Fenofibrate Micro 267mg Capsules
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Fenofibrate Micro 267 mg capsules
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each capsule contains 267 mg micronized fenofibrate.
For the full list of excipients, see section 6.1
3 PHARMACEUTICAL FORM
Capsules, hard Blue/blue capsule size 0
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Fenofibrate Micro 267 reduces elevated serum cholesterol and triglycerides and is of benefit in the treatment of severe dyslipidaemia in patients in whom dietary measures alone have failed to produce an adequate response. Fenofibrate Micro 267 is indicated in appropriate cases of dyslipidaemia (Fredrickson classification types IIa, IIb, III, IV and V).
|
Type |
Major lipid elevated |
Lipoproteins elevated |
|
IIa |
Cholesterol |
LDL |
|
IIb |
Cholesterol, triglycerides |
LDL, VLDL |
|
III (rare) |
Cholesterol, triglycerides |
IDL and chylomicron remnants |
|
IV |
Triglyceride |
VLDL |
|
V (rare) |
Triglyceride |
Chylomicrons, VLDL |
Fenofibrate Micro 267 should only be used in patients in whom a full investigation has been performed to define their abnormality. Other risk factors, such as hypertension and smoking, may also require management.
4.2 Posology and method of administration
Posology :
Adults
In patients with severe dyslipidaemia, an increased dose of 267mg (Fenofibrate Micro 267) is recommended. Fenofibrate Micro 267 should always be taken with food, because it is less well absorbed from an empty stomach. Dietary measures instituted before therapy should be instituted.
Children
This dosage is not recommended in children.
Elderly
In elderly patients without renal impairment, the normal adult dose is recommended.
Renal impairment
In renal dysfunction, the dosage may need to be reduced depending on the rate of creatinine clearance, for example:
|
Creatinine clearance (ml/min) |
Dosage |
|
< 60 |
Fenofibrate 140 mg capsule |
|
< 20 |
Fenofibrate 67 mg capsule |
Hepatic disease
Patients with hepatic disease have not been studied.
Paediatric population
The safety and efficacy of fenofibrate in children and adolescents younger than 18 years has not been established. No data are available. Therefore, the use of fenofibrate is not recommended in paediatric subjects under 18 years.
4.3 Contraindications
Fenofibrate Micro 267 is contra-indicated
• In children (see section 4.2)
• In patients with liver or renal dysfunction, gallbladder disease, biliary cirrhosis and
• In patients with known photoallergy or phototoxic reaction during treatment with fibrates or ketoprofen.
• In patients with Chronic or acute pancreatitis with the exception of acute pancreatitis due to severe hypertriglyceridemia.
• In patients with hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1
Use during pregnancy and lactation (see section 4.6).
4.4 Special warnings and precautions for use
Secondary causes of hyperlipidemia:
Secondary causes of hyperlipidemia, such as uncontrolled type 2 diabetes mellitus, hypothyroidism, nephrotic syndrome, dysproteinemia, obstructive liver disease, pharmacological treatment, alcoholism, should be adequately treated before fenofibrate therapy is considered.
Liver Function
Moderately elevated levels of serum transaminases may be found in some patients but rarely interfere with treatment. In the majority of cases these elevations were transient, minor and asymptomatic. However, it is recommended that serum transaminases should be monitored every three months during the first twelve months of treatment. Attention should be paid to patients who develop increases in transaminase levels and treatment should be discontinued in the event of ALAT (SGPT) or ASAT (SGOT) elevations to more than 3 times the upper limit of the normal range or more than one hundred international units.
Pancreatitis
Pancreatitis has been reported in patients taking fenofibrate (see sections 4.3 and 4.8). This occurrence may represent a failure of efficacy in patients with severe hypertriglyceridaemia, a direct drug effect, or a secondary phenomenon mediated through biliary tract stone or sludge formation, resulting in the obstruction of the common bile duct.
