PRAVAFENIX 40mg / 160mg capsules medication leaflet

Pravafenix 40 mg/160 mg hard capsules

Each hard capsule contains 40 mg pravastatin sodium and 160 mg fenofibrate.

Each hard capsule contains 19 mg of lactose monohydrate and 33.3 mg of sodium.

For the full list of excipients, see section 6.1.

Hard capsule.

Hard capsule, with light green body and olive cap, containing a waxy white beige mass and a tablet.

Pravafenix is indicated as an adjunct to diet and other non-pharmacological treatment (e.g. exercise,weight reduction) for the treatment of mixed hyperlipidaemia in adult patients at high cardiovascularrisk to reduce triglycerides and increase HDL-C when LDL-C levels are adequately controlled whileon a treatment with pravastatin 40 mg monotherapy.

Prior to initiating Pravafenix, secondary causes of combined dyslipidaemia should be excluded andpatients should be placed on a standard cholesterol and triglycerides-lowering diet which should becontinued during treatment.

The recommended dose is one capsule per day. Dietary restrictions instituted before therapy should becontinued.

Response to therapy should be monitored by determination of serum lipid values. Rapid reduction ofserum lipid levels usually follows Pravafenix treatment, but treatment should be discontinued if anadequate response has not been achieved within three months.

Elderly patients (≥ 65 years old)

Treatment initiation with Pravafenix should be decided after renal function has been evaluated (seesection 4.4 Renal and urinary disorders). Limited safety data on Pravafenix is available in patients >75years of age and care should be exercised.

Pravafenix is contraindicated in patients with moderate to severe renal impairment (defined as acreatinine clearance < 60 ml/min) (see section 4.3.)

No modification of posology should be necessary in patients with mild renal impairment.

Pravafenix is not recommended in patients with moderate hepatic impairment and is contraindicated inpatients with severe hepatic impairment (see section 4.3.). No posology adjustment is required inpatients with mild hepatic impairment.

Paediatric population (< 18 years old)

There is no relevant use of Pravafenix in the paediatric population (< 18 years old) for the indicationof mixed dyslipidaemia (see section 4.3).

Oral use.

The recommended dose is one capsule taken daily during the evening meal. Since it is less wellabsorbed from an empty stomach, Pravafenix should always be taken with food (see sections 4.5. and5.2).

- Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.

- Severe hepatic impairment including biliary cirrhosis or active liver disease including unexplainedpersistent elevations in liver function tests (including serum transaminase elevation) exceeding 3fold the upper limit of normal (ULN) (see section 4.4).

- Children and adolescents (age below 18 years).

- Moderate to severe renal impairment (defined as an estimated creatinine clearance < 60 ml/min).

- Known photo allergy or photo toxic reaction during treatment with fibrates or ketoprofen.

- Gallbladder disease (see section 4.4).

- Chronic or acute pancreatitis with the exception of acute pancreatitis due to severehypertriglyceridaemia (see section 4.4).

- Pregnancy and breast-feeding (see section 4.6).

- Personal history of myopathy and/or rhabdomyolysis with statins and/or fibrates or confirmedcreatine phosphokinase (CK) elevation above 5 times the ULN under previous statin treatment(see section 4.4).

The pharmacokinetics properties of Pravafenix are not completely identical to the co-administration ofthe existing monotherapies when taken with fat-meal or in fasting state. Patients should not beswitched from a free co-administration of fenofibrate and pravastatin preparation to Pravafenix (seesection 5.2.).

As with other lipid lowering substances, pravastatin or fenofibrate have been associated with the onsetof myalgia, myopathy and very rarely rhabdomyolysis with or without secondary renal insufficiency.

Rhabdomyolysis is an acute potentially fatal condition of skeletal muscle, which may develop at anytime during treatment and is characterised by massive muscle destruction associated with majorincrease in CK (usually > 30 or 40 times the ULN) leading to myoglobinuria.

The risk of muscle toxicity is increased when a fibrate and a 3-hydroxy-3-methyl-glutaryl-

Coenzyme A (HMG-CoA) reductase inhibitor are administered together. Myopathy must beconsidered in any patient presenting with unexplained muscle symptoms such as pain or tenderness,muscle weakness, or muscle cramps. In such cases CK levels should be measured (see below).

Consequently, the potential benefit/risk ratio of Pravafenix should be closely assessed before treatmentinitiation and patients should be monitored for any signs of muscle toxicity. Certain predisposingfactors such as age > 70, renal impairment, hepatic impairment, hypothyroidism, personal history ofmuscular toxicity with a statin or fibrate, personal or familial history of hereditary muscular disordersor alcohol abuse may increase the risk of muscular toxicity and therefore CK measurement is indicatedbefore starting the combination therapy in these patients (see below).

