Fenofibrate 200mg Capsules
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Fenofibrate 200 mg Capsules
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each capsule contains 200 mg micronised fenofibrate.
Excipients with known effect:
Each capsule contains 46.34mg lactose monohydrate. This capsule also contains sunset yellow FCF (E110).
For the full list of excipients, see section 6.1
3 PHARMACEUTICAL FORM
Hard Capsule
Orange cap/orange body, self locked hard gelatin capsules of size ‘0’ imprinted with ‘FB200’ on cap and body containing white to off white granular powder.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Fenofibrate is indicated as an adjunct to diet and other non-pharmacological treatment (e.g. exercise, weight reduction) for the following:
- Treatment of severe hypertriglyceridaemia with or without low HDL cholesterol.
- Mixed hyperlipidaemia when a statin is contraindicated or not tolerated.
- Mixed hyperlipidaemia in patients at high cardiovascular risk in addition to a statin when triglycerides and HDL cholesterol are not adequately controlled.
4.2 Posology and method of administration
Response to therapy should be monitored by determination of serum lipid values. If an adequate response has not been achieved after several months (e.g. 3 months), complementary or different therapeutic measures should be considered.
Posology
Adults:
The recommended dose is 200mg daily administered as one capsule Fenofibrate 200mg Capsule. The dose can be titrated up to 267mg daily administered as one capsule of Fenofibrate 267mg Capsule or 4 capsules of Fenofibrate 67mg, if required. This maximum dose is not recommended in addition to a statin.
Special populations
Older people:
In elderly patients, the usual adult dose is recommended.
Paediatric population:
The safety and efficacy of fenofibrate in children 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.
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 |
Two 67mg capsules |
|
□ 20 |
One 67mg capsule |
Hepatic impairment:
Fenofibrate 200mg Capsule is not recommended for use in patients with hepatic impairment due to the lack of data.
Method of administration
Capsules should be swallowed whole during a meal.
4.3 Contraindications
- Hepatic insufficiency (including billiary cirrhosis and unexplained persistent liver function abnormality)
- Known gallbladder disease
- Severe renal dysfunction
- Chronic or acute pancreatitis with the exception of acute pancreatitis due to severe hypertriglyceridemia
- Known photoallergy or phototoxic reaction during treatment with fibrates or ketoprofen
- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
4.4 Special warnings and precautions for use
Secondary causes of hyperlipidemia:
Secondary causes of hyperlipidemia, such as uncontrolled type 2 diabetes mellitus, hypothyroidism, nephritic syndrome, dysproteinemia, obstructive liver disease, pharmacological treatment, alcoholism, should be adequately treated before fenofibrate therapy is considered.
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 is measured during the first three months after initiation of treatment and thereafter periodically (for dose recommendations, see section 4.2).
Liver function:
As with other lipid lowering agents, increases have been reported in transaminase levels in some patients. In the majority of cases these elevations were transient, minor and asymptomatic. It is recommended that transaminase levels are monitored every 3 months during the first 12 months of treatment and thereafter periodically. Attention should be paid to patients who develop increase in transaminase levels and therapy should be discontinued if AST (SGOT) and ALT (SGPT) levels increase to more than 3 times the upper limit of the normal range. When symptoms indicative of hepatitis occur (e.g. jaundice, pruritus), and diagnosis is confirmed by laboratory testing, fenofibrate therapy should be discontinued.
Pancreas:
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, with obstruction of the common bile duct.
Muscle:
Muscle toxicity, including rare cases of rhabdomyolysis, with or without renal failure has been reported with administration of fibrates and other lipid-lowering agents. 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 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 pre-existing muscular disease. Consequently, the co-prescription of fenofibrate with a HMG-CoA reductase inhibitor or another fibrate should be reserved to patients with severe combined dyslipidaemia and high cardiovascular risk without any history of muscular disease and a close monitoring of potential 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).
This medicinal product contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
This medicinal product also contains small amounts of sunset yellow (E 110) which is a colouring agent and can cause allergic reactions.
4.5 Interaction with other medicinal products and other forms of interaction
Oral Anti-coagulants
Fenofibrate enhances oral anti-coagulant effect and may increase risk of bleeding.
In patients receiving oral anti-coagulant therapy, the dose of anti-coagulant 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 a fibrate 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.
Therefore, Fenofibrate 200mg Capsules should only be used during pregnancy after a careful benefit/risk assessment.