Myopathy
Patients with pre-disposing factors for myopathy and/or rhabdomyolysis, including age above 70 years, personal or familial history of hereditary muscular disorders, renal impairment, hypothyroidism and high alcohol intake, may be at an increased risk of developing rhabdomyolysis. For these patients, the putative benefits and risks of fenofibrate therapy should be carefully weighed up.
Muscle toxicity, including very rare cases of rhabdomyolysis, with or without renal failure has been reported with administration of fibrates and other lipidlowering agents. The incidence of this disorder increases in cases of hypoalbuminaemia and previous renal insufficiency. Muscle toxicity should be suspected in patients presenting diffuse myalgia, myositis, muscular cramps and weakness and/or marked increases in CPK (levels exceeding 5 times the normal range). In such cases treatment with fenofibrate should be stopped.
The risk of muscle toxicity may be increased if the drug is administered with another fibrate or an HMG-CoA reductase inhibitor, especially in cases of preexisting muscular disease. Consequently, the co-prescription of fenofibrate with a statin should be reserved to patients with severe combined dyslipidaemia and high cardiovascular risk without any history of muscular disease. This combination therapy should be used with caution and patients should be monitored closely for signs of muscle toxicity.
For hyperlipidaemic patients taking oestrogens or contraceptives containing oestrogen it should be ascertained whether the hyperlipidaemia is of primary or secondary nature (possible elevation of lipid values caused by oral oestrogen).
Renal _ function
Treatment should be interrupted in case of an increase in creatinine levels> 50% ULN (upper limit of normal). It is recommended that creatinine measurement be considered during the first three months after initiation of treatment.
In renal dysfunction the dose of fenofibrate may need to be reduced, depending on the rate of creatinine clearance, (see section 4.2). Dose reduction should be considered in elderly patients with impaired renal function.
Excipients:
Patients with rare hereditary problems of galactose intolerance the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
4.5 Interaction with other medicinal products and other forms of interaction
Oral anti-coagulants
Fenofibrate enhances oral anti-coagulant effect and may increase the risk of bleeding. In patients receiving oral anti-coagulant therapy, the dose of anticoagulant should be reduced by about one-third at the commencement of treatment and then gradually adjusted if necessary according to INR (International Normalised Ratio) monitoring.
HMG-CoA reductase inhibitors or other fibrates
The risk of serious muscle toxicity is increased if fenofibrate is used concomitantly with HMG-CoA reductase inhibitors or other fibrates. Such combination therapy should be used with caution and patients monitored closely for signs of muscle toxicity (see section 4.4).
There is currently no evidence to suggest that fenofibrate affects the pharmacokinetics of simvastatin.
Ciclosporin
Some severe cases of reversible renal function impairment have been reported during concomitant administration of fenofibrate and ciclosporin. The renal function of these patients must therefore be closely monitored and the treatment with fenofibrate stopped in the case of severe alteration of laboratory parameters.
Glitazones
Some cases of reversible paradoxical reduction of HDL-cholesterol have been reported during concomitant administration of fenofibrate and glitazones. Therefore it is recommended to monitor HDL-cholesterol if one of these components is added to the other and stopping of either therapy if HDL-cholesterol is too low.
Cytochrome P450 enzymes
In vitro studies using human liver microsomes indicate that fenofibrate and fenofibric acid are not inhibitors of cytochrome (CYP) P450 isoforms CYP3A4, CYP2D6, CYP2E1, or CYP1A2. They are weak inhibitors of CYP2C19 and CYP2A6, and mild-to-moderate of CYP2C9 at therapeutic concentrations.
Patients co-administered fenofibrate and CYP2C19, CYP2A6, and especially CYP2C9 metabolised drugs with a narrow therapeutic index should be carefully monitored and, if necessary, dose adjustment of these drugs is recommended.
Other
No proven clinical interactions of fenofibrate with other drugs have been reported, although in vitro interaction studies suggest displacement of phenylbutazone from plasma protein binding sites. In common with other fibrates, fenofibrate induces microsomal mixed-function oxidases involved in fatty acid metabolism in rodents and may interact with drugs metabolised by these enzymes.