Statins including pravastatin must not be co-administered with systemic formulations of fusidic acid orwithin 7 days of stopping fusidic acid treatment. In patients where the use of systemic fusidic acid isconsidered essential, statin treatment should be discontinued throughout the duration of fusidic acidtreatment. There have been reports of rhabdomyolysis (including some fatalities) in patients receivingfusidic acid and statins in combination (see section 4.5). The patient should be advised to seek medicaladvice immediately if they experience any symptoms of muscle weakness, pain or tenderness.

Statin therapy may be re-introduced seven days after the last dose of fusidic acid.

In exceptional circumstances, where prolonged systemic fusidic acid is needed, e.g., for the treatmentof severe infections, the need for co-administration of Pravafenix and fusidic acid should only beconsidered on a case by case basis and under close medical supervision.

Before treatment initiation

CK levels should be measured prior to initiation of therapy. The baseline CK levels may also be usefulas a reference in the event of a later increase during the combination therapy. When measured, CKlevels should be interpreted in the context of other potential factors that can cause transient muscledamage, such as strenuous exercise or muscle trauma and repeated if necessary.

If CK levels are significantly elevated > 5 times the ULN at baseline, the results should be controlledafter 5-7 days. If confirmed, the treatment should definitively not be initiated (see section 4.3).

Routine monitoring of CK is systematically recommended every 3 months during the first 12 monthsof the combination therapy and let to the appreciation of the clinician beyond this initial period.

Patients should be advised to report promptly unexplained muscle pain, tenderness, weakness orcramps. In these cases, CK levels should be measured.

If a markedly elevated (> 5 times the ULN) CK level is detected and confirmed, Pravafenix therapymust be discontinued. Treatment discontinuation should also be considered if the muscular symptomsare severe and cause daily discomfort (whatever CK levels). If a hereditary muscular disease issuspected in such patients, restarting Pravafenix therapy is not recommended.

There have been very rare reports of an immune-mediated necrotizing myopathy (IMNM) during orafter treatment with some statins. IMNM is clinically characterized by persistent proximal muscleweakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment.

As with other lipid lowering medicinal products, moderate increases in transaminase levels have beenreported in some patients treated with pravastatin or fenofibrate. In the majority of cases, livertransaminase levels have returned to their baseline value without the need for treatmentdiscontinuation.

It is recommended that transaminase levels be monitored every 3 months during the first 12 months oftreatment and let to the appreciation of the clinician beyond this initial period.

Special attention should be paid to patients who develop increase in transaminase levels and therapyshould be discontinued if increases in aspartate aminotransferase (AST) and alanine aminotransferase(ALT) exceed 3 times the ULN and persist.

Caution should be exercised when Pravafenix is administered to patients with a history of liver diseaseor heavy alcohol ingestion.

Pancreatitis has been reported in patients taking fenofibrate or pravastatin (see sections 4.3). Thisoccurrence may represent a failure of efficacy in patients with severe hypertriglyceridaemia, a directmedicinal product effect, or a secondary phenomenon mediated through biliary tract stone or sludgeformation, resulting in the obstruction of the common bile duct.

Pravafenix is contraindicated in moderate to severe renal impairment (section 4.3).

It is recommended to systematically assess the estimated creatinine clearance at the initiation of thetreatment and every 3 months during the first 12 months of the combination therapy then let to theappreciation of the clinician beyond this period.

Treatment should be discontinued in case of an estimated creatinine clearance < 60 ml/min.

Exceptional cases of interstitial lung disease have been reported with some statins, especially withlong term therapy (see section 4.8). Presenting features can include dyspnoea, non-productive coughand deterioration in general health (fatigue, weight loss and fever). If it is suspected a patient hasdeveloped interstitial lung disease, Pravafenix therapy should be discontinued.

Fenofibrate may increase cholesterol excretion into the bile, potentially leading to cholelithiasis. Ifcholelithiasis is suspected, gallbladder studies are indicated. Pravafenix should be discontinued ifgallstones are found.

Venothromboembolic events

In the FIELD study, a statistically significant increase was reported in the incidence of pulmonaryembolism (0.7% in the placebo group versus 1.1% in the fenofibrate group; p=0.022) and astatistically non significant increase in deep vein thrombosis (placebo 1.0% 48/4,900 patients) versusfenofibrate 1.4% (67/4,895); p=0.074. The increased risk of venous thrombotic events may be relatedto the increased homocysteine level, a risk factor for thrombosis and other unidentified factors. Theclinical significance of this is not clear. Therefore, caution should be exercised in patients with historyof pulmonary embolism.

Diabetes Mellitus

Some evidence suggests that statins as a class raise blood glucose and in some patients, at high risk offuture diabetes, may produce a level of hyperglycaemia where formal diabetes care is appropriate.

