Gemfibrozil

Gemfibrozil 600mg film-coated Tablets

Each film-coated tablet contain 600mg gemfibrozil

For the full list of excipients, see section 6.1

Film-coated tablet.

White oblong, film-coated tablet of 9 x 19mm dimension with three break marks on both sides.

The score line is only to facilitate breaking for ease of swallowing and not to divide into equal doses

Gemfibrozil tablets are indicated for the primary prevention of coronary heart disease in men between 40-55 years of age and with hyperlipidaemias who have not responded to diet and other appropriate measures.

Gemfibrozil tablets are also indicated for the treatment of patients with hyperlipidaemias of Fredrickson Type IIa (Primary hypercholesterolaemia) when a statin is contraindicated or not tolerated, Fredrickson Type IIb (mixed hyperlipidaemia), Fredrickson Type III (familial dysbetalipoproteinaemia), Fredrickson Type IV (hypertriglyceridaemia) and Type V (severe hypertriglyceridaemia) with or without low HDL cholesterol.

Gemfibrozil Tablets should be prescribed only for patients with lipid or lipoprotein abnormalities demonstrated by laboratory tests and where diet alone is insufficient to correct the condition.

Primary prevention

Reduction of cardiovascular morbidity in males with increased non-HDL cholesterol and at high risk for a first cardiovascular event when a statin is contraindicated or not tolerated (see section 5.1).

Posology

Prior to initiating gemfibrozil, other medical problems such as hypothyroidism and diabetes mellitus must be controlled as best as possible and patients should be placed on a standard lipid-lowering diet, which should be continued during treatment.

Adults

The dose range is 900 mg to 1200 mg daily, in divided doses usually twice daily, half an hour before breakfast and half an hour before the evening meal. The only dose with documented effect on morbidity is 1200 mg daily.

The 1200 mg dose is taken as 600 mg twice daily, half an hour before breakfast and half an hour before the evening meal.

The 900 mg dose is taken as a single dose half an hour before the evening meal.

900 mg as a total daily dose may be given in cases of intolerance at normal dosage. When maximum triglyceride reduction is desired, as in Type V patients, up to 1500 mg daily may be needed.

Older people (over 65 years)

As for adults. Patients 60 years or older with lipid levels consistent with increased risk of coronary heart disease patients should be treated with diet for at least three months. If diet therapy is not effective, treatment with gemfibrozil in this age group should be considered. The incidence of side effects associated with treatment with gemfibrozil has not been shown to be different in elderly subjects compared with younger ones.

Paediatric population

Gemfibrozil therapy has not been investigated in children. Due to the lack of data Gemfibrozil Tablets are not recommended for administration to children.

Renal impairment

In patients with mild to moderate renal impairment (Glomerular filtration rate 50 - 80 and 30 - < 50 ml/min/1.73 m², respectively), start treatment at 900 mg daily and assess renal function before increasing dose. Gemfibrozil should not be used in patients with severely impaired renal function (see section 4.3).

Hepatic impairment

Gemfibrozil is contraindicated in hepatic impairment (see section 4.3).

Method of administration:

For oral use only.

- Hypersensitivity to the active substance or any of the other ingredients listed in section 6.1

- Alcoholism.

- Hepatic dysfunction .

- Severe renal impairment.

- History of/or pre-existing gall bladder or biliary tract disease including gallstones.

- Patients with previous history of photoallergy or phototoxic reaction during treatment with fibrates.

- Concomitant use of repaglinide (see section 4.5) or simvastatin (see section 4.4 and 4.5).

Muscle disorders (myopathy/rhabdomyolysis)

There have been reports of myositis, myopathy and marked elevations of creatine phosphokinase associated with gemfibrozil. Rhabdomyolysis has also been reported rarely. Patients who develop signs of muscle toxicity (presenting with diffuse myalgia, muscle tenderness) should be monitored closely and CPK levels checked. Treatment with gemfibrozil should be stopped if myopathy is suspected or if CPK rises to above (>5x times the upper limit of normal.