4.6 Fertility, pregnancy and lactation
Pregnancy
There are no adequate data from the use of fenofibrate in pregnant women. Animal studies have not demonstrated any teratogenic effects. Embryotoxic effects have been shown at doses in the range of maternal toxicity (see section 5.3). The potential risk for humans is unknown.
Breast-feeding
There are no data on the excretion of fenofibrate and/or its metabolites into breast milk. It is therefore recommended that Fenofibrate Micro 267 should not be administered to women who are pregnant or are breast feeding.
4.7 Effects on ability to drive and use machines
Fenofibrate has no or negligible influence on the ability to drive and use machines.
4.8 Undesirable effects
Estimated frequencies of events are ranked according to 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), not known (cannot be estimated from the available data).
Investigations
Rare: Increases in serum creatinine and urea
Blood and lymphatic system disorders
Rare: Decrease in haemoglobin and leukocytes
Immune system disorders Rare: Hypersensitivity
Nervous system disorders Rare: Headache
Reproductive system and breast disorders Rare: Sexual dysfunction
Ear and labyrinth disorders Rare: Vertigo
Respiratory, thoracic and mediastinal disorders Very rare: Interstitial pneumopathies
Gastrointestinal disorders
Common: Digestive, gastric or intestinal disorders (abdominal pain,
nausea, vomiting, diarrhoea, and flatulence)
Uncommon: Pancreatitis*
Skin and subcutaneous tissue disorders
Uncommon: Reactions such as rashes, pruritus, urticaria or
photosensitivity reactions Rare: Alopecia
Very rare: Cutaneous photosensitivity with erythema, vesiculation or
nodulation on parts of the skin exposed to sunlight or artificial UV light (e.g. sun lamp) in individual cases (even after many months of uncomplicated use)
Musculoskeletal and connective tissue disorders
Rare: Muscle toxicity (diffuse myalgia, myositis, muscular cramps
and weakness)
Very rare: Rhabdomyolysis.
Vascular disorders
Uncommon: Thromboembolism (pulmonary embolism, deep vein
thrombosis)*
General disorders and administration site conditions
Rare: Fatigue
Hepatobiliary disorders
Common: Moderately elevated levels of serum transaminases may be
found in some patients but rarely interfere with treatment (see section 4.4).
Uncommon: Development of gallstones has been reported.
Very rare: Episodes of hepatitis have been reported very rarely. When
symptoms (e.g. jaundice, pruritus) indicative of hepatitis occur, laboratory tests are to be conducted for verification and fenofibrate discontinued, if applicable (see section 4.4).
* In the FIELD-study, a randomized placebo-controlled trial performed in 9,795 patients with type 2 diabetes mellitus, a statistically significant increase in pancreatitis cases was observed in patients receiving fenofibrate versus patients receiving placebo (0.8% versus 0.5%; p = 0.031). In the same study, a statistically significant increase was reported in the incidence of pulmonary embolism (0.7% in the placebo group versus 1.1% in the fenofibrate group; p = 0.022) and a statistically non-significant increase in deep vein thromboses (placebo: 1.0 % [48/4,900 patients] versus fenofibrate 1.4% [67/4,895 patients]; p = 0.074).
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
Only anecdotal cases of fenofibrate overdosage have been received. In the majority of cases no overdose were reported.
No specific antidote is known. If overdose is suspected, treat symptomatically and institute appropriate supportive measures as required. Fenofibrate cannot be eliminated by haemodialysis.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Serum Lipid Reducing Agents/Cholesterol and Triglyceride Reducers/Fibrates.
ATC code:C10 AB 05
Fenofibrate Micro 267 is a formulation containing 267 mg of micronised fenofibrate.
The lipid lowering properties of fenofibrate seen in clinical practice have been explained in vivo in transgenic mice and in human hepatocyte cultures by activation of Peroxisome Proliferator Activated Receptor type a (PPARa). Through this mechanism, fenofibrate increases lipolysis and elimination of triglyceride-rich particles from plasma by activating lipoprotein lipase and reducing production of Apoprotein C-III. Activation of PPARa also induces an increase in the synthesis of Apoproteins A-I, A-II and of HDL cholesterol.