This risk, however, is outweighed by the reduction in vascular risk with statins and therefore shouldnot be a reason for stopping statin treatment. Patients at risk (fasting glucose 5.6 to 6.9 mmol/L,

BMI>30kg/m 2, raised triglycerides, hypertension) should be monitored both clinically andbiochemically according to national guidelines.

Concomitant use with glecaprevir/pibrentasvir

The use of Pravafenix is not recommended in patients treated with glecaprevir/pibrentasvir.

Concomitant use of pravastatin and glecaprevir/pibrentasvir may increase the plasma concentration ofpravastatin and may lead to an increase of dose-dependent adverse events including myopathy risk.

Patients treated with glecaprevir/pibrentasvir should not exceed 20 mg per day of pravastatin.

This medicinal product contains lactose. Patients with rare hereditary problems of galactoseintolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

This medicinal product contains 33.3 mg sodium per capsule (excipients and active substance),equivalent to 1.7% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

There have been no formal interaction studies for Pravafenix; however the concomitant use of theactive substances in patients in clinical studies has not resulted in any unexpected interactions. Thefollowing statements reflect the information available on the individual active substances (fenofibrateand pravastatin).

Interactions relevant to pravastatin

Colestyramine/Colestipol

Concomitant administration resulted in approximately 40 to 50% decrease in the bioavailability ofpravastatin. There was no clinically significant decrease in bioavailability or therapeutic effect whenpravastatin was administered one hour before or four hours after colestyramine or one hour beforecolestipol.

Concomitant administration of pravastatin and ciclosporin leads to an approximately 4 fold increase inpravastatin systemic exposure. In some patients, however, the increase in pravastatin exposure may belarger. Clinical and biochemical monitoring of patients receiving this combination is recommended.

Medicinal products metabolised by cytochrome P450

Pravastatin is not metabolised to a clinically significant extent by the cytochrome P450 system. This iswhy medicinal products that are metabolised by, or are inhibitors of, the cytochrome P450 system canbe added to a stable regimen of pravastatin without causing significant changes in the plasma levels ofpravastatin, as have been seen with other statins. The absence of a significant pharmacokineticinteraction with pravastatin has been specifically demonstrated for several medicinal products,particularly those that are substrates/inhibitors of CYP3A4 e.g. diltiazem, verapamil, itraconazole,ketoconazole, protease inhibitors, grapefruit juice and CYP2C9 inhibitors (e.g. fluconazole).

In one of two interaction studies with pravastatin and erythromycin a statistically significant increasein the area under the curve (AUC) (70%) and Cmax (121%) of pravastatin was observed. In a similarstudy with clarithromycin a statistically significant increase in AUC (110%) and Cmax (127%) wasobserved. Although these changes were minor, caution should be exercised when associatingpravastatin with erythromycin or clarithromycin.

Fusidic acid

The risk of myopathy including rhabdomyolysis may be increased by the concomitant administrationof systemic fusidic acid with statins. The mechanism of this interaction (whether it ispharmacodynamic or pharmacokinetic, or both) is yet unknown. There have been reports ofrhabdomyolysis (including some fatalities) in patients receiving this combination.

If treatment with systemic fusidic acid is necessary, pravastatin treatment should be discontinuedthroughout the duration of the fusidic acid treatment. Also see section 4.4.

Glecaprevir/pibrentasvir

Concomitant use of pravastatin and glecaprevir/pibrentasvir may increase the plasma concentration ofpravastatin and may lead to an increase of dose-dependent adverse events including myopathy risk.

Patients treated with glecaprevir/pibrentasvir should not exceed 20 mg per day of pravastatin.

Therefore Pravafenix is not recommended in those patients.

Other medicinal products

In interaction studies, no statistically significant differences in bioavailability were observed whenpravastatin was administered with acetylsalicylic acid, antacids (when given one hour prior topravastatin), nicotinic acid or probucol.

Interactions relevant to fenofibrate

Bile acid resin

Bile acid binding resins frequently reduce the absorption of medicinal products and when resins arebeing co-administered, fenofibrate should be taken 1 hour before, or 4 to 6 hours after, the resin so asnot to impede the absorption of fenofibrate.

Oral anticoagulants

Fenofibrate enhances oral anticoagulant effect and may increase risk of bleeding. It is recommendedthat the dose of anticoagulants is reduced by about one third at the start of treatment and thengradually adjusted if necessary according to INR (International Normalised Ratio) monitoring. Thiscombination is, therefore, not recommended.

Some severe cases of reversible renal function impairment have been reported during concomitantadministration of fenofibrate and ciclosporin. The renal function of these patients must therefore beclosely monitored and the treatment with fenofibrate stopped in the case of severe alteration oflaboratory parameters.