Before starting treatment with gemfibrozil, attempts should be made to control serum lipids with appropriate diet, exercise, cessation of smoking, limitation of alcohol intake, weight loss in obese patients and treatment of the causes of secondary hyperlipidaemias such as hypothyroidism and diabetes mellitus.

Concomitant HMG-CoA reductase inhibitor

The risk of serious muscle toxicity is increased if gemfibrozil is used concomitantly with HMG-CoA reductase inhibitors or other fibrates. Combination therapy should be used with caution and patients monitored closely for signs of muscle toxicity.

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 (see sections 4.3 and 4.5). Pharmacokinetic interactions may also be present (see also section 4.5) and dosage adjustments may be necessary.

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.

A creatine phosphokinase (CPK) level should be measured before starting such a combination in patients with pre-disposing 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.

In most subjects who have had an unsatisfactory lipid response to either drug alone, the possible benefits of combined therapy with HMG-CoA reductase inhibitors and gemfibrozil does not outweigh the risks of severe myopathy, rhabdomylosis and acute renal failure.

Use in patients wtih gallstone formation

Gemfibrozil Tablets 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 Tablet therapy should be discontinued if gallstones are found.

Monitoring serum lipids

Since long-term administration of gemfibrozil is recommended, all baseline values, including lipid profile, blood count and liver function tests, should be measured before treatment and periodic determinations of serum lipids should be obtained. Sometimes a paradoxical increase of (total and LDL) cholesterol can occur in patients with hypertriglyceridaemia. The drug should be withdrawn or additional therapy instituted if the lipid response is inadequate after three months. In addition, gemfibrozil should be withdrawn if after three months the response is paradoxical. Paradoxical response has been occasionally observed, usually in patients with alcoholic hepatic disease. The blood level of LDL cholesterol occasionally rises on treatment with gemfibrozil. A further estimation of LDL cholesterol should therefore be made during treatment to confirm that the desired therapeutic effect has been achieved.

Monitoring liver function

Elevated liver function tests (AST and ALT) increased alkaline phosphates, LDH, creatine kinase (CK) and bilirubin have occasionally been reported with gemfibrozil administration. These are usually reversible when gemfibrozil is discontinued. Therefore periodic liver function tests are recommended during the first year of therapy and treatment with gemfibrozil should be terminated if abnormalities persist.

Monitoring blood counts

Eosinophilia has been occasionally reported. Rarely, severe anaemia, leucopenia, thrombocytopenia, eosinophilia and bone marrow hypoplasia have been reported. Therefore periodic blood counts are recommended during the first 12 months of treatment.

Interactions with other medicinal products (see also sections 4.5).

• Concomitant use 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.

• Gemfibrozil potently inhibits CYP2C8, CYP2C9, CYP2C19, CYP1A2, UGTA1 and UGTA3 enzymes (see section 4.5)

• 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 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 Section 4.5.).

Concomitant anticoagulant dosage may need to be reduced and frequent determinations of prothrombin carried out to confirm that the desired prothrombin level has been re-established.

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.

The interaction profile of gemfibrozil is complex.

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 CYP 2C19, CYP1A2 and UGTA1 and UGTA3 (see Section 4.4).

Repaglinide

The combination of gemfibrozil with repaglinide is contra-indicated (see Section 4.3). Concomitant administration has resulted in 8-fold increase in repaglinide plasma concentration probably by inhibition of the CYP2C8 enzyme, resulting in hypoglycaemic reactions.

Rosiglitazone

The combination of gemfibrozil with rosiglitazone should be approached with caution. Co-administration with rosiglitazone has resulted in 2.3-fold increase in rosiglitazone systemic exposure, probably by inhibition of the CYP2C8 isozyme (see section 4.4).

