Consumer medicine information

Gemhexal Tablets

Gemfibrozil

BRAND INFORMATION

Brand name

Gemhexal Tablets

Active ingredient

Gemfibrozil

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Gemhexal Tablets.

WHAT IS IN THIS LEAFLET

This leaflet answers some common questions about Gemhexal.

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 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 GEMHEXAL IS USED FOR

This medicine is used to lower high cholesterol, triglycerides and other fats in the blood.

Gemhexal does not reduce the cholesterol that comes from fat in food. Therefore, other measures such as a low fat diet, exercise and weight control need to be followed.

It contains the active ingredient gemfibrozil.

Gemfibrozil belongs to a group of medicines called fibric acid derivatives (fibrates).

It is not exactly known how gemfibrozil works. It is thought to work by lowering "bad" (LDL) cholesterol and triglyceride levels while raising "good" (HDL) cholesterol. Lowering "bad" cholesterol and triglyceride levels helps to keep your blood vessels unblocked. This reduces the risk of heart and blood vessel disease, heart attacks, angina and strokes.

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.

This medicine is not addictive.

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

There is not enough information to recommend the use of this medicine for children.

BEFORE YOU TAKE GEMHEXAL

When you must not take it

Do not take this medicine if you have an allergy to:

  • gemfibrozil, the active ingredient, or to any of the other ingredients listed at the end of this leaflet under Product Description.
  • any other similar medicines.

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 have or have had any of the following medical conditions:

  • liver problems
  • severe kidney problems
  • gallstones or gall bladder disease
  • Type I hyperlipoproteinaemia, a rare enzyme condition where you have high levels of fat in the blood
  • increased sensitivity to the sun resulting in allergic reactions (photoallergy) during treatment with fibrates.

Do not take this medicine if you are also taking any of the following medicines:

  • repaglinide or rosiglitazone , a medicine used to treat diabetes
  • cerivastatin (Lipobay), a medicine used to lower cholesterol levels.

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 Gemhexal may pass into breast milk and there is a possibility that your baby may be affected.

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering.

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

If you are not sure whether you should start taking this medicine, talk to your doctor.

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:

  • diabetes
  • liver problems
  • kidney problems
  • gallstones or gall bladder problems
  • a thyroid condition
  • muscle pain, tenderness or weakness from other medicines used to treat high levels of cholesterol or triglycerides
  • jaundice, yellowing of the skin and/or eyes.

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

Taking other medicines

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

Some medicines and Gemhexal may interfere with each other. These include:

  • other fibrates, such as fenofibrate
  • other medicines used to treat high cholesterol or triglyceride levels. Examples include atorvastatin, simvastatin, fluvastatin, pravastatin, cerivastatin and colestipol
  • medicines used to treat diabetes, such as repaglinide, rosiglitazone, other oral antidiabetic medicines or insulin
  • warfarin, a medicine used to prevent blood clots
  • bexarotene, a medicine used to treat some cancers.

These medicines may be affected by Gemhexal 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 and pharmacist have more information on medicines to be careful with or avoid while taking this medicine.

HOW TO TAKE GEMHEXAL

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, ask your doctor or pharmacist for help.

How much to take

The usual dose for this medicine is one tablet twice a day, one tablet in the morning and one tablet in the evening.

Ask your doctor or pharmacist if you are unsure of the correct dose for you.

They will tell you exactly how much to take.

Follow the instructions they give you.

If you take the wrong dose, Gemhexal may not work as well and your problem may not improve.

How to take it

Swallow the tablets whole with a full glass of water.

When to take Gemhexal

Take your medicine 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.

The tablets are best taken on an empty stomach, half an hour before food.

Food can interfere with the absorption of this medicine.

However, if taking the tablets on an empty stomach makes you feel unwell, you may take them with food.

How long to take Gemhexal

Continue taking your medicine for as long as your doctor tells you.

This medicine helps to control your condition, but does not cure it. It is important to keep taking your medicine even if you feel well.

If you forget to take it

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

If it is less than 6 hours before your next dose, skip the dose you missed and take your next dose when you are meant to.

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

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

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

If you have trouble remembering to take your medicine, ask your pharmacist for some hints.

