Cholib 145 mg/20 mg film-coated tablets

 

One film-coated tablet contains 145 mg of fenofibrate and 20 mg of simvastatin.

 

Excipient(s) with known effect:

One film-coated tablet contains 160.1 mg of lactose (as monohydrate), 145 mg of sucrose, 0.7 mg of lecithin (derived from soya bean (E322)) and 0.17 mg of sunset yellow FCF (E110).

For the full list of excipients, see section 6.1.

 

Film-coated tablet (tablet).

Oval, biconvex, tan coloured, 19.3 x 9.3 mm film-coated tablet with bevelled edges and the inscription 145/20 on one side and the Abbott logo “A” on the other side.

 

 

Cholib is indicated as adjunctive therapy to diet and exercise in high cardiovascular risk adult patients with mixed dyslipidaemia to reduce triglycerides and increase HDL-C levels when LDL-C levels are adequately controlled with the corresponding dose of simvastatin monotherapy.

 

Secondary causes of hyperlipidaemia, such as uncontrolled type 2 diabetes mellitus, hypothyroidism, nephrotic syndrome, dysproteinemia, obstructive liver disease, pharmacological treatment (like oral oestrogens), alcoholism should be adequately treated, before Cholib therapy is considered and patients should be placed on a standard cholesterol and triglycerides-lowering diet which should be continued during treatment.

 

Posology

The recommended dose is one tablet per day. Grapefruit juice should be avoided (see section 4.5).

Response to therapy should be monitored by determination of serum lipid values (total cholesterol (TC), LDL-C, triglycerides (TG)).

 

Elderly patients (≥ 65 years old)

No dose adjustment is necessary. The usual dose is recommended, except for decreased renal function with estimated glomerular filtration rate < 60 mL/min/1.73 m² where Cholib is contraindicated (see section 4.3).

 

Patients with renal impairment

Cholib is contraindicated in patients with moderate to severe renal insufficiency whose estimated glomerular filtration rate is < 60 mL/min/1.73 m² (see section 4.3).

Cholib should be used with caution in patients with mild renal insufficiency whose estimated glomerular filtration rate is 60 to 89 mL/min/1.73 m² (see section 4.4).

 

Patients with hepatic impairment

Cholib has not been studied in patients with hepatic impairment and is therefore contraindicated in this population (see section 4.3).

 

Paediatric population

Cholib is contraindicated in children and adolescents up to 18 years old. (see section 4.3).

 

Method of administration

Each tablet should be swallowed whole with a glass of water. The tablets should not be crushed or chewed. They may be taken with or without food (see section 5.2).

 

• Hypersensitivity to the active substances, peanut, soya or to any of the excipients listed in section 6.1 (see also section 4.4)

• Known photoallergy or phototoxic reaction during treatment with fibrates or ketoprofen

• Active liver disease or unexplained persistent elevations of serum transaminases

• Known gallbladder disease

• Chronic or acute pancreatitis with the exception of acute pancreatitis due to severe hypertriglyceridaemia

• Moderate to severe renal insufficiency (estimated glomerular filtration rate < 60 mL/min/1.73 m2)

• Concomitant administration of fibrates, statins, danazol, ciclosporin or potent cytochrome P450 (CYP) 3A4 inhibitors (see section 4.5)

• Paediatric population (age below 18 years)

• Pregnancy and breast-feeding (see section 4.6)

• Personal history of myopathy and/or rhabdomyolysis with statins and/or fibrates or confirmed creatine phosphokinase elevation above 5 times the upper limit of normal (ULN) under previous statin treatment (see section 4.4)

 

Muscle

Skeletal muscle toxicity, including rare cases of rhabdomyolysis with or without renal failure, has been reported with administration of lipid-lowering substances like fibrates and statins. The risk of myopathy with statins and fibrates is known to be related to the dose of each component and to the nature of the fibrate.

 

Reduced function of transport proteins

Reduced function of hepatic OATP transport proteins can increase the systemic exposure of simvastatin and increase the risk of myopathy and rhabdomyolysis. Reduced function can occur as the result of inhibition by interacting medicines (eg ciclosporin) or in patients who are carriers of the SLCO1B1 c.521T>C genotype.

Patients carrying the SLCO1B1 gene allele (c.521T>C) coding for a less active OATP1B1 protein have an increased systemic exposure of simvastatin and increased risk of myopathy. The risk of high dose (80 mg) simvastatin related myopathy is about 1 % in general, without genetic testing. Based on the results of the SEARCH trial, homozygote C allele carriers (also called CC) treated with 80 mg have a 15% risk of myopathy within one year, while the risk in heterozygote C allele carriers (CT) is 1.5%. The corresponding risk is 0.3% in patients having the most common genotype (TT) (See section 5.2).

 

Immune-mediated necrotizing myopathy (IMNM)

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.

