposal

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

Product description

What it looks like

Lipigem is a deep convex, white oval tablet marked "GL600" on one side and a Greek alpha symbol on the other.

Each bottle of Lipigem contains 60 tablets.

Ingredients

Lipigem contains 600 mg of gemfibrozil as the active ingredient.

It also contains the following inactive ingredients:

  • microcrystalline cellulose
  • pregelatinised maize starch
  • crospovidone
  • hyprolose
  • polysorbate 80
  • colloidal anhydrous silica
  • magnesium stearate
  • Opadry White OY-LS-28908

Lipigem also contains lactose and traces of sulfites.

Manufacturer/Supplier

Lipigem is supplied in Australia by:

Alphapharm Pty Ltd
Level 1, 30 The Bond
30-34 Hickson Road
Millers Point NSW 2000
www.mylan.com

Australian registration number:

AUST R 61430

This leaflet was prepared in December 2021.

Lipigem_cmi\Dec21/00

Published by MIMS January 2022

BRAND INFORMATION

Brand name

Lipigem

Active ingredient

Gemfibrozil

Schedule

S4

 

1 Name of Medicine

Gemfibrozil.

2 Qualitative and Quantitative Composition

Each Lipigem tablet contains 600 mg of gemfibrozil.

Excipient with known effects.

Lipigem also contains lactose and traces of sulfites.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Lipigem: 19 mm ± 0.3 mm x 9.2 mm ± 0.3 mm, deep convex, white, film coated oval shape tablet, debossed "GL600" on one side and "α" on the other.

4 Clinical Particulars

4.1 Therapeutic Indications

Lipigem is indicated as an adjunct to diet and other therapeutic measures for:
severe hypertriglyceridaemia (type IV and V) who present a risk of pancreatitis and who do not respond adequately to a determined dietary effort to control them;
dyslipidaemia associated with diabetes;
reduction of risk of coronary heart disease in patients with type IIa and IIb hypercholesterolaemia.
Because of potential toxicity such as malignancy, gall bladder disease, abdominal pain leading to appendectomy and other abdominal surgeries, an increased incidence in noncoronary mortality, and the 29% increase in all cause mortality seen with the chemically and pharmacologically related drug, clofibrate, the potential benefits of gemfibrozil in treating type IIa patients with elevations of LDL cholesterol only is not likely to outweigh the risks. In a subgroup analysis of patients in the Helsinki Heart Study with above median HDL cholesterol values at baseline (greater than 1.2 mmol/L), the incidence of serious coronary events was similar for gemfibrozil and placebo subgroups.

Note.

Lipigem is indicated when exercise, weight loss and specific dietary or other nondrug measures such as limiting alcohol intake have failed. Other medical disorders such as hypothyroidism and diabetes should be controlled as much as possible.
Periodic determination of serum lipids should be obtained during treatment with Lipigem the drug should be withdrawn or additional therapy instituted if the lipid response is deemed inadequate after three months.

4.2 Dose and Method of Administration

The recommended dose for adults is 600 mg twice daily (total daily dose 1200 mg) administered one half hour before the morning and evening meal.
For patients who cannot tolerate Lipigem when given half an hour before food, Lipigem may be taken with food. The bioavailability of gemfibrozil is higher when administered half an hour before food.

Use in patients with hepatic dysfunction.

Lipigem is contraindicated in patients with hepatic dysfunction (see Section 4.4 Special Warnings and Precautions for Use; Section 4.3 Contraindications).

Use in patients with renal dysfunction.

Lipigem is contraindicated in patients with severe renal dysfunction (see Section 4.4 Special Warnings and Precautions for Use; Section 4.3 Contraindications).

