Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: Pfizer Limited, Ramsgate Road, Sandwich, Kent CT13 9NJ, United Kingdom
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 ULN); under these conditions treatment must be discontinued.
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:
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.
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.
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 3 months of therapy at recommended doses treatment should be discontinued and alternative treatment methods considered.
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.
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).
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 glucuronyltransferase (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.
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.
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 – 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).
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 and UGTA1 and UGTA3 (see section 4.4). Gemfibrozil 1-O-β-glucuronide also inhibits OATP1B1.
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).
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).
Co-administration of gemfibrozil with selexipag 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).
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).
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).
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 simvastatin, 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.
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).
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.
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.
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.
There are no adequate data on use of Lopid 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. Lopid should not be used during pregnancy unless it is clearly necessary.
There are no data on excretion of gemfibrozil in milk. Lopid should not be used when breast-feeding.
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 to <1/10), Uncommon (≥1/1,000 to <1/100), Rare (≥1/10,000 to <1/1,000), Very rare (<1/10,000), including isolated reports:
Rare: Bone marrow failure, severe anaemia, thrombocytopenia, leukopenia, eosinophilia
Rare: Depression, decreased libido
Common: Vertigo, headache
Rare: Neuropathy peripheral, paraesthesia, dizziness, somnolence
Rare: Vision blurred
Uncommon: Atrial fibrillation
Rare: Laryngeal oedema
Very common: Dyspepsia
Common: Diarrhoea, vomiting, nausea, abdominal pain constipation, flatulence
Rare: Pancreatitis, appendicitis
Rare: Jaundice cholestatic, hepatitis, cholelithiasis, cholecystitis, hepatic function abnormal
Common: Eczema, rash
Rare: Angioedema, dermatitis exfoliative, urticaria, dermatitis, alopecia, photosensitivity reaction, pruritus
Rare: Rhabdomyolysis, myopathy, myositis, muscular weakness, synovitis, myalgia, arthralgia, pain in extremity
Rare: Erectile dysfunction
Common: Fatigue
Rare: Haemoglobin decreased, haematocrit decreased, white blood cell count decreased, blood creatine phosphokinase increased
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.
Not applicable.
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