Glitazones

Some cases of reversible paradoxical reduction of HDL-cholesterol have been reported duringconcomitant administration of fenofibrate and glitazones. Therefore, it is recommended to monitor

HDL-cholesterol if Pravafenix is co-administered with a glitazone and to stop one of the twotreatments if HDL-cholesterol is too low.

Pravafenix must be taken with food, as food enhances the bioavailability of fenofibrate (see sections4.2 and 5.2).

In all clinical trials, patients were instructed to take Pravafenix daily during the evening meal anddietary restrictions instituted before therapy should be continued. Since current safety and efficacydata are based upon administration with food and with dietary restrictions, it is recommended that

Pravafenix is administered with food. (see sections 4.2 and 5.2).

Pravafenix

There are no data from the combined use of pravastatin and fenofibrate in pregnant women. Thecombination has not been tested in reproductive toxicity studies. The potential risk for humans isunknown. Therefore, as far as pravastatin is contra indicated (see below), Pravafenix is contraindicatedduring pregnancy (see section 4.3).

Pravastatin sodium

Pravastatin is contraindicated during pregnancy and should be administered to women of childbearingpotential only when such patients are unlikely to conceive and have been informed of the potentialrisk. Special caution is recommended in women of childbearing potential to ensure properunderstanding of the potential risk associated with pravastatin therapy during pregnancy. If a patientplans to become pregnant or becomes pregnant, the physician has to be informed immediately andpravastatin should be discontinued because of the potential risk to the foetus.

Fenofibrate

There are no data from the use of fenofibrate in pregnant women. Animal studies have notdemonstrated any teratogenic effects. Embryotoxic effects have been shown at doses in the range ofmaternal toxicity (see section 5.3). The potential risk for humans is unknown.

Pravafenix

No studies in lactating animals have been conducted with Pravafenix. Therefore, taking into accountthe contra indication of pravastatin during lactation, Pravafenix is contraindicated during breastfeeding(see section 4.3).

Pravastatin sodium

A small amount of pravastatin is excreted in human breast milk; therefore pravastatin iscontraindicated during breastfeeding (see section 4.3).

Fenofibrate

Fenofibrate is excreted in milk of female rat.

There are no data on the excretion of fenofibrate and/or its metabolites into human breast milk.

No effect on fertility in reproductive toxicity studies have been observed with both fenofibrate andpravastatin (see section 5.3)

There are no data on fertility from the combined use of fenofibrate and pravastatin

Pravafenix has no or negligible influence on the ability to drive and use machines. However, whendriving vehicles or using machines, it should be taken into account that dizziness and visualdisturbances may occur during treatment.

The most commonly reported adverse reactions (ADRs) during Pravafenix therapy are increasedtransaminase and gastrointestinal disorders.

In clinical trials, over 1,566 patients received Pravafenix. Adverse reactions have usually been mildand transient.

The frequencies of adverse reactions are ranked according to the following: Very common (≥ 1/10),

Common (≥ 1/100 to < 1/10), Uncommon (≥ 1/1,000 to < 1/100), Rare (≥ 1/10,000 to < 1/1,000), Veryrare (< 1/10,000).

System organ class Adverse reaction Frequency

Immune system Hypersensitivity reactions Uncommondisorders

Metabolism and Diabetes mellitus aggravated, Obesity Uncommonnutrition disorders

Psychiatric disorders Sleep disturbance including insomnia and nightmares Uncommon

Nervous system Dizziness, headache, paraesthesia Uncommondisorders

Cardiac disorders Palpitations Uncommon

Gastrointestinal Abdominal distension, abdominal pain, abdominal pain upper, Commondisorders constipation, diarrhoea, dry mouth, dyspepsia, eructation,flatulence, nausea, abdominal discomfort, vomiting.

Hepatobiliary disorders Transaminases increased. Common

Hepatic pain, gammaglutamyl transferase increased. Uncommon

Skin and subcutaneous Pruritus, urticaria Uncommontissue disorders

Arthralgia, back pain, blood creatine phosphokinase increased, Uncommon

Musculoskeletal, muscle spasms, musculoskeletal pain, myalgia, pain in extremity.connective tissue andbone disorders

Renal and urinary Blood creatinine increased, creatinine renal clearance decreased, Uncommondisorders creatinine renal clearance increased, Renal failure

General disorders and Asthenia, fatigue, influenza like illness Uncommonadministration siteconditions

Investigation Blood cholesterol increased, blood triglycerides increased, low- Uncommondensity lipoprotein increased, weight increased.

Skeletal muscle: Marked and persistent increases of creatine phosphokinase (CK) have been reportedinfrequently. In clinical studies, the incidence of important elevations in creatine phosphokinase (CK ≥3 times the ULN, < 5 times the ULN) was 1.92% for patients treated with Pravafenix. Clinicallyimportant elevations in creatine phosphokinase (CK ≥ 5 times the ULN, < 10 times the ULN withoutmuscular symptoms) were seen in 0.38% of the patients treated with Pravafenix. Clinically importantelevation (CK ≥ 10 times the ULN without muscular symptoms) was seen in 0.06% of the patientstreated with Pravafenix. (see section 4.4).