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 Gemhexal. Do this even if there are no signs of discomfort or poisoning.

You may need urgent medical attention.

Symptoms of an overdose may include abdominal cramps, diarrhoea, joint and muscle pain, nausea and vomiting.

WHILE YOU ARE TAKING GEMHEXAL

Things you must do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking Gemhexal.

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

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

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

Your doctor may do some blood tests from time to time to make sure the medicine is working and to prevent unwanted side effects such as liver or blood problems.

Things you must not do

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

Do not give your medicine 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 Gemhexal affects you.

This medicine may cause dizziness in some people. If you have any of these symptoms, do not drive, operate machinery or do anything else that could be dangerous.

Be careful when drinking alcohol while you are taking this medicine.

If you drink alcohol, dizziness may be worse.

SIDE EFFECTS

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking Gemhexal.

All medicines can have side effects. Sometimes they are serious, 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 the following lists of 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 and abdominal pain
  • heartburn
  • constipation or diarrhoea
  • nausea (feeling sick) and/or vomiting
  • tiredness, dizziness, headache
  • changes in taste
  • decreased libido
  • skin rash
  • depression.

These are mild but more common side effects of the medicine.

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

  • 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
  • swelling of the face, lips, mouth or throat which may cause difficulty in swallowing or breathing
  • severe pain, discomfort and bloating in the abdomen
  • painful, weak or tender muscles or joints
  • tingling in the hands or feet
  • signs of kidney and liver problems, such as passing little or no urine
  • temporary paralysis or weakness of muscles.

The above list includes serious side effects. You may need urgent medical attention or hospitalisation. 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 also occur in some people.

AFTER TAKING GEMHEXAL

Storage

Keep your medicine in the original container.

If you take it out of its original container it may not keep well.

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

Do not store Gemhexal 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 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 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

Gemhexal 600mg - white oblong tablets.

Available in blisters and bottles of 60 tablets.

Ingredients

Active ingredients:

  • Gemhexal 600mg - 600mg gemfibrozil.

Inactive ingredients:

  • lactose
  • microcrystalline cellulose
  • maize starch
  • hydroxypropylcellulose
  • sodium starch glycollate
  • magnesium stearate
  • polysorbate 80
  • colloidal anhydrous silica
  • hypromellose
  • titanium dioxide
  • macrogol 4000.

Supplier

Sandoz Pty Ltd
ABN 60 075 449 553
19 Harris Street
Pyrmont NSW 2009
Australia
Tel: 1800 634 500

This leaflet was revised in May 2012.

Australian Register Numbers
600mg tablets: AUST R 64873 (blisters)
600mg tablets: AUST R 62537 (bottles)

BRAND INFORMATION

Brand name

Gemhexal Tablets

Active ingredient

Gemfibrozil

Schedule

S4

 

Name of the medicine

Gemfibrozil.

Excipients.

Lactose, microcrystalline cellulose, maize starch, hydroxypropyl cellulose, sodium starch glycollate, magnesium stearate, polysorbate 80, anhydrous colloidal silica, hypromellose, titanium dioxide, macrogol 4000.

Description

Chemical name: 5-(2,5 -dimethylphenoxy)-2,2 -dimethylpentanoic acid. Molecular formula: C15H22O3. MW: 250.35. CAS: 25812-30-0. Melting point: 58 to 61°C. Gemfibrozil is a nonhalogenated phenoxypentanoic acid. It is a white, waxy powder which is stable under ordinary conditions. Its solubility is 0.0019% (w/v) in water and in acid, and over 1% in dilute base.

Pharmacology

Pharmacodynamics.

Gemfibrozil is a lipid regulating agent which decreases serum triglycerides and total cholesterol, and increases high density lipoprotein (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. Its mechanism of action has not been definitely established in humans. 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. Epidemiological studies have shown that both low HDL cholesterol and high LDL cholesterol are independent risk factors for coronary heart disease.

Pharmacokinetics.

Absorption.

Gemfibrozil is well absorbed from the gastrointestinal tract after oral administration. Peak plasma levels occur in 1 to 2 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 70% 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 (6%) of the dose is accounted for in the faeces.

