Fenogal 200mg Capsules
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Fenogal 200mg capsules
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Fenogal 200mg capsules contain 200mg fenofibrate.
For a full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Hard gelatin capsules.
Fenogal is presented in capsules with an orange body and green cap.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Fenogal 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
Adults
The recommended initial dose is one capsule taken daily, during a main meal.
In elderly patients without renal impairment, the normal adult dose is recommended. Since it is less well absorbed from an empty stomach, Fenogal should always be taken with food. Dietary restrictions instituted before therapy should be continued.
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
Fenogal is contra-indicated in children, in patients with severely impaired liver or renal function, gall bladder disease, biliary cirrhosis and unexplained persistent liver function abnormality e.g. persistent elevations in serum transaminases and in patients hypersensitive to fenofibrate or any other component of this medication, or with a known photoallergy or phototoxic reaction during treatment with fibrates or ketoprofen.
Chronic or acute pancreatitis with the exception of acute pancreatitis due to severe hypertriglyceridemia
4.4 Special warnings and precautions for use
Secondary causes of dyslipidaemia, 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 initiated.
Response to therapy should be monitored by determination of serum lipid values (total cholesterol, LDL-C, trigliycerides). If an adequate response has not been achieved after several months (e.g. 3 months) complementary of different therapeutic measures should be considered.
Renal function
In renal dysfunction, the dose of fenofibrate may need to be reduced, depending on the rate of creatinine clearance. In this case, fenofibrate 67mg ( micronized fenofibrate) should be used e.g. 2 capsules of fenofibrate 67mg daily for creatinine clearance levels of < 60 ml/min and 1 capsule of fenofibrate 67mg for creatinine clearance levels of < 20 ml/min.
It is recommended that creatinine is measured during the first three months after initiation and therefore periodically. Treatment should be interrupted in case of an increase in creatinine levels > 50 % of upper limit of normal.
Use of fenofibrate 67mg is also to be preferred in elderly patients with renal impairment where dosage reduction may be preferred.
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 be 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 ASAT (SGOT) and ALAT (SPGT) levels increase to more than 3 times the upper limit of the normal range. When symptoms indicative of hepatitis occur (e.g. jaundice, pruritis) and diagnosis is confirmed by laboratory, fenofibrate therapy should be discontinued.
Pancreatitis:
Pancreatitis has been reported in some patients taking fenofibrate (see sections 4.3 and 4.8). This occurrence may represent a failure of efficacy in patients with severe hypertriglyceridemia, a direct effect of the drug, or a secondary phenomenon mediated through biliary tract stone or sludge formation, resulting in the obstruction of the common bile duct.
Myopathy:
Muscle toxicity, including very rare cases of rhabdomyolysis, have been reported with administration of fibrates and other lipid lowering agents. The incidence of this disorder increases in cases of hypoalbuminaemia and previous renal insufficiency. Patients with pre-disposing factors for rhabdomyolysis, including age above 70 years, personal or familial history of hereditary muscular disorders, renal impairment, hypothyroidism and high alcohol intake, may be at 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 a HMG-CoA reductase inhibitor, especially in cases of pre-existing 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).
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 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 fenofibrates 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 isomers CYP3A1, CYP2E1 or CYP1A2. They are weak inhibitors of CYP2C19 and CYP3A6 and mild and moderate of CYP2CP 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. Pregnancy and lactation
There is 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 in unknown.
There are no data on the excretion of fenofibrate and/or its metabolites into breast milk. It is therefore recommended that Fenogal should not be administered to women who are pregnant or breast feeding.
4.7. Effects on ability to drive and use machines
No effect noted to date.
4.8 Undesirable effects
The frequencies of adverse events are ranked according to the following:
|
MedDRA |
Common |
Uncommon |
Rare |
Very rare |
|
system |
>1/100, <1/10 |
>1/1,000, |
>1/10,000 |
< |
|
< 1/1000 |
<1/1000 |
1/10,000 | ||
|
Isolated | ||||
|
reports |
|
Blood and lymphatic system disorders |
Haemoglobin Decreased White blood cell count decreased | |||
|
Immune systems disorders |
Hypersensitivity | |||
|
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, diarrhea, flatulence) |
Pancreatitis* | ||
|
Hepatobiliary disorders |
Transaminases increased (see section 4.4.) |
Cholelithiasis |
Hepatitis | |
|
Skin and subcutaneous tissue disorders |
Cutaneous hypersensitivity (e.g. rashes, pruritis, utricaria) |
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 |
*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 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 form the available data and is therefore classified as not known.
Respiratory, thoracic and mediastinal disorders: interstitial lung disease
Musculoskeletal, connective tissue and bone disorders: rhabdomyolysis
Hepatobiliary disorders: jaundice, complications of choleithiasis (e.g. cholecystitis, cholangitis, biliary colic)
Fatigue
Vertigo
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 overdosage 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: C10AB05.
Mechanism of action: Fenogal is a formulation containing 200mg of micronised fenofibrate. The administration of this product results in effective plasma concentrations identical to those obtained with 3 capsules of fenofibrate 67mg containing 67mg of micronized fenofibrate.
The lipid-lowering properties of fenofibrate seen in clinical practice have been explained in vivo in transgenic mice and 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 abnormally increased serum lipid levels and an increase risk of coronary heart disease. The control of such dyslipidaemia forms the rationale for treatment with Fenogal. 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 Fenogal 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.
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 0.791.08, 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-by-gender 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.
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 disease. Fenogal has a uricosuric effect and is therefore of additional benefit in such patients.
Patients with raised levels of fibrinogen and Lipoprotein 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 15pg/ml for a daily dose of 200mg of micronised fenofibrate, equivalent to 3 capsules of fenofibrate 67mg Steady state levels are observed throughout continuous treatments.
Fenofibric acid is highly bound to plasma albumin; it can displace antivitamin K compounds from protein binding sites and may potentiate their anti-coagulant effect. 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 hour and 88% in 6 days, at which time the 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 doses, 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
Lauroyl macrogolglycerides, Macrogol 20,000, Hydroxypropylcellulose, Gelatin capsules (containing black, yellow and red iron oxide (E172), indigo carmine (E132), titanium dioxide (E171)).
6.2
Incompatibilities
Not applicable.
6.3 Shelf life
36 months.
6.4 Special precautions for storage
Do not store above 25°C. Store the capsules in their original container
6.5 Nature and contents of container
PVC blister, sealed with aluminium foil, packaged in a carton containing 30 capsules.
6.6. Special precautions for disposal
No special requirements.
7 MARKETING AUTHORISATION HOLDER
Genus Pharmaceuticals Limited
T/A Genus Pharmaceuticals
Linthwaite
Huddersfield
HD75QH
UK
8 MARKETING AUTHORISATION NUMBER(S)
PL 06831/0089
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation: 20 May 2002 Date of latest renewal: 20 February 2009
10 DATE OF REVISION OF THE TEXT
24/02/2015