Fenofibrate 200mg Capsules
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Fenofibrate 200mg Capsule, hard
2. Qualitative and Quantitative Composition
Each capsule, hard contains : fenofibrate 200 mg For excipients see section 6.1.
3. Pharmaceutical Form
Capsule, hard
Size 1 capsules, hard, with opaque yellow caps and transparent bodies, containing white spherical microgranules.
Clinical Particulars
4.1. Therapeutic Indications Adults only
Hypercholesterolaemia and hypertriglyceridaemia alone or combined (type IIa, IIb, IV dyslipidaemias, as well type III and V dyslipidaemia although only few patients have been treated during clinical trials) in patients unresponsive to dietary and other nondrug therapeutic measures (e.g. weight reduction or increased physical activity), particularly when there is evidence of associated risk factors.
The treatment of secondary hyperlipoproteinaemias is indicated if the hyperlipoproteinaemia persists despite effective treatment of the underlying disease (e.g. dyslipidaemia in diabetes mellitus).
Dietary measures initiated before therapy should be continued.
No long-term controlled trials demonstrating the efficacy of fenofibrate in the primary or secondary prevention of complications of atherosclerosis are available to date.
4.2. Posology and Method of Administration
In combination with diet, this medication constitutes a long-term symptomatic treatment, the efficacy of which should be monitored periodically.
- The dosage of FENOFIBRATE 200 mg is one capsule (i.e. 200 mg fenofibrate) per day during one of the main meals; the 200 mg capsules should only be used in patients who need this form (see 5.2 : "Pharmacokinetic properties").
- Once the cholesterol level has been normalised, it is recommended to reduce the dosage by using a formulation of fenofibrate 67 mg at a dose of 2 capsules per day, (or, if the strength is not available, by using appropriate lower strength)
Response to therapy should be monitored by determination of serum lipid values. Rapid reduction of serum lipid levels usually follows 200 mg fenofibrate, but if an adequate response has not been achieved after several months (e.g 3 months), different therapeutic measures should be considered.
In elderly
In elderly patients without renal impairment, the usual adult dose is recommended.
In patients with renal impairment
In patients with renal impairment, the dosage may need to be reduced depending on the rate of creatinine clearance.
4.3. Contra-indications
This medicinal product should never be prescribed in the following situations:
- impaired liver function,
- severe renal dysfunction
- known phototoxic or photoallergic reactions during treatment with fenofibrate or a substance of related structure and in particular ketoprofen,
- in combination with another fibrate (see 4.5 "Interaction with other medicinal products and other forms of interaction"),
- hypersensitivity to fenofibrate or to any of the excipients,
- In children.
4.4. Special Warnings and Precautions for Use Warnings
There have been reports of muscle damage, including exceptional cases of rhabdomyolysis, with fibrates. This may occur more frequently in patients with hypoalbuminaemia.
Muscle damage should be suspected in any patient who has diffuse myalgia, painful muscular sensitivity and/or a major elevation of muscular creatine phosphokinase (CPK) (to 5 times the normal level): in this situation the treatment should be discontinued and patients monitored.
Moreover, the risk of muscle damage may be increased if the drug is administered in combination with another fibrate or with an HMG-CoA reductase inhibitor (see 4.5 "Interaction with other medicinal products and other forms of interaction").
- The use in combination with HMG-CoA reductase inhibitors is not recommended (see 4.5 : " Interaction with other medicinal products and other forms of interaction").
- The prescription of fenofibrate during lactation is not recommended (see 4.6 : "Pregnancy and lactation").
- Patients with a rare hereditary problems of fructose intolerance, glucose and galactose malabsorption syndrome or sucrase-isomaltase deficiency should not take this medicine.
Precautions for use
- Fenofibrate capsule should only be used in patient in whom a full investigation has been performed to define their abnormality. Other risk factors, such as hypertension and smoking, may also require management.
- Elevation, generally transient, of transaminase levels has been observed in some patients. On the basis of current knowledge, this would appear to justify:
• systematic monitoring of the transaminases every 3 months during the first 12 months of treatment,
• withdrawal of the treatment in the event of elevations of SGOT and SGPT to more than 3 times the upper normal limit.
- If the patient is receiving concomitant oral anticoagulant treatment, closer monitoring of INR, is essential (see 4.5 "Interaction with other medicinal products and other forms of interaction").
4.5. Interactions with other medicinal products and other forms of Interaction Contra-indicated combination + Other fibrates : increased risk of undesirable effects such as rhabdomyolysis and pharmacodynamic antagonism between the two molecules (See 4.3 "Contra-indications").
Combination not recommended (see 4.4 "Special warnings and precautions for use")
+ HMG-CoA reductase inhibitors : increased risk of undesirable effects such as rhabdomyolysis.
Combination involving precautions for use
+ Oral anticoagulants : increased effect of the oral anticoagulant and greater risk of haemorrhage (due to displacement from its plasma protein binding sites).
The INR should be more frequently monitored. The dosage of the oral anticoagulant should be reduced at the commencement of therapy, and then adjusted, based on INR, during and 8 days after withdrawal of fenofibrate therapy.
+ Other concomitant therapy :
The potential for fenofibrate/fenofibric acid to affect the metabolism of the protein binding level of other medicinal products has not been fully investigated in vitro/in vivo. The clinical relevance of these interactions cannot be predicted, and therefore, caution is recommended if fenofibrate is combined with other medical products.
4.6. Pregnancy and Lactation
Pregnancy
- Results of animal studies have shown no evidence of a teratogenic effect.
- No malformations or foetotoxic effects have been observed in clinical use to date. However, the available data relating to pregnancies exposed to fenofibrate are not sufficient to rule out any risk.
- There is no indication for prescribing fibrates during pregnancy, with the exception of major hypertriglyceridaemia (> 10g/l) insufficiently corrected by dietary measures, which exposes the mother to the risk of acute pancreatitis.
Lactation
No information is available on the excretion of fenofibrate in breast milk.
Prescription of the product during lactation is consequently not recommended
(see 4.4 : "Special warnings and precautions for use").
4.7. Effects on Ability to Drive and Use Machines
No effect noted to date.
4.8. Undesirable Effects
The following undesirable effects have been observed and reported during treatment with Fenofibrate Hexal 200 mg
Very common >1/10
Common >1/100 and <1/10
Uncommon >1/1000 and <1/100
Rare >1/10000 and <1/1000
Very rare <1/10000 including isolated cases
Musculoskeletal, connective tissue and bone disorders:
Common: myalgia, myositis, muscular cramps and weakness (as with other lipid lowering agents).
Very rare: rhabdomyolysis
These effects are usually reversible when the drug is withdrawn (see 4.4 “Special warnings and precautions for use).
Gastrointestinal disorders
Common: abdominal pain, nausea, vomiting, diarrhoea, and flatulence
Very rare cases of pancreatitis have been reported during treatment with fenofibrate (see section 4.4 Special warnings and precautions for use)
Skin and subcutaneous tissue disorders Common: rash, pruritus, urticaria
Very rare: photosensitivity with erythema, vesiculation or nodulation on parts of the skin exposed to sunlight or artificial UV light (even after many months of uncomplicated use)
Hepatobiliary disorders
Common: Moderately elevated levels of serum transaminases (see 4.4 “Special warnings and precautions for use”).
Rare: gallstones (but any causal relationship remains inconclusive)
Very rare: Episodes of hepatitis. When symptoms (e.g. jaundice, pruritus) indicative of hepatitis occur, laboratory tests are to be conducted for verification and fenofibrate discontinued, if applicable (see 4.4 : “Special warnings and precautions for use”).
Nervous system disorders Rare: headache and dizziness
Reproductive system and breast disorders
Rare: sexual asthenia
Investigations
An increase in the homocysteine levels has been reported on fenofibrate.
Increases in serum creatinine and urea, which are generally slight, and also a slight decrease in haemoglobin and leukocytes may be observed.
4.9. Overdose
No case of overdosage has been reported. No specific antidote is known. If an overdosage is suspected, treat symptomatically and institute appropriate supportive measures as required. Fenofibrate can not be eliminated by haemodialysis.
Pharmacological Properties
5.1. Pharmacodynamic Properties
Pharmacotherapeutic group : Cholesterol and Triglycerides reducers/Fibrates ATC code : C 10 AB05
Fenofibrate is capable of lowering serum cholesterol by 20 to 25% and serum
triglycerides by 40 to 50%.
- The decrease in the cholesterol level is due to a reduction of the low-density atherogenic fractions (VLDL and LDL). It improves the distribution of cholesterol in plasma by reducing the total cholesterol:HDL cholesterol ratio, which increases in atherogenic hyperlipidaemia.
- A relationship has been established between hypercholesterolaemia and atherosclerosis, and between atherosclerosis and the risk of coronary heart disease. Low HDL levels are associated with an increased risk of coronary disease. High triglyceride levels are associated with an increased vascular risk, but it has not been established that this relation is independent. In addition, triglycerides may be involved in the process of atherogenesis, and also of thrombogenesis.
- Extravascular cholesterol deposits (tendinous and tuberous xanthomata) may regress considerably or even disappear completely with prolonged effective treatment (a major decrease in the serum cholesterol level).
- A uricosuric effect has been demonstrated in hyperlipidaemic patients, with a resultant average reduction of about 25% in plasma uric acid.
- With fenofibrate treatment, an increase in apoproteins A1 and a decrease in apoproteins B improve the apo. A1:apo. B ratio, which can be regarded as an indicator of the risk of atherogenesis.
- An inhibitory effect of fenofibrate on platelet aggregation has been demonstrated in animals, and subsequently in man in the course of a clinical trial. It is manifested in a reduction of aggregation induced by ADP, arachidonic acid and adrenaline.
- Through activation of the Peroxisome Proliferator Activated Receptor type a (PPAR a), fenofibrate increases lipolysis and elimination of particles rich in triglycerides from plasma by activating lipoprotein lipase and reducing production of apoprotein C III.
5.2. Pharmacokinetic Properties
This FENOFIBRATE 200 mg formulation, contains 200 mg of highly bioavailable fenofibrate. The product is not recovered in unchanged form in the plasma. The major metabolite found in the plasma is fenofibric acid which is an active metabolite.
The maximum plasma concentration is reached 5 hours on average after ingestion of the product.
The mean plasma concentration is about 15pg/ml for a daily dosage of 200 mg of this formulation of fenofibrate. Intra-individual plasma concentrations are stable with continuous treatment.
The absorption of fenofibrate is increased when taken with food.
Fenofibric acid is highly bound (> 99%) to plasma albumin and may displace oral anticoagulants from their protein binding sites and potentiate their anticoagulant effect (see 4.5 "Interaction with other medicinal products and other forms of interaction").
The plasma elimination half-life of fenofibric acid is about 20 hours.
The product is eliminated essentially by the urinary route, and elimination is virtually complete in 6 days.
Fenofibrate is excreted principally as fenofibric acid and its glucuronide derivative.
Kinetic studies after single doses and continuous treatment show that there is no 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 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 humans. 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
Capsule content:
- Sucrose*
- maize starch*
- hypromellose
- sodium laurilsulfate
- dimeticone (35% emulsion), containing : dimeticone, polyethylene glycol sorbitan monolaurate, (t-octylphenoxy) polyethoxyethanol, sorbic acid,
sodium benzoate, propylene glycol, propyl p-hydroxybenzoate, methyl p-hydroxybenzoate
- simeticone (30% emulsion), containing : simeticone, polyethylene glycol stearate, polyethylene glycol sorbitan tristearate, glycerides, xanthan gum, methyl cellulose, sorbic acid, benzoic acid, sulfuric acid
- talc.
* In the form of sucrose and maize starch microgranules.
Composition of the capsule shell:
gelatin
titanium dioxide (E 171)
Yellow iron oxide (E 172).
6.2. Incompatibilities
Not applicable.
6.3. Shelf-Life
3 years.
6.4. Special Precautions for Storage
No special precautions for storage.
6.5. Nature and Content of Container
Capsules in blister packs (PVC/Aluminium) of 20, 28, 30, 50, 90 or 100 capsules (for Fenofibrate 200 mg Capsules, hard)
Not all pack sizes may be marketed
6.6 Special precautions for disposal
No special requirements.
7. MARKETING AUTHORISATION HOLDER
TILLOMED Laboratories Limited 3 Howard Road Eaton Socon St Neots
Cambridgeshire PE19 3ET United Kingdom
8. MARKETING AUTHORISATION NUMBER(S)
PL 11311/0184
9. DATE OF FIRST AUTHORISATION/RENEWAL OF AUTHORISATION
13 May 2002
10 DATE OF REVISION OF THE TEXT
17/05/2005