Liver reactions: Marked and persistent increases of serum transaminases have been reportedinfrequently. In clinical studies, the incidence of important elevations in serum transaminases (ALTand/or AST ≥ 3 times the ULN, < 5 times the ULN) was 0.83% for patients treated with Pravafenix.

Clinically important elevations in serum transaminases (ALT and/or AST ≥ 5 times the ULN) wereseen in 0.38% of the patients treated with Pravafenix. (see section 4.4).

Additional information on the individual active substances of the fixed dose combination

Pravafenix contains pravastatin and fenofibrate. Additional adverse reactions associated with the useof medicinal products containing pravastatin or fenofibrate observed in clinical trials and post-marketing experience that may potentially occur with Pravafenix are listed below. Frequencycategories are based on information available from pravastatin and fenofibrate Summary of Productcharacteristics available in the EU.

System Organ Class Adverse reaction Adverse reaction Frequency(fenofibrate) (Pravastatin)

Blood and lymphatic Haemoglobin decreased, Raresystem disorders White blood cell countdecreased

Nervous system Fatigue and vertigo Raredisorders

Peripheral polyneuropathy Very Rare

Eye disorders Vision disturbance (including Uncommonblurred vision and diplopia)

Vascular disorders Thromboembolism Uncommon(pulmonary embolism, deepvein thrombosis)*

Respiratory, thoracic Intersticial pneumopathies Not knownand mediastinaldisorders

Hepatobiliary disorders Cholelithiasis Uncommon

Jaundice, fulminant hepatic Very rarenecrosis, hepatitis

Jaundice, complications of Not knowncholelithiasis (e.gcholecystitis, cholangitis,biliary colic, etc).

Skin and subcutaneous Skin rash, Scalp/hair abnormality Uncommontissue disorders (including alopecia)

Dermatomyositis Very rare

Alopecia, photosensitivity Rarereactions

Lichenoid eruption Not known

Musculoskeletal, Muscle disorder (e.g. Uncommonconnective tissue and myositis, muscularbone disorders weakness)

Rhabdomyolysis, which can be Very rareassociated with acute renal failuresecondary to myoglobinuria,myopathy (see section 4.4);myositis, polymyositis. Isolatedcases of tendon disorders,sometimes complicated byrupture. Erythematous lupus likesyndrome.

Rhabdomyolysis Immune-mediated necrotizing Not knownmyopathy (see section 4.4).

Renal and urinary Abnormal urination (including Uncommondisorders: dysuria, frequency, nocturia)

Reproductive system Sexual dysfunction Sexual dysfunction Uncommonand breast disorders

General disorders: Fatigue Uncommon

Investigations Blood urea increased Rare

* In the FIELD-study (fenofibrate study), a randomised placebo-controlled trial performed in 9,795patients with type 2 diabetes mellitus, a statistically significant increase in pancreatitis cases wasobserved 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 ofpulmonary embolism (0.7% in the placebo group versus 1.1% in the fenofibrate group; p = 0.022) anda 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).

The following adverse events have been reported with some statins:

- Nightmares

- Memory loss

- Depression

- Exceptional cases of interstitial lung disease, especially with long term therapy (see section 4.4).

- Diabetes Mellitus: Frequency will depend on the presence or absence of risk factors (fasting bloodglucose ≥ 5.6 mmol/L, BMI>30kg/m2, raised triglycerides, history of hypertension).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

In the event of an overdose, symptomatic and supportive measures should be employed.

Pravastatin

Reported cases of overdose were asymptomatic and did not give rise to abnormal laboratory tests. Nospecific antidote is known. If overdose is suspected, treat symptomatically and institute appropriatesupportive measures as required.

Fenofibrate

No specific antidote is known. If an overdose is suspected, treat symptomatically and instituteappropriate supportive measures as required. Fenofibrate cannot be eliminated by haemodialysis.

Pharmacotherapeutic group: Lipid modifying agents, HMG CoA reductase inhibitors in combinationwith other lipid modifying agents, ATC code: C10BA03

Pravafenix contains fenofibrate and pravastatin, which have different modes of action and showadditive effects in terms of reduction of serum lipid. The following statements reflect thepharmacodynamic/pharmacokinetic properties of the individual active substances of Pravafenix.

Fenofibrate

Fenofibrate is a fibric acid derivative whose lipid modifying effects reported in humans are mediatedvia activation of Peroxisome Proliferator Activated Receptor type alpha (PPARα). Studies withfenofibrate on lipoprotein fractions show decreases in levels of LDL and VLDL cholesterol. HDLcholesterol levels are frequently increased. LDL and VLDL triglycerides are reduced. The overalleffect is a decrease in the ratio of low and very low-density lipoproteins to high-density lipoproteins.

