| 4.3. Contraindications
Fenofibrate 267mg is contraindicated in children, in patients with severe liver or renal dysfunction, hepatic insufficiency (including biliary cirrhosis and unexplained persistent liver function abnormality e.g. persistent elevations in serum transaminases), gallbladder disease, biliary cirrhosis and in patients hypersensitive to fenofibrate or any component of this medication, known photoallergy or phototoxic reaction during treatment with fibrates or ketoprofen.
Use during pregnancy and lactation (see section 4.6).
Liver function Transaminases
Moderately elevated levels of serum transaminases may be found in some patients but rarely interfere with treatment. However, iAs 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 serum transaminases levels areshould be monitored every three months during the first twelve 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 Treatment should be interrupted in the event of ALAT (SGPT) or ASAT (SGOT) elevations 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. 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.
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.
OtherNo 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.
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 inhibitors 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.
4.8 Undesirable effects
Fenofibrate is generally well tolerated. Adverse reactions observed during fenofibrate treatment are not very frequent; they are generally minor, transient and do not interfere with treatment.
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:
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MedDRA system organ class
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Common
>1/100, <1/10
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Uncommon
>1/1,000, <1/100
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Rare
>1/10,000, <1/1,000
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Very rare
<1/10,000 incl. isolated reports
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Blood and lymphatic system disorders
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Haemoglobin decreased
White blood cell count decreased
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Immune system disorders
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Hypersensitivity
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Nervous system disorders
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Headache
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Vascular disorders
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Thromboembolism (pulmonary embolism, deep vein thrombosis)*
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Gastrointestinal disorders
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Gastrointestinal signs and symptoms (abdominal pain, nausea, vomiting, diarrhoea, flatulence)
Moderate in severity
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Pancreatitis*
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Hepatobiliary disorders
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Transaminases increased (see section 4.4)
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Cholelithiasis
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Hepatitis
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Skin and subcutaneous tissue disorders
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Cutaneous hypersensitivity (e.g. Rashes, pruritus, urticaria) **
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Alopecia
Photosensitivity reactions
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Musculoskeletal, connective tissue and bone disorders
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Muscle disorder (e.g. myalgia, myositis, muscular spasms and weakness)
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-
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Reproductive system and breast disorders
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Sexual dysfunction
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-
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Investigations
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Blood creatinine increased
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Blood urea increased
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* 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).
The most commonly reported adverse reactions include:
Gastrointestinal: Digestive, gastric or intestinal disorders (abdominal pain, nausea, vomiting, diarrhoea, and flatulence) moderate in severity.
Uncommon: Pancreatitis*
Cardiovascular system
Uncommon: Thromboembolism (pulmonary embolism, deep vein thrombosis)*
** Skin: Reactions such as rashes, pruritus, urticaria or photosensitivity reactions; in individual cases (even after many months of uncomplicated use) cutaneous photosensitivity may occur with erythema, vesiculation or nodulation on parts of the skin exposed to sunlight or artificial UV light (e.g. sun lamp).
Neurological disorders: Headache.
General disorders: Fatigue
Disorders of the ear: Vertigo
Less frequently reported adverse reactions:
Liver: Moderately elevated levels of serum transaminases may be found in some patients but rarely interfere with treatment (see also section 4.4). 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 Special Warnings). Development of gallstones has been reported.
Muscle: As with other lipid lowering agents, cases of muscle toxicity (diffuse myalgia, myositis, muscular cramps and weakness) and very rare cases of rhabdomyolysis have been reported. These effects are usually reversible when the drug is withdrawn (see Special Warnings).
In rare cases, the following effects are reported:
Sexual asthenia and alopecia. Increases in serum creatinine and urea, which are generally slight, and also a slight decrease in haemoglobin and leukocytes may be observed.
Very rare cases of interstitial pneumopathies have been reported.
* 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 from 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 cholelithiasis (e.g. cholecystitis, cholangitis, biliary colic)
- Fatigue
- Vertigo
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.
No case of overdosage has been 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.
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