Breastfeeding
It is unknown whether fenofibrate is excreted in human milk. A risk to the newborns/infants cannot be excluded. Therefore fenofibrate should not be used during 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
The most commonly reported ADRs during Fenofibrate therapy are digestive, gastric or intestinal disorders.
|
The following undesirable effects have been observed during placebo-controlled clinical trials (n=2344) with the below indicated frequencies:System Organ Class |
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 incl. isolated reports |
|
Blood and lymphatic system disorders |
Haemoglobin decreased White blood cell count decreased | |||
|
Immune system |
Hypersensitivity |
|
disorders | ||||
|
Nervous system disorders |
Headache | |||
|
Vascular disorders |
Thromboembolism (pulmonary embolism, deep vein thrombosis) * | |||
|
Respiratory, thoracic and mediastinal disorders | ||||
|
Gastrointestinal disorders |
Gastrointestinal signs and symptoms (abdominal pain, nausea, vomiting, diarrhoea, flatulence) |
Pancreatitis1 | ||
|
Hepatobiliary disorders |
Transaminases increased (see section 4.4) |
Cholelithiasis (see section 4.4) |
Hepatitis | |
|
Skin and subcutaneous tissue disorders |
Cutaneous hypersensitivity (eg. Rashes, pruritus, urticaria) |
Alopecia Photosensitivity reactions | ||
|
Musculoskeletal, connective tissue and bone disorders |
Muscle disorder (e.g. myalgia, myositis, muscular spasms and weakness) | |||
|
Reproductive system and breast disorders |
Sexual dysfunction | |||
|
Investigations |
Blood creatinine increased |
Blood urea increased |
increase in deep vein thromboses (placebo: 1.0 % [48/4900 patients] versus fenofibrate 1.4% [67/4895 patients]; p = 0.074).
In addition to those events reported during clinical trials, the following side effects have been reported spontaneously during postmarketing use of Fenofibrate. A precise frequency cannot be estimated from the available data and is therefore classified as “not known”.
Ear and labyrinth disorders: Vertigo
Respiratory, thoracic and mediastinal disorders: Interstitial lung disease Hepatobiliary disorders: Jaundice, complications of cholelithiasis (e.g. cholecystitis, cholangitis, biliary colic)
General and administrative site condition: Fatigue 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, website www.mhra.gov.uk/yellowcard.
4.9 Overdose
Only anecdotal cases of fenofibrate overdosage have been received. In the majority of cases no overdose symptoms 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
Pharmacotherapeutic group:
Serum Lipid Reducing Agents/Cholesterol and Triglyceride Reducers/Fibrates. ATC code: C10 AB 05
Fenofibrate 200 mg Capsules is a formulation containing 200mg of micronized fenofibrate; the administration of this product results in effective plasma concentrations identical to those obtained with 3 capsules of 67mg of micronized fenofibrate.
Mechanism of action:
Fenofibrate is a fibric acid derivative whose lipid modifying effects reported in humans are mediated via activation of Peroxisome Proliferator Activated Receptor type a (PPARa). Through activation of PPARa, fenofibrate increases lipolysis and elimination of atherogenic 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 andA-II.
Pharmacodynamic effects:
Because of its effect on LDL cholesterol and triglycerides, treatment with fenofibrate should be beneficial in hypercholesterolaemic patients with hypertriglyceridaemia, including secondary hyperlipoproteinaemia such as type 2 diabetes mellitus.
Epidemiological studies have demonstrated a positive correlation between abnormally increased serum lipid levels and an increased risk of coronary heart disease. The control of such dyslipidaemia forms the rationale for treatment with Fenofibrate Micro 200. However the possible beneficial and adverse long term consequences of drugs used in the management of dyslipidaemia are still the subject of scientific discussion. Therefore the presumptive beneficial effect of Fenofibrate Micro 200 on cardiovascular morbidity and mortality is as yet unproven.
There is evidence that treatment with fibrates may reduce coronary heart disease events but they have not been shown to decrease all cause mortality in the primary or secondary prevention of cardiovascular disease.
Clinical efficacy and safety
The Action to Control Cardiovascular Risk in Diabetes (ACCORD) lipid trial was a randomized placebo-controlled study of 5518 patients with type 2 diabetes mellitus treated with fenofibrate in addition to simvastatin. Fenofibrate plus simvastatin therapy did not show any significant differences compared to simvastatin monotherapy in the composite primary outcome of non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death (hazard ratio [HR] 0.92, 95% CI 0.79-1.08, p = 0.32; absolute risk reduction: 0.74%). In the pre-specified subgroup of dyslipidaemic patients, defined as those in the lowest tertile of HDL-C (<34 mg/dl or 0.88 mmol/L) and highest tertile of TG (>204 mg/dl or 2.3 mmol/L) at baseline, fenofibrate plus simvastatin therapy demonstrated a 31% relative reduction compared to simvastatin monotherapy for the composite primary outcome (hazard ratio [HR] 0.69, 95% CI 0.49-0.97, p = 0.03; absolute risk reduction: 4.95%). Another prespecified subgroup analysis identified a statistically significant treatment-bygender interaction (p = 0.01) indicating a possible treatment benefit of combination therapy in men (p=0.037) but a potentially higher risk for the primary outcome in
women treated with combination therapy compared to simvastatin monotherapy (p=0.069). This was not observed in the aforementioned subgroup of patients with dyslipidaemia but there was also no clear evidence of benefit in dyslipidaemic women treated with fenofibrate plus simvastatin, and a possible harmful effect in this subgroup could not be excluded.