Clinical Trials

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, therapy with gemfibrozil was associated with significant reductions in total plasma triglycerides and a significant reduction in high density lipoprotein cholesterol. (See Table 1.) 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. (See Table 2.) There was a 37% reduction in nonfatal myocardial infarction. There was no significant difference in death due to all causes between the gemfibrozil group and the placebo group.
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.

Indications

An adjunct to diet and other therapeutic measures for the following.
Severe hypertriglyceridaemia (types IV and V) in persons 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 type IIb hypercholesterolaemia.
Because of potential toxicity, e.g. malignancy, gall bladder disease, abdominal pain leading to appendicectomy 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.

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

Contraindications

Hepatic or severe renal dysfunction, including primary biliary cirrhosis.
Pre-existing gall bladder disease or biliary tract disease including gallstones (see Precautions).
Hypersensitivity to gemfibrozil or any of the excipients in the formulation.
Pregnant or lactating women.
Type I hyperlipoproteinaemia.
Concurrent use of cerivastatin, due to a risk of myopathy and rhabdomyolysis (see Interactions with Other Medicines).
Concomitant use with repaglinide (see Interactions with Other Medicines).
Patients with previous history of photoallergy or phototoxic reaction during treatment with fibrates.

Precautions

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 Organization (WHO), 5000 subjects without known coronary heart disease were treated with clofibrate for five years and followed for 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 1.5 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 1.5 years since the trial was completed was 39 in the gemfibrozil group and 29 in the placebo group (difference not statistically different). 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 a 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. Gemfibrozil 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 the Indications section. If a significant serum response is not obtained, gemfibrozil should be discontinued.

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 been stabilised.

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 creatine phosphokinase (CPK) levels (≥ 5 x ULN); under these conditions treatment must be discontinued.
A 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 HMG-CoA reductase inhibitors.

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. The benefit of further alterations in lipid levels by the combined use of gemfibrozil and HMG-CoA reductase inhibitors should be carefully weighed against the potential risks of such combinations and clinical monitoring is recommended.
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 Interactions with Other Medicines). 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.
The risk of serious toxicity is increased if gemfibrozil is used concomitantly with other fibrates. Such combination therapy should be used with caution and 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.

Use in patients with gallstone formation.

Gemfibrozil may increase cholesterol excretion into the bile raising the potential for gallstone formation. Cases of cholelithiasis have been reported with gemfibrozil therapy. If cholelithiasis is suspected, gallbladder studies are indicated. Gemfibrozil therapy should be discontinued if gallstones are found.

Monitoring serum lipids.

Periodic determinations of serum lipids are necessary during therapy with gemfibrozil. Sometimes a paradoxical increase of (total and LDL) cholesterol can occur in patients with hypertriglyceridaemia. If the response is insufficient after 3 months of therapy at recommended doses treatment should be discontinued and alternative treatment methods should be considered.

Monitoring liver function.

Elevated levels of ALAT, ASAT, alkaline phosphatase, LDH, CK and bilirubin have been reported. These are usually reversible when gemfibrozil is discontinued. Therefore liver function tests should be performed periodically. Gemfibrozil therapy should be terminated if abnormalities persist.

Monitoring blood counts.

Periodic blood count determinations are recommended during the first 12 months of gemfibrozil administration. Anaemia, leucopenia, thrombocytopenia, eosinophilia and bone marrow hypoplasia have been reported rarely.

Cataracts.

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

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.

Haematological changes.

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

Hepatic function.

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

Hepatobiliary disease.

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

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 gemfibrozil 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, e.g. diabetes mellitus or hypothyroidism.

Long-term therapy.

Because long-term administration of gemfibrozil 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 gemfibrozil administration, including measurement of the 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.

Carcinogenesis, mutagenesis, impairment of fertility.

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 also increased 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.
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 8 weeks and it was not transmitted to the offspring. Minor foetotoxicity was manifested by reduced birth rates observed at the high dose levels.
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.

Effect on fertility.

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.

Use in pregnancy.