HMG CoA reductase inhibitors

The concomitant administration of gemfibrozil with simvastatin is contraindicated (see sections 4.3 and 4.4). The combined use of gemfibrozil and a statin should generally be avoided (see section 4.4). 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 co-administered with statins.

Gemfibrozil has also been reported to influence the pharmacokinetics of simvaststin, lovastatin, pravastatin and rosuvastatin. Gemfibrozil caused an almost 3-fold increased in AUC of simvastatin acid possibly due to inhibition of glucoronidation via UGTA1 and UGTA3, and a 3-fold increase in pravastatin AUC which may be due to interference with transport proteins. One study indicated that the co-administration of a single rosuvastatin dose of 80 mg to healthy volunteers on gemfibrozil (600 mg twice daily) resulted in a 2.2-fold increase in mean Cmax and a 1.9-fold increase in mean AUC of rosuvastatin.

Oral anticoagulants

Gemfibrozil may potentiate the effects of oral anticoagulants, which necessitates careful monitoring of the anticoagulant dosing (see section 4.4).

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 products two hours or more apart is recommended.

Colchicine

Risk of myopathy 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. Clinical and biological monitoring are recommended, especially at the start of combined treatment.

Gemfibrozil is highly bound to plasma proteins and there is potential for displacement interactions with other drugs

Pregnancy

Safe use in human pregnancy has not been established. Animal studies are insufficiently clear to allow conclusions to be drawn on pregnancy and foetal development (see section 5.3). The potential risk for humans is

Unknown. It is not known whether gemfibrozil is secreted in human milk. Like most drugs, gemfibrozil should not be used during pregnancy unless it is clearly necessary.

Breast-feeding

There are no data on excretion of gemfibrozil in milk. Gemfibrozil should not be used when breast feeding. .

Fertility

Reversible decreases in male fertility have been observed in reproductive toxicity studies in rats (see section 5.3).

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.

Most commonly reported adverse reactions are of gastrointestinal character and are seen in approximately 7% of the patients. These adverse reactions do not usually lead to discontinuation of the treatment.

Adverse reactions are ranked according to frequency using the following convention: 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 Not Known (cannot be estimated from the available data):

Cardiac disorders

Uncommon: atrial fibrillation.

Respiratory, thoracic and mediastinal disorders

Rare: laryngeal oedema

Not Known: cough

Blood and lymphatic system disorders

Rare: Thrombocytopenia, severe anaemia, leucopoenia, eosinophilia, bone marrow hypoplasia, bone marrow failure Self-limiting, mild haemoglobin and haematocrit decrease, white cell count decrease and blood creatine phosphokinase increased have been observed on initiating gemfibrozil therapy.

Ear and labyrinth disorders

Not Known: tinnitus

Gastrointestinal disorders

Very Common: dyspepsia.

Common: Abdominal pain, diarrhoea, nausea/vomiting, constipation, flatulence.

Rare: Pancreatitis, acute appendicitis

Not Known: epigastric pain, Dry mouth

Hepatobiliary disorders

Rare: Cholestatic jaundice, disturbed liver function, hepatitis, cholelithiasis, cholecystitis.

Skin and subcutaneous tissue disorders

Common: Rash, eczema

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

Nervous system disorders

Common: Headache, Vertigo

Rare: dizziness, somnolence, paresthesia, peripheral neuritis, Neuropathy peripheral.

Not Known: syncope

Psychiatric disorders

Rare: depression, decreased libido

Not Known: insomnia

Musculoskeletal and connective tissue disorders

Rare: Myaesthenia, myopathy, rhabdomyolysis, painful extremities and myalgia, arthralgia, synovitis and myositis accompanied by increase in creatine kinase (CK) .

Not Known: back pain, muscle cramps, swollen joints

Reproductive system and breast disorders

Rare: Erectile dysfunction.

Eye disorders

Rare: Blurred vision.

General disorders and administration site conditions

Common: Fatigue

Not Known: malaise

Metabolism and nutrition disorders

Not Known: anorexia, hypokalaemia

Infections and infestations

Not Known: Viral and bacterial infections, common cold, urinary tract infections

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard.