4.3 Contraindications

Lipigem is contraindicated in:
hypersensitivity to gemfibrozil or any of the excipients in the formulation;
hepatic dysfunction including primary biliary cirrhosis;
severe renal dysfunction;
pregnant or lactating women;
pre-existing gall bladder or biliary tract disease including gallstones (see Section 4.4 Special Warnings and Precautions for Use);
patients with previous history of photoallergy or phototoxic reaction during treatment with fibrates;
type I hyperlipoproteinaemia;
concomitant use with any of the following: simvastatin, repaglinide, dasabuvir.
(See Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.)

4.4 Special Warnings and Precautions for Use

Because of chemical, pharmacological and clinical similarities between gemfibrozil and clofibrate, the adverse findings with clofibrate in two large clinical studies may also apply to gemfibrozil. In the first of those studies, the Coronary Drug Project, 1000 subjects with previous myocardial infarction were treated for five years with clofibrate. There was no difference in mortality between the clofibrate treated subjects and 3000 placebo treated subjects, but twice as many clofibrate treated subjects developed cholelithiasis and cholecystitis requiring surgery. In the other study, conducted by the World Health Organisation (WHO), 5000 subjects without known coronary heart disease were treated with clofibrate for five years and followed one year beyond. There was a statistically significant, 29%, higher total mortality in the clofibrate treated than in a comparable placebo treated control group. The excess mortality was due to a 33% increase in noncardiovascular causes, including malignancy postcholecystectomy complications, and pancreatitis. The higher risk of clofibrate treated subjects for gall bladder disease was confirmed.
During the Helsinki Heart Study and in the one and a half years follow-up period since the trial was completed, mortality from any cause was 59 (2.9%) in the gemfibrozil group and 55 (2.7%) in the placebo group. Mortality from any cause during the double blind portion of the study was 44 deaths in the gemfibrozil group and 43 in the placebo group. Because of the more limited size of the Helsinki Heart Study, this result is not statistically significantly different from the 29% excess mortality seen in the clofibrate group in the separate WHO study. Noncoronary heart disease related mortality showed a 58% greater trend in the gemfibrozil group (43 versus 27 patients in the placebo group, p = 0.056).
In the Helsinki Heart Study, the incidence of total malignancies discovered during the trial and in the one and a half years since the trial was completed was 39 in the gemfibrozil group and 29 in the placebo group (difference not statistically significant). This includes 5 basal cell carcinomas in the gemfibrozil group and none in the placebo group (p = 0.06); historical data predicted an expected 4.7 cases in the placebo group. Gastrointestinal malignancies and deaths from malignancies were not statistically different between gemfibrozil and placebo subgroups. Follow-up of the Helsinki Heart Study participants will provide further information on cause specific mortality and cancer morbidity.
A gallstone prevalence substudy of 450 Helsinki Heart Study participants showed a trend toward greater prevalence of gallstones during the study within the gemfibrozil treatment group (7.5% versus 4.9% for the placebo group, a 55% excess for the gemfibrozil group). A trend toward a greater incidence of gall bladder surgery was observed for the gemfibrozil group (17 versus 11 subjects, a 54% excess).
This result did not differ statistically from the increased incidence of cholecystectomy observed in the WHO study in the group treated with clofibrate. Both clofibrate and gemfibrozil may increase cholesterol excretion into the bile leading to cholelithiasis. If cholelithiasis is suspected, gall bladder studies are indicated. Lipigem therapy should be discontinued if gallstones are found.
Since a reduction of mortality from coronary artery disease has not been demonstrated and because liver and interstitial cell testicular tumours were increased in rats, gemfibrozil should be administered only to those patients described in Therapeutic Indications. If a significant serum response is not obtained, Lipigem should be discontinued.

Muscle disorders (myopathy/rhabdomyolysis).

