4.1. Therapeutic indications

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 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.

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

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).

4.2. Posology and method of administration

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 and elderly (over 65 years old):

The dose range is 900mg to 1200mg daily. The only dose with documented effect on morbidity is 1200mg daily.

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

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

Paediatric population:

Gemfibrozil therapy has not been investigated in children. Due to the lack of data, the use of gemfibrozil tablets in children is not recommended.

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 900mg 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.

4.3. Contraindications

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

- Hepatic impairment.

- 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, dasabuvir, selexipag (see section 4.5), simvastatin or rosuvastatin at 40 mg (see sections 4.4 and 4.5).

4.4. Special warnings and precautions for use

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 (>5x times the upper limit of normal); under these conditions treatment must be discontinued.

Concomitant HMG-CoA reductase inhibitors

The concomitant administration of gemfibrozil with simvastatin, as well as with rosuvastatin at 40 mg is contraindicated. Concomitant therapy of gemfibrozil with lower doses of rosuvastatin should be used only when the benefit outweighs the risks. 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, rhabdomyolysis and acute renal failure.

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 treatment with gemfibrozil. Sometimes a paradoxical increase of (total and LDL) cholesterol can occur in patients with hypertriglyceridaemia. If the response is insufficient after three months of therapy at recommended doses, treatment should be discontinued and alternative treatment methods considered.

Monitoring liver function

Elevated levels of ALAT, ASAT, alkaline phosphatase, LDH, creatine kinase (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 (see section 4.8).

Interactions with other medicinal products (see also sections 4.3 and 4.5)

Concomitant use with CYP2C8, CYP2C9, CYP2C19, CYP1A2, UGTA1, UGTA3 and OATP1B1 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, and UDP glucuronyl transferase (UGTA1 and UGTA3) enzymes and also inhibits organic anion-transporting polypeptide 1B1 (OATP1B1) (see section 4.5). In addition, gemfibrozil is metabolised to gemfibrozil 1-O-β-glucuronide which also inhibits CYP2C8 and OATP1B1.

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 coumarin type vitamin K antagonist oral anticoagulants such as warfarin, acenocoumarol, or phenprocoumon. The concomitant administration of gemfibrozil with these anticoagulants necessitates careful monitoring of prothrombin time (INR – International Normalised Ratio). Caution should be exercised when such a coumarin type vitamin K antagonist anticoagulant is given concomitantly with gemfibrozil. The dosage of the anticoagulant may need to be reduced to maintain desired prothrombin time levels (see section 4.5).

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5. Interaction with other medicinal products and other forms of interaction

The interaction profile of gemfibrozil is complex.

In vivo studies indicate that gemfibrozil and its metabolite gemfibrozil 1-O-β-glucuronide are potent inhibitors of CYP2C8 (an enzyme important for the metabolism of e.g. dabrafenib, enzalutamide, loperamide, montelukast, repaglinide, rosiglitazone, pioglitazone, dasabuvir, selexipag and paclitaxel). Co-administration of gemfibrozil with repaglinide, dasabuvir or selexipag is contraindicated (see section 4.3). In addition, dosing reduction of drugs that are mainly metabolised by CYP2C8 enzyme may be required when gemfibrozil is used concomitantly. 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, OATP1B1, UGTA1 and UGTA3 (see section 4.4). Gemfibrozil 1-O-β-glucuronide also inhibits OATP1B1.

Repaglinide

In healthy volunteers, co-administration with gemfibrozil increased the AUC and Cmax of repaglinide by 8.1-fold and 2.4-fold, respectively. In the same study, co-administration with gemfibrozil and itraconazole increased the AUC and Cmax of repaglinide by 19.4-fold and 2.8-fold, respectively. In addition, co-administration with gemfibrozil or with gemfibrozil and itraconazole prolonged its hypoglycaemic effects. Therefore, co-administration of gemfibrozil and repaglinide increases the risk for severe hypoglycaemia and is contraindicated (see section 4.3).

Dasabuvir

Co-administration of gemfibrozil with dasabuvir increased dasabuvir AUC and Cmax (ratios: 11.3 and 2.01, respectively) due to CYP2C8 inhibition. Increased dasabuvir exposure may increase the risk of QT prolongation, therefore, co-administration of gemfibrozil with dasabuvir is contraindicated (see section 4.3).

Selexipag

Co-administration of gemfibrozil with selexipag, a substrate for CYP2C8, doubled exposure (AUC) to selexipag and increased exposure (AUC) to the active metabolite, ACT-333679, by approximately 11-fold. Concomitant administration of gemfibrozil with selexipag is contraindicated (see section 4.3).

Enzalutamide

In healthy volunteers given a single 160 mg dose of enzalutamide after gemfibrozil 600 mg twice daily, the AUC of enzalutamide plus active metabolite (N-desmethyl enzalutamide) was increased by 2.2-fold and corresponding Cmax was decreased by 16%. Increased enzalutamide exposure may increase the risk of seizures. Concomitant treatment of gemfibrozil and enzalutamide should be avoided; if co-administration is considered necessary, the dose of enzalutamide should be reduced (see section 4.4).

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, as well as with rosuvastatin at 40 mg 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 simvastatin, lovastatin, pravastatin, rosuvastatin and atorvastatin. Gemfibrozil caused an almost 3-fold increase 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. The co-administration of a single lovastatin dose of 40 mg with gemfibrozil (600 mg twice daily for 3 days) in healthy volunteers resulted in a 2.8-fold increase of the mean AUC and Cmax of lovastatin acid. The co-administration of a single atorvastatin dose of 40 mg with gemfibrozil (600 mg twice daily for 7 days) in healthy volunteers resulted in a 1.35-fold increase in mean AUC and no increase in mean Cmax of atorvastatin.

Anticoagulants

Gemfibrozil may potentiate the effects of coumarin type vitamin K antagonist anticoagulants such as warfarin, acenocoumarol, or phenprocoumon. The concomitant administration of gemfibrozil with these anticoagulants necessitates careful monitoring of prothrombin time (INR) (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.

4.6. Pregnancy and lactation

Pregnancy

There are no adequate data on use of gemfibrozil in pregnant women. 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. 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).

4.7. 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.

4.8. Undesirable effects

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:

System Organ Class

Undesirable effect

Blood and lymphatic system disorders

Rare

Bone marrow failure, severe anaemia, thrombocytopenia, leukopenia, 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 disorder

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

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 or search for MHRA Yellow Card in the Google Play or Apple App store.

4.9. Overdose

Overdose has been reported. Symptoms reported with overdosage were abdominal cramps, abnormal LFT's, diarrhoea, increased CPK, joint and muscle pain, nausea and vomiting. The patients fully recovered. Symptomatic supportive measures should be taken if overdose occurs.