Abbott Healthcare Products Limited

Section 4.3:

FROM:

Lipantil Micro 200 is contra-indicated 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.

Chronic or acute pancreatitis with the exception of acute pancreatitis due to severe hypertriglyceridemia.

Use during pregnancy and lactation (see section 4.6).

TO:

Lipantil Micro 200 is contra-indicated in children, in patients with severe renal dysfunction, hepatic insufficiency (including biliary cirrhosis and unexplained persistent liver function abnormality e.g. persistent elevations in serum transaminases), gallbladder disease, in patients hypersensitive to fenofibrate or any component of this medication, 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.

Section 4.9:

No case of overdosage has been reported. 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.

TO:

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.

Section 7:

From:

Solvay Healthcare Ltd

Mansbridge Road

West End

Southampton

SO18 3JD

United Kingdom

To:

Abbott Healthcare Products Ltd

Mansbridge Road

West End

Southampton

SO18 3JD

United Kingdom

Section 4.1:

FROM:

Lipantil Micro 200 reduces elevated serum cholesterol and triglyceride and is of benefit  in the treatment of severe dyslipidaemia in patients in whom dietary measures alone have failed to produce an adequate response. Lipantil Micro 200 is therefore indicated in appropriate cases of hyperlipidaemia (Fredrickson classification types IIa, IIb, III, IV and V).

Lipantil Micro 200 should only be used in patients whose disease is unresponsive to dietary control and in whom a full investigation has been performed to define their abnormality, and where long-term risks associated with their condition warrant treatment.  Other risk factors, such as hypertension and smoking, may also require management.

TO:

Lipantil^Ò Micro 200mg 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.

Section 5.1: The following has been included;

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 0.79-1.08, 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-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.

The following updates to the Lipantil 200mg SPC have been approved:

4.2  Posology and method of administration

From:

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, Lipantil Micro 200 should always be taken with food.  Dietary restrictions instituted before therapy should be continued.

Response to therapy should be monitored by determination of serum lipid values.  Rapid reduction of serum lipid levels usually follows Lipantil Micro 200 treatment, but treatment should be discontinued if an adequate response has not been achieved within three months.

To:

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, Lipantil Micro 200 should always be taken with food.  Dietary restrictions instituted before therapy should be continued.

4.4 Special warnings and precautions for use

From:

In renal impairment

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.

Transaminases

Moderately elevated levels of serum transaminases may be found in some patients but rarely interfere with treatment.  However, it is recommended that serum transaminases should be monitored every three months during the first twelve months of treatment.  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 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 rhabdomyolysis, including renal impairment, hypothyroidism and high alcohol intake, may be at an increased risk of developing rhabdomyolysis.

Muscle toxicity, including very rare cases of rhabdomyolysis, has 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. 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 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).

For patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption:  although the amount of lactose contained in Lipantil Micro 67 mg is low, caution should be exercised in these patients (as no study has been formally conducted in this special population).

In children

Only an hereditary disease (familial hyperlipidaemia) justifies early treatment, and the precise nature of the hyperlipidaemia must be determined by genetic and laboratory investigations.  It is recommended to begin treatment with controlled dietary restrictions for a period of at least 3 months.  Proceeding to medicinal treatment should only be considered after specialist advice and only in severe forms with clinical signs of atherosclerosis and/or xanthomata and/or in cases where patients suffer from atherosclerotic cardiovascular disease before the age of 40.

To:

Secondary causes of dyslipidaemia, 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 initiated.

Response to therapy should be monitored by determination of serum lipid values (total cholesterol, LDL-C, triglycerides). If an adequate response has not been achieved after several months (e.g. 3 months) complementary or 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, (see section 4.2).  Dose reduction should be considered in elderly patients with impaired renal function.

It is recommended that creatinine is measured during the first three months after initiation of treatment and thereafter periodically. Treatment should be interrupted in case of an increase in creatinine levels > 50% of (upper limit of normal).

Liver function abnormalities

Moderately elevated levels of serum transaminases may be found in some patients but rarely interfere with treatment.  However, it is recommended that serum transaminases should be monitored every three months during the first twelve months of treatment.  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 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

Muscle toxicity, including rare cases of rhabdomyolysis, has 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 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 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).

For patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption:  although the amount of lactose contained in Lipantil Micro 67 mg is low, caution should be exercised in these patients (as no study has been formally conducted in this special population).

In children

Only an hereditary disease (familial hyperlipidaemia) justifies early treatment, and the precise nature of the hyperlipidaemia must be determined by genetic and laboratory investigations.  It is recommended to begin treatment with controlled dietary restrictions for a period of at least 3 months.  Proceeding to medicinal treatment should only be considered after specialist advice and only in severe forms with clinical signs of atherosclerosis and/or xanthomata and/or in cases where patients suffer from atherosclerotic cardiovascular disease before the age of 40.

Solvay Healthcare Ltd

Mansbridge Road

West End

Southampton

SO18 3JD

United Kingdom

8.  MARKETING AUTHORISATION NUMBER(S)

PL 00512/0390

10.  DATE OF REVISION OF THE TEXT

        July 2007

Added (in blue)

4.3  Contraindications

Chronic or acute pancreatitis with the exception of acute pancreatitis due to severe hypertriglyceridemia.

4.4  Special warnings and precautions for use

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.

4.8  Undesirable Effects

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)*.

* 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).

10.  DATE OF REVISION OF THE TEXT

June 2007