(Category B3)
The physiological hyperlipidaemia of pregnancy does not require treatment.
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 foetus due to gemfibrozil. Minor foetotoxicity 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 foetuses from 22 litters of rabbits.
There are no studies in pregnant women. In view of the fact that gemfibrozil is tumorigenic in male and female rats, the use of gemfibrozil in pregnancy should be reserved for those patients in whom the benefit clearly outweighs the possible risk to the patient or foetus.
Gemfibrozil should not be used during pregnancy unless it is clearly necessary.

Use in lactation.

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. Gemfibrozil should not be used when breastfeeding.

Use in children.

Safety and efficacy in children have not been established.

Effects on ability to drive and use machines.

No studies on the effects on the ability to drive and use machines have been performed. In isolated cases dizziness and visual disturbances can occur which may negatively influence driving.

Interactions

Caution should be exercised with concomitant use of gemfibrozil with CYP2C8, CYP2C9, CYP2C19, CYP1A2, UGTA1 and UGTA3 substrates.
The interaction profile of gemfibrozil is complex resulting in increased exposure of many medicinal products if administered concomitantly with gemfibrozil. In vivo studies indicate that gemfibrozil is a potent inhibitor of CYP2C8 (an enzyme important for the metabolism of e.g. repaglinide, rosiglitazone and paclitaxel). In vitro studies have shown that gemfibrozil is a strong inhibitor of CYP2C9 (an enzyme involved in the metabolism of e.g. warfarin and glimepiride), but also of CYP2C19, CYP1A2 and UGTA1 and UGTA3.

Concomitant use with 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.

Concomitant use with 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 level has stabilised (see Precautions).

Concomitant oral anticoagulants.

Gemfibrozil may potentiate the effects of oral anticoagulants, which necessitates careful monitoring of the anticoagulant dosing. Caution should be exercised when anticoagulants are given in conjunction with gemfibrozil. The dosage of the anticoagulant may need to be reduced to maintain desired prothrombin time levels (see Interactions with Other Medicines).

HMG-CoA reductase inhibitors.

The combined use of gemfibrozil and a statin should generally be avoided. The use of fibrates alone is occasionally associated with myopathy. An increased risk of muscle related adverse events, including rhabdomyolysis, has been reported when fibrates are coadministered with statins.
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 three weeks after the 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 Precautions).

Bile acid binding resins.

Reduced bioavailability of gemfibrozil may result when given simultaneously with colestipol. Administration of the drugs two hours or more apart is recommended.
Gemfibrozil is highly bound to plasma proteins and there is potential for displacement interactions with other drugs.

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.

Concomitant use with 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.

Rosiglitazone.

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

Repaglinide.

The combination of gemfibrozil with repaglinide is contraindicated. Concomitant administration of gemfibrozil has resulted in a significant increase in repaglinide AUC probably by inhibition of the CYP2C8 isoenzyme, resulting in hypoglycaemic reactions.
In healthy volunteers, coadministration of gemfibrozil with repaglinide increased the plasma concentration of repaglinide and prolonged its hypoglycaemic effects. Coadministration of gemfibrozil and repaglinide increases the risk for severe hypoglycaemia and is contraindicated (see Contraindications).

Adverse 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 (expressed as gemfibrozil (n = 2046) /placebo (n = 2035).
Gastrointestinal reactions (34.2%/23.8%): dyspepsia 19.6%/11.9%, abdominal pain 9.8%/5.6%, acute appendicitis (histologically confirmed in most cases where data were available) 1.2%/0.6%. Atrial fibrillation 0.7%/0.1%.
Adverse events were reported in more than 1% of subjects, but without a significant difference between groups: diarrhoea 7.2%/6.5%, fatigue 3.8%/3.5%, nausea and/or vomiting 2.5%/2.1%, eczema 1.9%/1.2%, rash 1.7%/1.3%, vertigo 1.5%/1.3%, constipation 1.4%/1.3%, headache 1.2%/1.1%.
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 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 hypoaesthesia, paraesthesia 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 Precautions), and to abnormal liver function tests and haematological changes (see Precautions).
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 below by system. These are categorised according to whether a causal relationship to treatment with gemfibrozil is probable (*) or not established (#).

General.

Weight loss#, extrasystoles#.

Gastrointestinal.