There have been reports of myositis, myopathy and markedly elevated creatine phosphokinase associated with gemfibrozil. Rhabdomyolysis has also been reported rarely.
Muscle damage must be considered in any patient presenting with diffuse myalgia, muscle tenderness and/or marked increase in muscle CPK levels (> 5 x ULN); under these conditions treatment must be discontinued.
A creatine phosphokinase (CPK) level should be measured before starting such a treatment in patients with predisposing factors for rhabdomyolysis as follows: renal impairment; hypothyroidism; alcohol abuse; age > 70 years; personal or family history of hereditary muscular disorders; previous history of muscular toxicity with another fibrate or HMG-CoA reductase inhibitor.

Concomitant anticoagulants.

Caution should be exercised when anticoagulants are given in conjunction with gemfibrozil. The dosage of the anticoagulant should be reduced to maintain the prothrombin time at the desired level to prevent bleeding complications. Frequent prothrombin determinations are advisable until it has been definitely determined that the prothrombin time has stabilised.

Concomitant HMG-CoA reductase inhibitors.

The concomitant administration of gemfibrozil with simvastatin is contraindicated. There have been reports of severe myositis with markedly elevated creatine kinase and myoglobinuria (rhabdomyolysis) when gemfibrozil and HMG-CoA reductase inhibitors were used concomitantly. In most subjects who have had an unsatisfactory lipid response to either drug alone, the possible benefit of combined therapy with HMG-CoA reductase inhibitors and gemfibrozil does not outweigh the risks of severe myopathy, rhabdomyolysis, and acute renal failure (see Section 4.3 Contraindications; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). The use of fibrates alone, including gemfibrozil, may occasionally be associated with myositis. Patients receiving gemfibrozil and complaining of muscle pain, tenderness or weakness should have prompt medical evaluation for myositis including serum creatine kinase level determination. If myositis is suspected or diagnosed, gemfibrozil therapy should be withdrawn.

Concomitant CYP2C8 substrates.

Gemfibrozil, an inhibitor of CYP2C8, may increase exposure of CYP2C8 substrates when administered concomitantly (see Section 4.3 Contraindications; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Cataracts.

Subcapsular bilateral cataracts occurred in 10%, and unilateral in 6.3% of male rats treated with gemfibrozil at 10 times the human dose.

Use in patients with cholelithiasis.

Gemfibrozil may increase cholesterol excretion into the bile leading to cholelithiasis. However, in the Helsinki Heart Study, gemfibrozil did not significantly increase the need for cholecystectomy compared to placebo. If cholelithiasis is suspected, gall bladder studies are indicated. Gemfibrozil therapy should be discontinued if gallstones are found.

Monitoring haematologic changes.

Mild haemoglobin, haemotocrit and white cell decreases have been observed occasionally on initiating gemfibrozil therapy. However, these levels stabilise during long-term administration. Rarely, severe anaemia, leukopaenia, thrombocytopaenia, eosinophilia and bone marrow hypoplasia have been reported. Therefore, periodic blood counts are recommended during the first 12 months of Lipigem administration.

Cardiac arrhythmias.

Although no clinically significant abnormalities occurred that could be attributed to gemfibrozil, the possibility exists that such abnormalities may occur.

Monitoring serum levels.

Initial therapy.

Before instituting Lipigem therapy, attempts should be made to control serum lipids with appropriate diet, exercise, weight loss in obese patients and control of any causes of secondary hyperlipidaemia such as diabetes mellitus or hypothyroidism.

Long-term therapy.

Because long-term administration of Lipigem is recommended, pretreatment clinical chemistry studies should be performed to ensure that the patient has elevated serum lipid or low HDL cholesterol levels. Periodic determinations of serum lipids and lipoproteins should be done during Lipigem administration, including measurement of LDL cholesterol/ HDL cholesterol ratio, particularly in type IV hyperlipoproteinaemic patients.

Continued therapy.

Periodic determination of serum lipids should be obtained, and the drug withdrawn if lipid response is inadequate after 3 months of therapy.

Peroxisome proliferation.

Electron microscopy studies have demonstrated a florid hepatic peroxisome proliferation following gemfibrozil administration to the male rat. An adequate study to test for peroxisome proliferation has not been done in humans, but changes in peroxisome morphology have been observed.

