PRAVAFENIX Hard capsule Ref.[51225] Active ingredients: Fenofibrate Pravastatin Pravastatin and Fenofibrate

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

Nervous system disorders

In few cases, statins have been reported to induce de novo or aggravate pre-existing myasthenia gravis or ocular myasthenia (see section 4.8). Pravafenix should be discontinued in case of aggravation of symptoms. Recurrences when the same or a different statin was (re-) administered have been reported.

Musculoskeletal and connective tissue disorders

As with other lipid lowering substances, pravastatin or fenofibrate have been associated with the onset of 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 any time during treatment and is characterised by massive muscle destruction associated with major increase 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-glutarylCoenzyme A (HMG-CoA) reductase inhibitor are administered together. Myopathy must be considered 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 treatment initiation and patients should be monitored for any signs of muscle toxicity. Certain predisposing factors such as age >70, renal impairment, hepatic impairment, hypothyroidism, personal history of muscular toxicity with a statin or fibrate, personal or familial history of hereditary muscular disorders or alcohol abuse may increase the risk of muscular toxicity and therefore CK measurement is indicated before starting the combination therapy in these patients (see below).

Statins including pravastatin must not be co-administered with systemic formulations of fusidic acid or within 7 days of stopping fusidic acid treatment. In patients where the use of systemic fusidic acid is considered essential, statin treatment should be discontinued throughout the duration of fusidic acid treatment. There have been reports of rhabdomyolysis (including some fatalities) in patients receiving fusidic acid and statins in combination (see section 4.5). The patient should be advised to seek medical advice 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 treatment of severe infections, the need for co-administration of Pravafenix and fusidic acid should only be considered 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 useful as a reference in the event of a later increase during the combination therapy. When measured, CK levels should be interpreted in the context of other potential factors that can cause transient muscle damage, 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 controlled after 5-7 days. If confirmed, the treatment should definitively not be initiated (see section 4.3).

During treatment

Routine monitoring of CK is systematically recommended every 3 months during the first 12 months of 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 or cramps. In these cases, CK levels should be measured.

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

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

Hepatobiliary disorders

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

It is recommended that transaminase levels be monitored every 3 months during the first 12 months of treatment 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 therapy should 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 disease or heavy alcohol ingestion.

Pancreatitis

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

Renal and urinary disorders

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 the treatment and every 3 months during the first 12 months of the combination therapy then let to the appreciation of the clinician beyond this period.

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

Interstitial lung disease

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

Cholelithiasis

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

Venothromboembolic events

In the FIELD 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 thrombosis (placebo 1.0% 48/4,900 patients) versus fenofibrate 1.4% (67/4,895); p=0.074. The increased risk of venous thrombotic events may be related to the increased homocysteine level, a risk factor for thrombosis and other unidentified factors. The clinical significance of this is not clear. Therefore, caution should be exercised in patients with history of pulmonary embolism.

Diabetes Mellitus

Some evidence suggests that statins as a class raise blood glucose and in some patients, at high risk of future 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 should not be a reason for stopping statin treatment. Patients at risk (fasting glucose 5.6 to 6.9 mmol/L, BMI>30kg/m², raised triglycerides, hypertension) should be monitored both clinically and biochemically 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 of pravastatin 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.

Lactose

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

Sodium

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 the active substances in patients in clinical studies has not resulted in any unexpected interactions. The following statements reflect the information available on the individual active substances (fenofibrate and pravastatin).

Interactions relevant to pravastatin

Colestyramine/Colestipol

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

Ciclosporin

Concomitant administration of pravastatin and ciclosporin leads to an approximately 4 fold increase in pravastatin systemic exposure. In some patients, however, the increase in pravastatin exposure may be larger. 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 is why medicinal products that are metabolised by, or are inhibitors of, the cytochrome P450 system can be added to a stable regimen of pravastatin without causing significant changes in the plasma levels of pravastatin, as have been seen with other statins. The absence of a significant pharmacokinetic interaction 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 increase in the area under the curve (AUC) (70%) and C_max (121%) of pravastatin was observed. In a similar study with clarithromycin a statistically significant increase in AUC (110%) and C_max (127%) was observed. Although these changes were minor, caution should be exercised when associating pravastatin with erythromycin or clarithromycin.