Studies with fenofibrate on lipoprotein fractions show decreases in levels of LDL and VLDL cholesterol. HDL cholesterol levels are frequently increased. LDL and VLDL triglycerides are reduced. The overall effect is a decrease in the ratio of low and very low density lipoproteins to high density lipoproteins, which epidemiological studies have correlated with a decrease in atherogenic risk. Apolipoprotein-A and apolipoprotein-B levels are altered in parallel with HDL and LDL and VLDL levels respectively.
Extravascular deposits of cholesterol (tendinous and tuberous xanthoma) may be markedly reduced or even entirely eliminated during fenofibrate therapy.
Plasma uric acid levels are increased in approximately 20% of hyperlipidaemic patients, particularly in those with type IV disease.
The uricosuric effect of fenofibrate leading to reduction in uric acid levels of approximately 25% should be of additional benefit in those dyslipidaemic patients with hyperuricaemia.
Fenofibrate has been shown to possess an anti-aggregatory effect on platelets in animals and in a clinical study, which showed a reduction in platelet aggregation induced by ADP, arachidonic acid and epinephrine.
Patients with raised levels of fibrinogen treated with fenofibrate have shown significant reductions in this parameter, as have those with raised levels of Lp(a). Other inflammatory markers such as C Reactive Protein are reduced with fenofibrate treatment.
5.2 Pharmacokinetic properties
Absorption
Maximum plasma concentrations (Cmax) occur within 4 to 5 hours after oral administration. Plasma concentrations are stable during continuous treatment in any given individual.
The absorption of fenofibrate is increased when administered with food.
Distribution
Fenofibric acid is strongly bound to plasma albumin (more than 99%).it can displace antivitamin K compounds from protein binding sites and may potentiate their anticoagulant effect.
Metabolism and excretion
After oral administration, fenofibrate is rapidly hydrolised by esterases to the active metabolite fenofibric acid.
No unchanged fenofibrate can be detected in the plasma. Fenofibrate is not a substrate for CYP 3A4. No hepatic microsomal metabolism is involved.
The drug is excreted mainly in the urine; 70% in 24 hours and 88% in 6 days, at which time the total excretion in urine and faeces reaches 93%. Practically all the drug is eliminated within 6 days. Fenofibrate is mainly excreted as fenofibric acid and its derived glucuroconjugate.
In older patients, the fenofibric acid apparent total plasma clearance is not modified.
Kinetic studies following the administration of a single dose and continuos treatment have demonstrated that the drug does not accumulate.
Fenofibric acid is not eliminated during haemodialysis.
The plasma elimination half-life of fenofibric acid is approximately 20 hours.
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
Intragranular
Sodium lauryl sulphate
Lactose
Pregelatinised starch Crospovidone
Extragranular Crospovidone Pregelatinised starch Talc
Colloidal anhydrous silica Magnesium stearate
Capsule
Gelatin
Titanium dioxide (E171) Sunset yellow FCF (E110)
Printing Ink Shellac glaze Iron oxide black (E172) Propylene glycol
6.2 Incompatibilities
Not applicable
6.3 Shelf life
2 years
6.4 Special precautions for storage
Store in the original package. Do not store above 25°C.
6.5 Nature and contents of container
Blister strip of clear transparent PVC film coated with PVdC on the inner side with a backing of aluminium foil
Pack size of 10, 14, 20, 28, 30, 56, 60 or 90 capsules. Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirement
7
MARKETING AUTHORISATION HOLDER
Ranbaxy (UK) Limited 5th floor, Hyde Park, Hayes 3 11 Millington Road Hayes, UB3 4AZ United Kingdom
8 MARKETING AUTHORISATION NUMBER(S)
PL 14894/0368
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
02/01/2007
10 DATE OF REVISION OF THE TEXT
27/06/2016
In the FIELD-study, a randomized placebo-controlled trial performed in 9795 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