7.  MARKETING AUTHORISATION HOLDER

Mylan IRE Healthcare Limited

Unit 35/36

Grange Parade

Baldoyle Industrial Estate

Dublin 13

Ireland

BGP Products Ireland Limited

4051 Kingswood Drive,

Citywest Business Campus,

Dublin 24

8. MARKETING AUTHORISATION NUMBER

 

PA 2010/15/1 2007/12/1

10. DATE OF REVISION OF THE TEXT

 

June 2017

Section 4.2: Additional info added re: posology in Elderly patients and patients with Renal impairment.

Section 4.3: Contra-indications: Severe renal dysfunction deleted and 'Severe Renal Insufficiency' added

Section 4.4: Renal Function section: Additional information added regarding precautions for use

Section 4.6: Additional info. added re: Fertility

Section 4.8 Undesirable effects: UEs deleted and added

Section 5.3: Pre-clinical safety data: Additional information added re: non clinical study in rat species and a repeat dose toxicity study

Section 4.8 - addition of information regarding reporting of side effects

Section 7: Marketing authorisation holder changed from Abbott Healthcare Products Ltd. to BGP Products Ltd.
Section 8: PA number updated

Change in address from SHampton to Maidenhead

- section 4.6 : amendment to lactation statement
- section 4.8: addition of reference to ' skin and subcutaneous tissue disorders' in undesirable effects 

Significant updates to sections 4.2, 4.3, 4.4, 4.6, 4.8, 5.1 & 5.2

4.2.             Posology and Method of Administration

The following information has been added re: paediatric population:

Paediatric population:

The safety and efficacy of fenofibrate in children have not yet been established.  Only limited paediatric data are available  (see section 5.1).  Therefore, the use of fenofibrate is not recommended in paediatric subjects under 18 years.

 

Section 4.1
In the adult, hyperlipidaemia when modifications to diet have been insufficient.

It is always essential to continue the diet.

At the present time, no results of long-term controlled clinical trials are available to demonstrate the efficacy of fenofibrate in the primary or secondary prevention of atherosclerotic complications.

Lipantil^Ò Micro 67mg 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.

Section5.1

 

At the present time, no results of long-term controlled clinical trials are available to demonstrate the efficacy of fenofibrate in the primary or secondary prevention of atherosclerotic complications.

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.

Section 4.1: Has been updated as follows;

 

From:

 

In the adult, hyperlipidaemia when modifications to diet have been insufficient.

It is always essential to continue the diet.

 

At the present time, no results of long-term controlled clinical trials are available to demonstrate the efficacy of fenofibrate in the primary or secondary prevention of atherosclerotic complications.

To:

 

Lipantil^Ò Micro 67mg 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: Has been updated as follows;

 

At the present time, no results of long-term controlled clinical trials are available to demonstrate the efficacy of fenofibrate in the primary or secondary prevention of atherosclerotic complications.

 

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 additions/updates to the Lipantil Micro 67mg SPC have been made and are highlighted in bold and italics.

Section 2: addition of the following;

Excipients: each capsule contains 33.8 mg of lactose monohydrate.


Section 4.2: as well as an update of the subheadings the following information has been included;

Method of administration: Capsules should be swallowed whole with water.


Section 4.3: Bullet points have been introduced for clarity and the following has been modified;

• hepatic insufficiency (including biliary cirrhosis and unexplained persistent liver function abnormality e.g. persistent elevations in serum transaminases)


Section 4.4: as well as an update to the subheadings the following has been introduced/modified;


Liver Function: 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 and thereafter periodically. Treatment should be discontinued if ASAT (SGOT) and ALAT (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 are confirmed by laboratory testing, fenofibrate therapy should be discontinued.


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. 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 Posology and method of administration).