Epidemiological studies have demonstrated a positive correlation between increased serum lipid levels and an increased risk of coronary heart disease. The control of such dyslipidaemias forms the rationale for treatment with fenofibrate. However, the possible beneficial and adverse long-term consequences of drugs used in the management of dyslipidaemias are still the subject of scientific discussion. Therefore the presumptive beneficial effect of Fenofibrate Micro 267 on cardiovascular morbidity and mortality is as yet unproven.
Studies with fenofibrate consistently show decreases in levels of LDL-cholesterol. HDL-cholesterol levels are frequently increased. Triglyceride levels are also reduced. This results in a decrease in the ratio of low and very low density lipoproteins to high density lipoproteins, which has been correlated with a decrease in atherogenic risk in epidemiological studies. Apolipoprotein-A and apolipoprotein-B levels are altered in parallel with HDL and LDL and VLDL levels respectively.
Regression of xanthomata has been observed during fenofibrate therapy.
Plasma uric acid levels are increased in approximately 20% of hyperlipidaemic patients, particularly in those with type IV phenotype. Fenofibrate Micro 267 has a uricosuric effect and is therefore of additional benefit in such patients.
Patients with raised levels of fibrinogen and Lp(a) have shown significant reductions in these measurements during clinical trials with fenofibrate.
5.2 Pharmacokinetic properties
Absorption
The unchanged compound is not recovered in the plasma. Fenofibric acid is the major plasma metabolite. Peak plasma concentration occurs after a mean period of 5 hours following dosing.
Mean plasma concentration is 15 pg/ml for a daily dosage of 200 mg of micronised fenofibrate.
Steady state levels are observed throughout continuous treatments.
Fenofibric acid is highly bound to plasma albumin: it can displace antivitamin K compounds from the protein binding sites and potentiate their anti-coagulant effect.
Plasma half-life
The plasma half-life of elimination of fenofibric acid is approximately 20 hours.
Metabolism and excretion
The product is mainly excreted in the urine: 70% in 24 hours and 88% in 6 days, at which time total excretion in urine and faeces reaches 93%. Fenofibrate is mainly excreted as fenofibric acid and its derived glucuroconjugate.
Kinetic studies after administration of repeated doses show the absence of accumulation of the product.
Fenofibric acid is not eliminated during haemodialysis.
5.3 Preclinical safety data
Chronic toxicity studies have yielded no relevant information about specific toxicity of fenofibrate.
Studies on mutagenicity of fenofibrate have been negative.
In rats and mice, liver tumours have been found at high dosages, which are attributable to peroxisome proliferation. These changes are specific to small rodents and have not been observed in other animal species. This is of no relevance to therapeutic use in man.
Studies in mice, rats and rabbits did not reveal any teratogenic effect. Embryotoxic effects were observed at doses in the range of maternal toxicity. Prolongation of the gestation period and difficulties during delivery were observed at high doses. No sign of any effect on fertility has been detected.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Excipients: lactose monohydrate, pregelatinised starch, sodium lauryl sulphate, crospovidone, magnesium stearate, anhydrous colloidal silica.
Composition of the capsule shell: gelatin, brilliant blue (E133), titanium dioxide (E171).
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years
6.4 Special precautions for storage
Do not store above 25°C.
Store in the original package
6.5 Nature and contents of container
Pack of 28 capsules in blisters (PVC/Aluminium).
6.6 Special precautions for disposal and other handling
No special requirements for disposal.
7 MARKETING AUTHORISATION HOLDER
Teva UK Limited,
Brampton Road,
Hampden Park Eastbourne East Sussex BN22 9AG
MARKETING AUTHORISATION NUMBER(S)
PL 00289/1485
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
24/04/2009
10
DATE OF REVISION OF THE TEXT
15/01/2016