Fusidic acid

The risk of myopathy including rhabdomyolysis may be increased by the concomitant administration of systemic fusidic acid with statins. The mechanism of this interaction (whether it is pharmacodynamic or pharmacokinetic, or both) is yet unknown. There have been reports of rhabdomyolysis (including some fatalities) in patients receiving this combination. If treatment with systemic fusidic acid is necessary, pravastatin treatment should be discontinued throughout 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 of pravastatin 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 when pravastatin was administered with acetylsalicylic acid, antacids (when given one hour prior to pravastatin), 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 are being co-administered, fenofibrate should be taken 1 hour before, or 4 to 6 hours after, the resin so as not to impede the absorption of fenofibrate.

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. This combination is, therefore, not recommended.

Ciclosporin

Some severe cases of reversible renal function impairment have been reported during concomitant administration of fenofibrate and ciclosporin. 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 Pravafenix is co-administered with a glitazone and to stop one of the two treatments if HDL-cholesterol is too low.

Food interaction

Pravafenix must be taken with food, as food enhances the bioavailability of fenofibrate (see sections 4.2 and 5.2).

In all clinical trials, patients were instructed to take Pravafenix daily during the evening meal and dietary restrictions instituted before therapy should be continued. Since current safety and efficacy data 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).

Pregnancy

Pravafenix

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

Pravastatin sodium

Pravastatin is contraindicated during pregnancy and should be administered to women of childbearing potential only when such patients are unlikely to conceive and have been informed of the potential risk. Special caution is recommended in women of childbearing potential to ensure proper understanding of the potential risk associated with pravastatin therapy during pregnancy. If a patient plans to become pregnant or becomes pregnant, the physician has to be informed immediately and pravastatin 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 not demonstrated any teratogenic effects. Embryotoxic effects have been shown at doses in the range of maternal toxicity (see section 5.3). The potential risk for humans is unknown.

Breastfeeding

Pravafenix

No studies in lactating animals have been conducted with Pravafenix. Therefore, taking into account the 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 is contraindicated 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.

Fertility

No effect on fertility in reproductive toxicity studies have been observed with both fenofibrate and pravastatin (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, when driving vehicles or using machines, it should be taken into account that dizziness and visual disturbances may occur during treatment.

Summary of the safety profile

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

Tabulated list of adverse reactions

In clinical trials, over 1,566 patients received Pravafenix. Adverse reactions have usually been mild and 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), Very rare (<1/10,000).

Description of selected adverse reactions

Skeletal muscle

Marked and persistent increases of creatine phosphokinase (CK) have been reported infrequently. 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. Clinically important elevations in creatine phosphokinase (CK ≥5 times the ULN, <10 times the ULN without muscular symptoms) were seen in 0.38% of the patients treated with Pravafenix. Clinically important elevation (CK ≥10 times the ULN without muscular symptoms) was seen in 0.06% of the patients treated with Pravafenix. (see section 4.4).

Liver reactions

Marked and persistent increases of serum transaminases have been reported infrequently. In clinical studies, the incidence of important elevations in serum transaminases (ALT and/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) were seen 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 use of medicinal products containing pravastatin or fenofibrate observed in clinical trials and postmarketing experience that may potentially occur with Pravafenix are listed below. Frequency categories are based on information available from pravastatin and fenofibrate Summary of Product characteristics available in the EU.

^* In the FIELD-study (fenofibrate study), a randomised 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).

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 blood glucose ≥5.6 mmol/L, BMI>30kg/m², raised triglycerides, history of hypertension).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Not applicable.