Cholelithiasis*, pancreatitis*, colitis#.

Hepatobiliary disorders.

Cholestatic jaundice*, hepatoma#.

Nervous system disorders.

Dizziness*, somnolence*, paraesthesia*, peripheral neuritis*, headache*, confusion#, convulsions#, syncope#.

Psychiatric disorders.

Decreased libido*, depression*.

Eye disorders.

Blurred vision*, retinal oedema#.

Reproductive system and breast disorders.

Impotence*, decreased male fertility#.

Genitourinary.

Renal dysfunction, renal failure as a consequence of rhabdomyolysis#.

Musculoskeletal and connective tissue disorders.

Myopathy*, myasthenia*, myalgia*, painful extremities*, arthralgia*, synovitis*, rhabdomyolysis* (see Interactions with Other Medicines).

Investigations.

Increased creatine phosphokinase*, increased bilirubin*, increased liver transaminase (AST, ALT)*, increased alkaline phosphatase*, positive antinuclear antibody#.

Blood and lymphatic system disorders.

Anaemia*, leucopenia*, thrombocytopenia*, eosinophilia*, bone marrow hypoplasia* (see Precautions).

Respiratory, thoracic and mediastinal disorders.

Laryngeal oedema*.

Skin and subcutaneous tissue disorders.

Urticaria*, exfoliative dermatitis*, rash*, dermatitis*, pruritus*, angioedema*, anaphylaxis#, lupus-like syndrome#, vasculitis#, alopecia#.
Additional adverse reactions that have been reported include photosensitivity, cholecystitis (see Precautions).
Adverse reactions are ranked according to frequency using the following convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000).

Blood and lymphatic system disorders.

Rare: bone marrow failure, severe anaemia, thrombocytopenia, leucopenia, eosinophilia.

Psychiatric disorders.

Rare: depression, decreased libido.

Nervous system disorders.

Common: vertigo, headache.
Rare: neuropathy peripheral, paraesthesia, dizziness, somnolence.

Eye disorders.

Rare: vision blurred.

Cardiac disorders.

Uncommon: atrial fibrillation.

Respiratory, thoracic and mediastinal disorders.

Rare: laryngeal oedema.

Gastrointestinal disorders.

Very common: dyspepsia.
Common: diarrhoea, vomiting, nausea, abdominal pain, constipation, flatulence.
Rare: pancreatitis, appendicitis.

Hepatobiliary disorders.

Rare: jaundice cholestatic, hepatitis, cholelithiasis, cholecystitis, hepatic function abnormal.

Skin and subcutaneous tissue disorders.

Common: eczema, rash.
Rare: angioedema, dermatitis exfoliative, urticaria, dermatitis, alopecia, photosensitivity reaction, pruritus.

Musculoskeletal and connective tissue disorders.

Rare: rhabdomyolysis, myopathy, myositis, muscular weakness, synovitis, myalgia, arthralgia, pain in extremity.

Reproductive system and breast disorders.

Rare: erectile dysfunction.

General disorders and administration site conditions.

Common: fatigue.

Investigations.

Rare: haemoglobin decreased, haematocrit decreased, white blood cell count decreased, blood creatine phosphokinase increased.

Dosage and Administration

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

Use in patients with hepatic dysfunction.

Gemfibrozil is contraindicated in patients with hepatic dysfunction (see Contraindications).

Use in patients with renal dysfunction.

Gemfibrozil is contraindicated in patients with severe renal dysfunction (see Contraindications).

Overdosage

Contact the Poisons Information Centre on 131 126 for advice on management of overdose.

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. Symptomatic supportive measures should be taken if overdose occurs.

Treatment.

Symptomatic supportive measures should be provided should overdosage occur.
Monitor liver and renal function. There is no antidote.
Activated charcoal may reduce absorption of the drug if given within one or two hours after ingestion. In patients who are not fully conscious or have impaired gag reflex, consideration should be given to administering activated charcoal via a nasogastric tube, once the airway is protected.

Presentation

Tablets, 600 mg (white, oblong, film coated): 60's (bottle, blister pack).

Storage

Store below 25°C.

Poison Schedule

S4.