Overdosage has been reported with gemfibrozil. Symptoms reported with overdosage were abdominal cramps, abnormal LFT's, diarrhoea, increased CPK, joint muscle pain, nausea and vomiting.

The patients fully recovered.

Symptomatic supportive measures should be taken should overdose occur.

Pharmacotherapeutic group: Cholesterol & Triglyceride Reducer/Fibrates

ATC code: C10AB

Gemfibrozil is a lipid regulating agent which decreases total serum cholesterol and serum triglycerides. These decreases occur in the low density lipoprotein (LDL) fraction and in the very low density lipoprotein (VLDL) fraction. In addition, gemfibrozil increases high density lipoprotein (HDL) cholesterol.

The essential results of the pharmacokinetic properties of gemfibrozil investigated in various experiments are summarised in the following:

- Gemfibrozil is readily absorbed from the gastro-intestinal tract.

- Peak concentrations in plasma occur within 1 to 2 hours.

- The plasma half-life is about 1.5 hours.

- Plasma protein binding of gemfibrozil is about 98 %.

- Metabolism takes place in the liver, the principal metabolite being a benzoic acid derivative while other metabolites include phenol and benzyl alcohol derivatives.

- About 70 % of a dose is excreted in the urine mainly as glucuronide conjugates of gemfibrozil and its metabolites; little is excreted in the faeces.

In a 2-year study of gemfibrozil, subcapsular bilateral cataracts occurred in 10%, and unilateral in 6.3%, of male rats treated at 10 times the human dose.

In a mouse carcinogenicity study at dosages corresponding to 0.1 and 0.7 times the clinical exposure (based on AUC), there were no significant differences from controls in the incidence of tumors. In a rat carcinogenicity study at dosages corresponding to 0.2 and 1.3 times the clinical exposure (based on AUC), the incidence of benign liver nodules and liver carcinomas was significantly increased in high dose males, and the incidence of liver carcinomas increased also in the low dose males, but this increase was not statistically significant.

Liver tumours induced by gemfibrozil and other fibrates in small rodents are generally considered to be related to the extensive proliferation of peroxisomes in these species and, consequently, of minor clinical relevance.

In the male rat, gemfibrozil also induced benign Leydig cell tumors. The clinical relevance of this finding is minimal.

In reproductive toxicity studies, administration of gemfibrozil at approximately 2 times the human dose (based on body surface area) to male rats for 10 weeks resulted in decreased fertility. Fertility was restored after a drug-free period of 8 weeks. Gemfibrozil was not teratogenic in either rats or rabbits. Administration of 1 and 3 times the human dose (based on body surface area) of gemfibrozil to female rabbits during organogenesis caused a dose-related decrease in litter size. Administration of 0.6 and 2 times the human dose (based on body surface area) of gemfibrozil to female rats from gestation Day 15 through weaning caused dose-related decreases in birth weight and suppression of pup growth during lactation. Maternal toxicity was observed in both species and the clinical relevance of decreases in rabbit litter size and rat pup weight is uncertain.

Microcrystalline Cellulose

Maize Starch

Hydroxypropylcellulose

Sodium Starch Glycollate (type A)

Polysorbate 80 (Tween 80)

Colloidal Anhydrous Silica

Magnesium Stearate

Film-Coating:

Lactose monohydrate

Hypromellose

Titanium Dioxide (E171)

Macrogol 4000

Not applicable.

3 years.

This medicinal product does not require any special storage conditions

PVDC / PVC or 300 μm polypropylene/ 15μm aluminium blister foil packed in cardboard cartons of 28, 30, 56 or 100 tablets.

Not all pack sizes may be marketed.

No special requirements for disposal

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

Tillomed Laboratories Limited

220 Butterfield

Great Marlings

Luton

LU2 8DL

UK

PL 11311/0099

02/03/2009

04/02/2020