The lipid-lowering properties of fenofibrate seen in clinical practice have been explained in vivo intransgenic mice and in human hepatocyte cultures by activation of Peroxisome Proliferator Activated

Receptor type α (PPARα). Through this mechanism, fenofibrate increases lipolysis and elimination oftriglyceride rich particles from plasma by activating lipoprotein lipase and reducing production of

Apoprotein C-III. Activation of PPARα also induces an increase in the synthesis of Apoproteins A-I,

A-II and of HDL cholesterol.

There is evidence that treatment with fibrates may reduce coronary heart disease events but they havenot been shown to decrease all cause mortality in the primary or secondary prevention ofcardiovascular disease.

The Action to Control Cardiovascular Risk in Diabetes (ACCORD) lipid trial was a randomizedplacebo-controlled study of 5,518 patients with type 2 diabetes mellitus treated with fenofibrate inaddition to simvastatin. Fenofibrate plus simvastatin therapy did not show any significant differencescompared to simvastatin monotherapy in the composite primary outcome of non-fatal myocardialinfarction, 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, definedas those in the lowest tertile of HDL-C (≤34 mg/dl or 0.88 mmol/L) and highest tertile of TG (≥204mg/dl or 2.3 mmol/L) at baseline, fenofibrate plus simvastatin therapy demonstrated a 31% relativereduction 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 prespecifiedsubgroup 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 potentiallyhigher risk for the primary outcome in women treated with combination therapy compared tosimvastatin monotherapy (p=0.069). This was not observed in the aforementioned subgroup of patientswith dyslipidaemia but there was also no clear evidence of benefit in dyslipidaemic women treatedwith fenofibrate plus simvastatin, and a possible harmful effect in this subgroup could not beexcluded.

Plasma uric acid levels are increased in approximately 20% of hyperlipidaemic patients, particularly inthose with type IV disease. Fenofibrate has a uricosuric effect and is therefore of additional benefit insuch patients.

Pravastatin

Pravastatin is a competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA)reductase, the enzyme catalysing the early rate-limiting step in cholesterol biosynthesis, and producesits lipid-lowering effect in two ways. Firstly, with the reversible and specific competitive inhibition of

HMG-CoA reductase, it effects modest reduction in the synthesis of intracellular cholesterol. Thisresults in an increase in the number of LDL-receptors on cell surfaces and enhanced receptor-mediatedcatabolism and clearance of circulating LDL-cholesterol.

Secondly, pravastatin inhibits LDL production by inhibiting the hepatic synthesis of VLDL-cholesterol, the LDL-cholesterol precursor.

In both healthy subjects and patients with hypercholesterolaemia, pravastatin lowers the followinglipid values: total cholesterol, LDL-cholesterol, apolipoprotein B, VLDL-cholesterol and triglycerides;while HDL-cholesterol and apolipoprotein A are elevated.

Pravafenix

The respective effects of pravastatin and fenofibrate are complementary. Pravastatin is more effectivein reducing LDL-C and total cholesterol but presents only modest effects on TG and HDL-C whilefenofibrate is very effective in decreasing TG and increasing HDL-C, but with few effects on LDL-C.

Additionally, fibrates have the properties to modify the size and density of LDL-C particles to makethem less atherogenic.

Fibrates and statins in combination have also been shown to synergistically increase the transcriptionalactivities of PPARα receptors.

Four multicenter studies with either Pravafenix 40 mg/160 mg or Pravastatin 40 mg or Simvastatin20 mg were conducted: 3 studies included a 12 week randomized, double-blind, active controlledperiod with an open-label extension phase and one was a 24-week open-label study.

In total, these studies enrolled 1,637 patients who have not had an adequate response to treatment withpravastatin 40 mg monotherapy or simvastatin 20 mg in Europe and in the USA.

In the pivotal European multicenter 64-week clinical trial including 12 week randomised, double-blind, double-dummy, 2-arm, parallel study period, 248 high vascular risk patients with mixeddyslipidaemia were randomised to one of the two treatment groups: Pravafenix 40 mg/160 mg orpravastatin 40 mg. Only patients who had not met their NCEP ATP III target LDL-C and Triglyceridegoals (LDL >100 mg/dl and TG >150 mg/dl) after 8 weeks on pravastatin 40 mg (1 tablet, once daily)were randomized. Patients receiving Pravafenix 40 mg/160 mg were compared to those receivingpravastatin 40 mg: Pravafenix significantly lowered non-HDL-C, LDL-C, TG and significantlyincreased HDL-C to a greater extent than pravastatin 40 mg (table).