Use in hepatic impairment.

Hepatobiliary disease.

In patients with a past history of jaundice or hepatic disorder, Lipigem should be used with caution.

Use in the elderly.

No data available.

Paediatric use.

Safety and efficacy in children have not been established.

Effects on laboratory tests.

Monitoring liver function.

Abnormal liver function tests have been observed occasionally during gemfibrozil administration, including elevations of AST (SGOT), ALT (SGPT), LDH, alkaline phosphatase, creatine kinase (CK) and bilirubin. They are usually reversible when gemfibrozil is discontinued. Therefore, periodic liver function studies are recommended and Lipigem therapy should be terminated if abnormalities persist.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Anticoagulants.

Caution should be exercised when anticoagulants are given in conjunction with gemfibrozil. The dosage of the anticoagulant should be reduced to maintain the prothrombin time at the desired level to prevent bleeding complications. Frequent prothrombin determinations are advisable until it has stabilised (see Section 4.4 Special Warnings and Precautions for Use).

Hypoglycaemic agents.

There have been reports of hypoglycaemic reactions after concomitant use with gemfibrozil and hypoglycaemic agents (oral agents and insulin). Monitoring of glucose levels is recommended.

CYP2C8 substrates.

Gemfibrozil is an inhibitor of CYP2C8 and may increase exposure of drugs mainly metabolised by CYP2C8 (e.g. dabrafenib, loperamide, montelukast, paclitaxel, pioglitazone, rosiglitazone). Therefore, dosing reduction of drugs that are mainly metabolised by CYP2C8 enzyme may be required when gemfibrozil is used concomitantly.

Rosiglitazone.

The combination of gemfibrozil with rosiglitazone should be approached with caution. Coadministration with rosiglitazone has resulted in 2.3-fold increase in rosiglitazone systemic exposure, probably by inhibition of the CYP2C8 isozyme.

Repaglinide.

In healthy volunteers, coadministration of gemfibrozil with repaglinide increased the plasma concentration of repaglinide. The increase in the plasma concentration of repaglinide was more pronounced following the coadministration with the gemfibrozil-itraconazole combination. In addition, coadministration of gemfibrozil, or the gemfibrozil-itraconazole combination with repaglinide prolonged the hypoglycaemic effects of repaglinide. Therefore, coadministration of gemfibrozil and repaglinide increases the risk for severe hypoglycaemia and is contraindicated (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use).

Dasabuvir.

Coadministration of gemfibrozil with dasabuvir increased the plasma concentration of dasabuvir due to CYP2C8 inhibition. Increased dasabuvir exposure may increase the risk of QT prolongation, therefore, coadministration of gemfibrozil with dasabuvir is contraindicated (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use).

CYP enzymes, UGTA enzymes and OATP1B1 transporter.

In vitro studies have shown that gemfibrozil is an inhibitor of CYP2C8, CYP2C9, CYP2C19, CYP1A2, organic anion transporting polypeptide (OATP) 1B1 and UDP-glucuronosyltransferase (UGT) 1A1 and 1A3. Therefore, caution should be exercised with concomitant use of gemfibrozil with CYP2C8, CYP2C9, CYP2C19, CYP1A2, OATP1B1, UGT1A1 and UGT1A3 substrates.

Colchicine.

Risk of neuromuscular toxicity and rhabdomyolysis may be increased with concomitant administration of colchicine and gemfibrozil. This risk may be increased in the elderly and in patients with hepatic or renal dysfunction. Symptoms usually last between 1 week and several months after colchicine withdrawal. Clinical and biological monitoring is recommended, especially at the start of combined treatment.

HMG-CoA reductase.