Section 4.5:

Oral Anti-coagulants: Fenofibrate enhances oral anti-coagulant effect and may increase risk of bleeding. It is recommended that the dose of anti-coagulant is reduced by about one-third at the start of treatment and then gradually adjusted if necessary according to INR (International Normalised Ratio) monitoring. Therefore, this combination is not recommended.

Cyclosporin: Concomitant administration of fenofibrate (200mg once daily) and cyclosporin did not significantly alter steady-state pharmacokinetic parameters of cyclosporin in heart transplantation patients. However, Some severe cases of reversible renal function impairment have been reported during concomitant administration of fenofibrate and cyclosporin. 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 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.

Section 4.7:

Lipantil Micro 67 mg, capsules have no or negligible influence on the ability to drive and use machines.


Section 4.8: This section has been updated with the SPC guidelines and the undesirable effects tabulated according to the MedDRA system organ class and ranked under headings of frequency. ADRs noted in clinical trails are tabulated with information on post marketing ADRs (frequency not known) also included.


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 an overdose is suspected, treat symptomatically and institute appropriate supportive measures as required. Fenofibrate cannot be eliminated by haemodialysis.

Section 5.1:
During clinical trials with fenofibrate total cholesterol is reduced by 20 to 25%, triglycerides by 40-55% and HDL cholesterol is increased by 10 to 30%.
In hypercholesterolaemic patients, where LDL cholesterol levels are reduced by 20 to 35%, the overall effect on cholesterol results in a decrease in the ratios of total cholesterol to HDL cholesterol, LDL cholesterol to HDL cholesterol, or Apo B to Apo A-I, all of which are markers of atherogenic risk.
Section 6.4:

Store in the original package in order to protect from moisture.

This medicinal product does not require any special temperature storage conditions.

Name of the Marketing Authorisation Holder has been changed to Abbott Healthcare Products Ltd.

 

Section 2: Updated to include the excipient Lactose monohydrate. Further, standard comment added to refer to section 6.1 of the SPC

section 3: "s" removed from capsules to read capsule

section 6.1:each excipient is now listed on a separate line.

section 6.5:asterix removed

section 6.6:heading updated to be in line with current SPC guidelines. Following additonal sentence added; "Any unused product or waste material should be disposed of in accordance with local requirements."

section 4.8:frequency of hepatitis changed from very rare to rare.

section 9:date of last renewal changed to 13th July 2008

section 10 last revision of text changed to March 2009

 Section 4.3; Now reads as follows;

 Under renal impairment the following additional has been made:

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

Myopathy section: changed from

 Patients with pre-disposing factors for rhabdomyolysis, including renal impairment, hypothyroidism and high alcohol intake, may be at an increased risk of developing rhabdomyolysis.

 To read as follows:

 Patients with pre-disposing factors for myopathy and/or rhabdomyolysis, including age above 70 years old, 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.

 Also the following is now stated:

 This medicinal product contains lactose. Therefore patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

 Section 4.8

 ADRs are now ranked under headings of frequency

 Pancreatitis is now added

 Section 6.4: Now stated as follows:

 Store in the original package, in order to protect from moisture.

Section 9: Modified to read as follows;

 Date of first authorisation: 13th July 1998

Date of last renewal: 13th July 2003

 

 

 

PREVIOUS

7.                  MARKETING AUTHORIsATION HOLDER

FOURNIER Pharmaceuticals Ltd

19-20 Progress Business Center,

Whittle Parkway

SLOUGH SL1 6DQ

BERKSHIRE

United Kingdom

8.         MARKETING AUTHORISATION NUMBER (S)

                PA 810/1/1

10.        DATE OF REVISION OF THE TEXT

August 2003

 

AMENDED

7.                   MARKETING AUTHORIsATION HOLDER

 

Solvay Healthcare Limited,

Mansbridge Road,

West End,

Southampton, SO18 3JD

United Kingdom

8.         MARKETING AUTHORISATION NUMBER

                  PA 108/30/1

10.               DATE OF REVISION OF THE TEXT

January 2007