Mean percent changes from baseline to week 12for patients treated with Pravafenix 40 mg/160 mg or Pravastatin 40 mg once daily

Pravafenix40 mg/160 mg PRAVASTATIN 40 mg Pravafenix versus

Na = 120 Na = 119 PRAVASTATIN

Mean (%)± SEb Mean (%)± SEb p-valuec

Non-HDL-C(mg/dl) -14.1 ± 1.78 -6.1 ± 1.79 0.0018

LDL-C (mg/dl) -11.7 ± 1.75 -5.9 ± 1.76 0.019

HDL-C (mg/dl) +6.5 ± 1.12 +2.3 ± 1.13 0.0089

TG (mg/dl) -22.6 ± 4.37 -2.0 ± 4.39 0.0010

TC (mg/dl) -9.9 ± 1.37 -4.4 ± 1.38 0.006

Apo A1 (g/L) +5.5 ± 0.99 +2.8 ± 0.97 0.058

Apo B (g/L) -12.6 ± 1.57 -3.8 ± 1.53 <0.0001

Apo B/Apo A1 -16.3 ± 1.66 -6.0 ± 1.61 <0.0001

Fibrinogen (g/L) -8.8 ± 1.80 +1.4 ± 1.75 <0.0001

Hs-CRP (mg/L) -1.1 ± 0.61 +0.6 ± 0.70 0.003a Number of patientsb Mean percent change (least square mean ± standard error) between baseline measured after 8weeks on Pravastatin 40 mg and 12 additional weeks with Pravafenix 40 mg/160 mg or

Pravastatin 40 mgc Pairwise p-value is significant if <0.05

The effects of Pravafenix 40 mg/160 mg were confirmed in a similar multicenter, 64-week trialincluding a 12 week randomized, double-blind phase in a study performed in the USA and comparing

Pravafenix 40 mg/160 mg to Fenofibrate 160 mg monotherapy and Pravastatin 40 mg monotherapy inpatients with mixed dyslipidaemia. The incremental benefit of Pravafenix 40 mg/160 mg on main lipidparameters versus Pravastatin 40 mg and Fenofibrate 160 mg monotherapy was also established.

The European Medicines Agency has waived the obligation to submit the results of studies with

Pravafenix in all subsets of the paediatric population in disorders of lipoprotein metabolism and otherhyperlipidaemias (see section 4.2 for information on paediatric use).

No clinically significant pharmacokinetic interaction was seen when fenofibrate was coadministeredwith pravastatin.

Pravafenix is bioequivalent to coadministered fenofibrate and pravastatin in a single dose study.

However in a multiple dose study, the results showed that the product is not bioequivalent because itsbioavailability after multiple dosing is a 20% lower for the fenofibrate component of the combination.

This is due to the fat content of the meal.

Therefore the fixed dose combination (Pravafenix) could not be considered interchangeable with thefree co-administration of fenofibrate and pravastatin mono-component drug products.

A pharmacokinetic study after a single dose administration of Pravafenix has been performed in fedand fasting condition. The results of this study show that food has effect on the rate and extent ofabsorption in the fixed dose combination. The bioavailability of fenofibric acid is lower in fastingconditions after a single dose administration of the Fenofibrate-Pravastatin 160/40 mg combination.

The decreased in AUCt, AUC∞ and Cmax of fenofibric acid (point estimate) is of 30.94%, 10.9% and68.71% respectively.

The bioavailability of pravastatin is higher after a single dose administration of the test product

Fenofibrate/Pravastatin 160/40 mg in fasting conditions than after a single dose of the product in fedconditions. The increase in AUC∞, AUCt, and Cmax is of 111.88%, 114.06%, and 115.28%respectively. In line with several formulations for fenofibrate, the fixed combination is recommendedto be taken with food because the bioavailability of fenofibrate is increased when administered withfood and the lipid-lowering efficacy of pravastatin is not altered.

Pravastatin

Pravastatin is administered orally in the active form. It is rapidly absorbed; peak serum levels areachieved 1 to 1.5 hours after ingestion. On average, 34% of the orally administered dose is absorbed,with an absolute bioavailability of 17%.

The presence of food in the gastrointestinal tract leads to a reduction in the bioavailability, but thecholesterol-lowering effect of pravastatin is identical whether taken with or without food.

After absorption, 66% of pravastatin undergoes a first-pass extraction through the liver, which is theprimary site of its action and the primary site of cholesterol synthesis and clearance of LDL-cholesterol. In vitro studies demonstrated that pravastatin is transported into hepatocytes and withsubstantially less intake in other cells. In view of this substantial first pass through the liver, plasmaconcentrations of pravastatin have only a limited value in predicting the lipid-lowering effect.

The plasma concentrations are proportional to the doses administered.

Fenofibrate

Maximum plasma concentrations (Cmax) occur within 4 to 5 hours after oral administration. Plasmaconcentrations are stable during continuous treatment in any given individual.