The concomitant administration of gemfibrozil with simvastatin is contraindicated. There have been reports of severe myositis and myoglobinuria (rhabdomyolysis) when gemfibrozil and HMG-CoA reductase inhibitors were used concomitantly. It may be seen as early as 3 weeks after initiation of combined therapy or after several months. In most subjects who have had an unsatisfactory lipid response to either drug alone, the possible benefit of combined therapy with HMG-CoA reductase inhibitors and gemfibrozil does not outweigh the risks of severe myopathy, rhabdomyolysis, and acute renal failure. There is no assurance that periodic monitoring of creatine kinase will prevent the occurrence of severe myopathy and kidney damage (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use).
The risk of serious toxicity is increased if gemfibrozil is used concomitantly with other fibrates. Such combination therapy should be used with caution only in patients with severe combined dyslipidaemia who have high cardiovascular risk and no history of muscular disease. Patients should be monitored closely for signs of muscle toxicity, although toxicity may occur even in the presence of such monitoring.

Bexarotene.

Concomitant administration of gemfibrozil with bexarotene is not recommended. A population analysis of plasma bexarotene concentrations in patients with cutaneous T cell lymphoma (CTCL) indicated that concomitant administration of gemfibrozil resulted in substantial increases in plasma concentrations of bexarotene.

Bile acid binding resins.

Reduced bioavailability of gemfibrozil may result when given simultaneously with resin granule drugs such as colestipol. Administration of the drugs two hours or more apart is recommended.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Administration of approximately 2 times the human dose (based on surface area) to male rats for 10 weeks resulted in a dose related decrease of fertility. Subsequent studies demonstrated that this effect was reversed after a drug free period of about eight weeks and it was not transmitted to the offspring. Minor fetotoxicity was manifested by reduced birth rates observed at the high dose levels.
Gemfibrozil was administered in oral doses of approximately 95 and 325 mg/kg/day to male and female rats for 61 and 15 days respectively before mating. Dosing was continued through pregnancy and weaning of offspring. Gemfibrozil produced a dose related suppression of fertility but had no effect on length of gestation, duration of parturition, litter size, or embryonic or fetal wastage. Treated males were responsible for the reduced fertility rate, probably because of the marked suppression of weight gain they experienced.
(Category B3)
Reproduction studies have been performed in the rat at doses of 81 and 281 mg/kg/day and in the rabbit at 60 and 300 mg/kg/day. These studies have revealed no evidence of impaired fertility in females or harm to the fetus due to gemfibrozil. Minor fetotoxicity was manifested by reduced birth rates observed at the high dose levels. No significant malformations were found among almost 400 offspring from 36 litters of rats and 100 fetuses from 22 litters of rabbits.
There are no studies in pregnant women. In view of the fact that gemfibrozil is tumourigenic in male and female rats, the use of Lipigem in pregnancy should be reserved for those patients where the benefit clearly outweighs the possible risk to the patient or fetus.
The physiological hyperlipidaemia of pregnancy does not require treatment.
The safe use of gemfibrozil in lactation has not been established. It is not known whether gemfibrozil and its metabolites are excreted in human milk. Since many drugs are excreted in human milk, the patient should discontinue nursing before beginning gemfibrozil therapy.

4.7 Effects on Ability to Drive and Use Machines

No specific studies have been conducted to assess the direct effect of gemfibrozil on the ability to drive and use machines. However, adverse effects of gemfibrozil include dizziness and blurred vision which could affect the ability to drive or use machines (see Section 4.8 Adverse Effects (Undesirable Effects)).

4.8 Adverse Effects (Undesirable Effects)

In the double blind controlled phase of the Helsinki Heart Study, 2046 patients received gemfibrozil for up to five years. In that study, the following adverse reactions were statistically more frequent in subjects in the gemfibrozil group. See Tables 1 and 2.
Gall bladder surgery was performed in 0.9% of gemfibrozil and 0.5% of placebo subjects, a 64% excess, which is not statistically different from the excess of gall bladder surgery observed in the clofibrate compared to the placebo group in the WHO study.
Nervous system and special senses adverse reactions were more common in the gemfibrozil group. These included hypesthesia, paresthesia, and taste perversion. Other adverse reactions that were more common among the gemfibrozil treatment group subjects but where a causal relationship was not established included cataracts, peripheral vascular disease, and intracerebral haemorrhage.
From other studies it seems probable that gemfibrozil is causally related to the occurrence of musculoskeletal symptoms (see Section 4.4 Special Warnings and Precautions for Use), and to abnormal liver function tests and haematologic changes (see Section 4.4 Special Warnings and Precautions for Use).
Reports of viral and bacterial infections (common cold, cough, urinary tract infections) were more common in gemfibrozil treated patients in other controlled clinical trials of 805 patients.
Additional adverse reactions that have been reported for gemfibrozil are listed by system. These are categorised according to whether a causal relationship to treatment with gemfibrozil is probable or not established (see Table 3).
Additional adverse reactions that have been reported included photosensitivity and cholecystitis (see Section 4.4 Special Warnings and Precautions for Use).

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

Signs and symptoms.

Overdosage has been reported with gemfibrozil. Symptoms reported with overdosage were abdominal cramps, abnormal LFTs, diarrhoea, increased CPK, joint and muscle pain, nausea and vomiting. The patients fully recovered.

Treatment of overdosage.

Symptomatic supportive measures should be taken should overdosage occur. Monitor liver and renal function. There is no antidote.
Consider administration of activated charcoal in the event of potentially toxic ingestion. Activated charcoal is most effective when administered within 1 hour of ingestion. In patients who are not fully conscious, or have impaired gag reflex, consideration should be given to administering activated charcoal via nasogastric tube once the airway is protected.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Gemfibrozil's mechanism of action has not been definitely established. In man, gemfibrozil inhibits peripheral lipolysis and decreases the hepatic extraction of free fatty acids, thus reducing hepatic triglyceride production. Gemfibrozil also inhibits synthesis and increases clearance of apolipoprotein B, which is a carrier of VLDL, leading to a decrease in VLDL production.
Gemfibrozil is a lipid regulating agent which decreases serum triglycerides and total cholesterol, and increases high density lipoprotein cholesterol (HDL cholesterol). The lipid lowering changes occur primarily in the very low density lipoprotein (VLDL) fraction rich in triglycerides and to a lesser extent in the low density lipoprotein (LDL) fraction rich in cholesterol. Gemfibrozil treatment of patients with elevated triglycerides due to type IV hyperlipoproteinaemia may cause a rise in LDL cholesterol.
However, gemfibrozil increases the HDL cholesterol subfractions, HDL2 and HDL3, as well as apolipoproteins AI and AII.

Clinical trials.

Helsinki heart study.

Gemfibrozil is a lipid regulating agent which decreases serum triglycerides and very low density lipoprotein (VLDL) cholesterol, and increases high density lipoprotein (HDL) cholesterol. While modest decreases in total and low density lipoprotein (LDL) cholesterol may be observed with gemfibrozil therapy, treatment of patients with elevated triglycerides due to type IV hyperlipoproteinaemia often results in a rise in LDL cholesterol. LDL cholesterol levels in type IIb patients with elevations of both serum LDL cholesterol and triglycerides are, in general, minimally affected by gemfibrozil treatment; however, gemfibrozil usually raises HDL cholesterol significantly in this group. Gemfibrozil increases levels of high density lipoprotein (HDL) subfractions HDL2 and HDL3, as well as apolipoproteins AI and AII. Epidemiological studies have shown that both low HDL cholesterol and high LDL cholesterol are independent risk factors for coronary heart disease.
In the Helsinki Heart Study, a large randomised double blind, placebo controlled, primary prevention trial in 4081 male patients between the ages of 40 and 55, gemfibrozil therapy was associated with significant reductions in total plasma triglycerides and a significant increase in high density lipoprotein cholesterol. Moderate reductions in total plasma cholesterol and low density lipoprotein cholesterol were observed for the gemfibrozil treatment group as a whole, but the lipid response was heterogeneous, especially among different Fredrickson types. The study involved subjects with serum non-HDL cholesterol of over 5.2 mmol/L and no previous history of coronary heart disease. Over the five year study period, the gemfibrozil group experienced a 34% reduction in serious coronary events (sudden cardiac deaths plus fatal and nonfatal myocardial infarctions) compared to placebo. There was a 37% reduction in nonfatal myocardial infarction. There was no significant difference in death rate due to all causes between the gemfibrozil group and the placebo group. See Table 4.
The greatest reduction in the incidence of serious coronary events occurred in type IIb patients who had elevations of both LDL cholesterol and total plasma triglycerides. This subgroup of type IIb gemfibrozil group patients had a lower mean HDL cholesterol level at baseline than the type IIa subgroup that had elevations of LDL cholesterol and normal plasma triglycerides. The mean increase in HDL cholesterol in this study was 12.6% compared to placebo. It is not clear to what extent the findings of the Helsinki Heart Study can be extrapolated to other segments of the dyslipidaemic population not studied or to other lipid altering drugs. See Table 5.

5.2 Pharmacokinetic Properties

Absorption.

Gemfibrozil is well absorbed from the gastrointestinal tract after oral administration. Peak plasma levels occur in one to two hours with a biologic half-life of 1.5 hours following single doses and 1.3 hours following multiple doses. Plasma levels appear proportional to dose and do not demonstrate accumulation across time following multiple doses.

Metabolism.

Gemfibrozil mainly undergoes oxidation of a ring methyl group to successively form a hydroxymethyl and carboxyl metabolite.

Excretion.

Approximately seventy percent of the administered human dose is excreted in the urine, mostly as the glucuronide conjugate, with less than 2% excreted as unchanged gemfibrozil. Six percent of the dose is accounted for in the faeces.

5.3 Preclinical Safety Data

Genotoxicity.

No data available.

Carcinogenicity.

Long-term studies have been conducted in rats and mice at doses of 30 and 300 mg/kg/day. The incidence of benign liver nodules and liver carcinomas was significantly increased in high dose male rats. The incidence of liver carcinomas increased also in low dose males, but this increase was not statistically significant (p = 0.1). In high dose female rats, there was a significant increase in the combined incidence of benign and malignant liver neoplasms. In male and female mice, there were no statistically significant differences from controls in the incidence of liver tumours, but the doses tested were lower than those shown to be carcinogenic with other fibrates.
Male rats had a dose related and statistically significant increase of benign Leydig cell tumours at 1 and 10 times the human dose.

6 Pharmaceutical Particulars

6.1 List of Excipients

Microcrystalline cellulose, pregelatinised maize starch, crospovidone, hyprolose, polysorbate 80, colloidal anhydrous silica, magnesium stearate, Opadry White OY-LS-28908 (ARTG proprietary ingredient no. 2596).

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

Bottle pack: Store below 25°C.

6.5 Nature and Contents of Container

Pack size: 60 tablets.
Container: HDPE bottle.

6.6 Special Precautions for Disposal

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

6.7 Physicochemical Properties

Chemical structure.


Chemical name: 5-(2,5-dimethylphenoxy)- 2,2-dimethylpentanoic acid.
Strucural formula:
Molecular formula: C15H22O3.
Molecular weight: 250.35.
Gemfibrozil is a white, waxy powder which is stable under ordinary conditions. The melting point is 58-61°C. The solubility of gemfibrozil is 0.0019% (w/v) in water and in acid and over 1% in dilute base.

CAS number.

25812-30-0.

7 Medicine Schedule (Poisons Standard)

S4 (Prescription Only Medicine).

Summary Table of Changes