Gemfibrozil 600mg Film-Coated Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Gemfibrozil 600mg film-coated Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each film-coated tablet contain 600mg gemfibrozil For the full list of excipients, see section 6.1
3 PHARMACEUTICAL FORM
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
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 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).
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
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.
4.3 Contraindications
- 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).
4.4 Special warnings and precautions for use
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.).
4.5 Interaction with other medicinal products and other forms of interaction
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
4.6 Fertility, pregnancy and lactation 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).
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, 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, hyp okal aemia
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.
4.9. Overdose
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.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
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.
5.2
Pharmacokinetic properties
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.
5.3 Preclinical safety data
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.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
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
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years.
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions
6.5 Nature and contents of container
PVDC / PVC or 300 pm polypropylene/ 15pm aluminium blister foil packed in cardboard cartons of 28, 30, 56 or 100 tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
No special requirements for disposal
Any unused medicinal product or waste material should be disposed of in accordance with local requirements
MARKETING AUTHORISATION HOLDER
7
Tillomed Laboratories Ltd.
3 Howard Road
Eaton Socon
St. Neots
Cambs.
PE193ET United Kingdom
8. Marketing Authorisation Number
PL 11311/0099
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
02/03/2009
10 DATE OF REVISION OF THE TEXT
19/06/2015