The absorption of fenofibrate is increased when administered with food. The food effect increases withthe fat content: the larger the lipid content the larger the bioavailability of fenofibrate.

Pravastatin

About 50% of circulating pravastatin is bound to plasma proteins. The volume of distribution is about0.5 l/kg. A small quantity of pravastatin passes into the human breast milk.

Fenofibrate

Fenofibric acid is strongly bound to plasma albumin (more than 99%).

Pravastatin

Pravastatin is not significantly metabolised by cytochrome P450 nor does it appear to be a substrate oran inhibitor of P-glycoprotein but rather a substrate of other transport proteins.

Following oral administration, 20% of the initial dose is eliminated in the urine and 70% in the faeces.

Plasma elimination half-life of oral pravastatin is 1.5 to 2 hours.

After intravenous administration, 47% of the dose is eliminated by the renal excretion and 53% bybiliary excretion and biotransformation. The major degradation product of pravastatin is the 3-α-hydroxy isomeric metabolite. This metabolite has one-tenth to one-fortieth the HMG-CoA reductaseinhibitor activity of the parent compound.

The systemic clearance of pravastatin is 0.81 l/h/kg and the renal clearance is 0.38 l/h/kg indicatingtubular secretion.

Fenofibrate

No unchanged fenofibrate can be detected in the plasma where the principal metabolite is fenofibricacid. The drug is excreted mainly in the urine. Practically all the drug is eliminated within 6 days.

Fenofibrate is mainly excreted in the form of fenofibric acid and its glucuronide conjugate. In elderlypatients, the fenofibric acid apparent total plasma clearance is not modified. The plasma eliminationhalf-life of fenofibric acid is approximately 20 hours.

Kinetic studies following the administration of a single dose and continuous treatment havedemonstrated that the drug does not accumulate. Fenofibric acid is not eliminated by haemodialysis.

The safety of concomitant administration of pravastatin and fenofibrate was assessed in rats.

Toxicological findings in these co-administration studies were consistent with those seen withpravastatin and fenofibrate administered individually.

Pravastatin

Based on conventional studies of safety pharmacology, repeated dose toxicity and toxicity onreproduction, there are no other risks for the patient than those expected due to the pharmacologicalmechanism of action.

Repeated dose studies indicate that pravastatin may induce varying degrees of hepatotoxicity andmyopathy; in general, substantive effects on these tissues were only evident at doses 50 or more timesthe maximum human mg/kg dose. In vitro and in vivo genetic toxicology studies have shown noevidence of mutagenic potential. In mice, a 2-year carcinogenicity study with pravastatin demonstratesat doses of 250 and 500 mg/kg/day (> 310 times the maximum human mg/kg dose), statisticallysignificant increases in the incidence of hepatocellular carcinomas in males and females, and lungadenomas in females only. In rats a 2-year carcinogenicity study demonstrates at a dose of100 mg/kg/day (125 times the maximum human mg/kg/dose) a statistically significant increase in theincidence of hepatocellular carcinomas in males only.

Fenofibrate

Chronic toxicity studies have yielded no relevant information about specific toxicity of fenofibrate.

Studies on mutagenicity of fenofibrate have been negative. In rats and mice, liver tumours have beenfound at high dosages, which are attributable to peroxisome proliferation. These changes are specificto small rodents and have not been observed in other animal species. This is of no relevance totherapeutic use in man.

Studies in mice, rats and rabbits did not reveal any teratogenic effect. Embryotoxic effects wereobserved at doses in the range of maternal toxicity. Prolongation of the gestation period anddifficulties during delivery were observed at high doses. No sign of any effect on fertility has beendetected.

Lactose monohydrate

Cellulose microcrystalline

Ascorbyl palmitate

Povidone K29-32

Sodium starch glycolate

Magnesium stearate

Talc

Triacetin

Sodium hydrogen carbonate

Lauroyl macrogolglycerides Type 1500

Hydroxypropylcellulose

Macrogol 20 000

Gelatine

Indigo carmine

Black iron oxide

Titanium dioxide

Yellow iron oxide

Not applicable

Polyamide-Aluminium-PVC/aluminium blister2 years.

HDPE bottle3 years.

This medicinal product does not require any special storage conditions.

Polyamide-Aluminium-PVC/aluminium blister packs containing 30, 60 and 90 hard capsules.

Opaque white HDPE bottles containing 14, 30, 60 and 90 hard capsules.

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Laboratoires SMB s.a.

Rue de la Pastorale, 26-28

B-1080 Brussels

Belgium

Tel. +32 (2) 411 48 28

Fax. +32 (2) 411 28 28

EU/1/11/679/001-007

Date of first authorisation: 14 April 2011

Date of latest renewal: 14 January 2016

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu