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 2010/015/004 2007/12/4

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

- SPC section 4.8: Update of HPRA Reporting details for Suspected Adverse Reactions

 

- SPC section 6.4: Change of storage condition from “Store in the original package in order to protect from light and moisture” to “Store below 30°C”

- SPC section 6.4: Change of storage condition from “Store in the original package in order to protect from light and moisture” to “Store below

 

Section 2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 145.0 mg fenofibrate (nanoparticles).

Excipients with known effect: each tablet contains:

-                      132.00 mg of Lactose monohydrate

-                      145.00 mg of Sucrose

-                      0.50 mg of Soybean lecithin.

For the full list of excipients, see section 6.1


Section 6.5 Nature and contents of container:

Storage conditions updated to state: Store in the original package in order to protect from light and moisture.

Section 4.1: Has been updated as follows;

 

From:

Hypercholesterolaemia and hypertriglyceridaemia alone or combined (types IIa, IIb, IV dyslipidaemias, as well as types III and V dyslipidaemias ) in patients unresponsive to dietary and other non-drug therapeutic measures (e.g. weight reduction or increased physical activity), particularly when there is evidence of associated risk such as hypertension and smoking.

The treatment of secondary hyperlipoproteinaemias is indicated if the hyperlipoproteinaemia persists despite effective treatment of the underlying disease (e.g. dyslipidaemia in diabetes mellitus).

Appropriate dietary measures initiated before therapy should be continued.

To:

Lipantil Supra145mg 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.

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

The following changes to the Lipantil Supra 145 mg SPC have been made and are highlighted in bold and italics.

 

Section 4.3:

 

From :

 

·        hepatic insufficiency (including biliary cirrhosis)

·        renal insufficiency

·        children

·        hypersensitivity to fenofibrate or any component of this medication,

·        known photoallergy or phototoxic reaction during treatment with fibrates or ketoprofen

·        gallbladder disease

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

·        Use during pregnancy and lactation: see section 4.6.

·        Lipantil Supra 145 mg film-coated tablet should not be taken in patients allergic to peanut or arachis oil or soya lecithin or related products due to the risk of hypersensitivity reactions.

 

To :

 

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

·        renal insufficiency

·        children (age below 18 years)

·        hypersensitivity to the active substance or to any of the excipients

·        known photoallergy or phototoxic reaction during treatment with fibrates or ketoprofen

·        gallbladder disease

·        chronic or acute pancreatitis with the exception of acute pancreatitis due to severe hypertriglyceridemia

·        Lipantil Supra 145 mg film-coated tablet should not be taken in patients allergic to peanut or arachis oil or soya lecithin or related products due to the risk of hypersensitivity reactions.

 

 

Section 4.4:

 

From :

 

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. Attention should be paid to patients who develop increase in transaminase levels and therapy should be discontinued if ASAT and ALAT levels increase to more than 3 times the upper limit of the normal range or 100 IU.

 

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 hypertriglyceridemia, 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.

 

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 measurement may be considered during the first three months after initiation of treatment.

 

To :

 

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 are 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 (SGPT) levels increase to more than 3 times the upper limit of the normal range or 100 IU. When symptoms indicative of hepatitis occur (e.g. jaundice, pruritus), laboratory tests are to be conducted for verification and discontinuation of fenofibrate therapy may be considered.

Pancreatitis Pancreas: 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 hypertriglyceridemia, a direct drug effect, or a secondary phenomenon mediated through biliary tract stone or sludge formation with obstruction of the common bile duct.

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 measurement may be considered is measured during the first 3 months after initiation of treatment and thereafter periodically (for dose recommendations, see section 4.2 Posology and method of administration).

Section 4.5:

 

From :

 

Oral anticoagulants: Fenofibrate enhances oral anticoagulant effect and may increase risk of bleeding. It is recommended that the dose of anticoagulants 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: 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.

HMG-CoA reductase inhibitors and 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.).

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.

 

To : 

 

Oral anticoagulants: Fenofibrate enhances oral anticoagulant effect and may increase risk of bleeding. It is recommended that the dose of anticoagulants 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: 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.

HMG-CoA reductase inhibitors and 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.).

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 4.8:

 

From :

 

The frequencies of adverse events are ranked according to the following: Very common (>1/10); common (>1/100, <1/10); uncommon (>1/1,000, <1/100); rare (>1/10,000, <1/1,000); very rare (<1/10,000), including isolated reports.

 

Gastrointestinal disorders:

Common: Digestive, gastric or intestinal disorders (abdominal pain, nausea, vomiting, diarrhoea, and flatulence) moderate in severity

Uncommon : Pancreatitis *

 

Hepato-biliary disorders:

Common: Moderately elevated levels of serum transaminases (see Special precautions for use)

Uncommon: Development of gallstones

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 Special warnings)

 

Skin and subcutaneous tissue disorders:

Uncommon: rashes, pruritus, urticaria or photosensitivity reactions

Rare: alopecia

Very rare: cutaneous photosensitivity with erythema, vesiculation or nodulation on parts of the skin exposed to sunlight or artificial UV light (e.g. sunlamp)  in individual cases (even after many months of uncomplicated use)

 

Musculoskeletal, connective tissue and bone disorders:

Rare: diffuse myalgia, myositis, muscular cramps and weakness

Very rare: rhabdomyolysis

 

Cardiovascular system

Uncommon: Thromboembolism (pulmonary embolism, deep vein thrombosis)*.

 

Blood and lymphatic system disorders:

Rare: decrease in haemoglobin and leukocytes

 

Nervous system disorders:

Rare: sexual asthenia, headache

 

Respiratory, thoracic and mediastinal disorders:

Very rare: interstitial pneumopathies

 

Investigation:

Uncommon: Increases in serum creatinine and urea.

 

* 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).

 

To:

 

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:

MedDRA system organ class	Common >1/100, <1/10	Uncommon >1/1,000, <1/100	Rare >1/10,000, <1/1,000	Very rare <1/10,000 incl. isolated reports	Not knowna
Blood and lymphatic system disorders			Decrease in Haemoglobin and leukocytes decreased  White blood cell count decreased
Immune system disorders			Hypersensitivity
Nervous system disorders		Headache	Sexual asthenia Headache
Vascular disorders		Thromboembolism (pulmonary embolism, deep vein thrombosis)*
Respiratory, thoracic and mediastinal disorders					Interstitial pneumopathies

 

Gastrointestinal disorders	Digestive, gastric or intestinal disorders Gastrointestinal signs and symptoms (abdominal pain, nausea, vomiting, diarrhoea, flatulence) Moderate in severity	Pancreatitis*
Hepatobiliary disorders	Moderately elevated levels of Transaminases  increased (see section 4.4)	Development of gallstones Cholelithiasis	Hepatitis (see section 4.4)	Episodes of hepatitis
Skin and subcutaneous tissue disorders		Cutaneous hypersensitivity (e.g. Rashes, pruritus, urticaria, photosensitivity reactions)	Alopecia Photosensitivity reactions	Cutaneous photosensitivity with erythema, vesiculation or nodulation
Musculoskeletal, connective tissue and bone disorders		Muscle disorder (e.g. myalgia, myositis, muscular spasms and weakness)	Diffuse Myalgia, myositis, muscular cramps and weakness Rhabdomyolysis		Rhabdomyolysis
Reproductive system and breast disorders		Sexual dysfunction
Investigations		Increases in serum creatinine and urea Blood creatinine increased	Blood urea increased

*:   In the FIELD-study, a randomized placebo-controlled trial performed in 9,795 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% [48/4,900 patients] versus fenofibrate 1.4% [67/4,895 patients];
p = 0.074).

^a: In addition to those events reported during clinical trials, the following side effects have been reported spontaneously during postmarketing use of <Tradename>. 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.

 

Section 4.9:

 

From :

 

No case of overdosage has been 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.

 

To :

 

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 6.6:

 

From :

 

Special precautions for disposal and other handling

No special requirements.

 

To :

 

Instructions for use and handling Special Precautions for Disposal

No special requirements.

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 hypertriglyceridemia, a direct drug effect, or a secondary phenomenon mediated through biliary tract stone or sludge formation with obstruction of the common bile duct.

4.8        Undesirable effects

Gastrointestinal disorders:

Common: 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

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 810/1/7

10.        DATE OF REVISION OF THE TEXT

May 2006

 

AMENDED

7.                   MARKETING AUTHORIsATION HOLDER

 

Solvay Healthcare Limited,

Mansbridge Road,

West End,

Southampton, SO18 3JD

United Kingdom

8.         MARKETING AUTHORISATION NUMBER

PA 108/30/5

10.               DATE OF REVISION OF THE TEXT

January 2007