 

Measures to reduce the risk of myopathy caused by medicinal product interactions

The risk of muscle toxicity may be increased if Cholib is administered with another fibrate, statin, niacin, fusidic acid or other specific concomitant substances (for specific interactions see section 4.5). Physicians contemplating combined therapy with Cholib and lipid-modifying doses (≥ 1 g/day) of niacin (nicotinic acid) or medicinal products containing niacin should carefully weigh the potential benefits and risks and should carefully monitor patients for any signs and symptoms of muscle pain, tenderness, or weakness, particularly during the initial months of therapy and when the dose of either medicinal product is increased.

The risk of myopathy and rhabdomyolysis is significantly increased by concomitant use of simvastatin with potent inhibitors of (CYP) 3A4 (see section 4.5).

Cholib must not be co-administered with fusidic acid. There have been reports of rhabdomyolysis (including some fatalities) in patients receiving a statin in combination with fusidic acid (see section 4.5). In patients where the use of systemic fusidic acid is considered essential, statin treatment should be discontinued throughout the duration of fusidic acid treatment. 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 Cholib and fusidic acid should only be considered on a case by case basis and under close medical supervision.

 

Creatine kinase measurement

Creatine Kinase should not be measured following strenuous exercise or in the presence of any plausible alternative cause of Creatine Kinase increase as this makes value interpretation difficult. If Creatine Kinase levels are significantly elevated at baseline (> 5 x ULN), levels should be re-measured within 5 to 7 days later to confirm the results.

 

Before the treatment

All patients starting therapy, or whose dose of simvastatin is being increased, should be advised of the risk of myopathy and told to report promptly any unexplained muscle pain, tenderness or weakness.

Caution should be exercised in patients with pre-disposing factors for rhabdomyolysis. In order to establish a reference baseline value, a Creatine Kinase level should be measured before starting a treatment in the following situations:

• Elderly ≥ 65 years

• Female gender

• Renal impairment

• Uncontrolled hypothyroidism

• Hypoalbuminaemia

• Personal or familial history of hereditary muscular disorders

• Previous history of muscular toxicity with a statin or a fibrate

• Alcohol abuse

In such situations, the risk of treatment should be considered in relation to possible benefit, and clinical monitoring is recommended.

In order to establish a reference baseline value, creatine phosphokinase levels should be measured and clinical monitoring is recommended.

If a patient has previously experienced a muscle disorder on a fibrate or a statin, treatment with a different member of the class should only be initiated with caution. If Creatine Kinase levels are significantly elevated at baseline (> 5 x ULN), treatment should not be started.

If myopathy is suspected for any other reason, treatment should be discontinued.

Therapy with Cholib should be temporarily stopped a few days prior to elective major surgery and when any major medical or surgical condition supervenes.

 

Hepatic disorders

Increases in transaminase levels have been reported in some patients treated with simvastatin or fenofibrate. In the majority of cases these elevations were transient, minor and asymptomatic without the need for treatment discontinuation.

Transaminase levels have to be monitored before treatment begins, 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 aspartate aminotransferase (AST) or also known as serum glutamic oxaloacetic transaminase (SGOT) and alanine aminotransferase (ALT) or also known as serum glutamic pyruvic transaminase (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 diagnosis is confirmed by laboratory testing, Cholib therapy should be discontinued.

Cholib should be used with caution in patients who consume substantial quantities of alcohol.

 

Pancreatitis

Pancreatitis has been reported in patients taking fenofibrate (see sections 4.3 and 4.8). This occurrence may represent a failure of efficacy in patients with severe hypertriglyceridaemia, an induced pancreatic enzymes increase or a secondary phenomenon mediated through biliary tract stone or sludge formation with obstruction of the common bile duct.

 

Renal function

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

Cholib should be used with caution in patients with mild renal insufficiency whose estimated glomerular filtration rate is 60 to 89 mL/min/1.73 m² (see section 4.2).

Reversible elevations in serum creatinine have been reported in patients receiving fenofibrate monotherapy or co-administered with statins. Elevations in serum creatinine were generally stable over time with no evidence for continued increases in serum creatinine with long term therapy and tended to return to baseline following discontinuation of treatment.

During clinical trials, 10% of patients had a creatinine increase from baseline greater than 30 µmol/L with co-administered fenofibrate and simvastatin versus 4.4% with statin monotherapy. 0.3% of patients receiving co-administration had clinically relevant increases in creatinine to values > 200 µmol/L.

Treatment should be interrupted when creatinine level is 50% above the upper limit of normal. It is recommended that creatinine is measured during the first 3 months after initiation of treatment and periodically thereafter.

 

Interstitial lung disease

Cases of interstitial lung disease have been reported with some statins and with fenofibrate, 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, Cholib therapy should be discontinued.

 

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>30 kg/m², raised triglycerides, hypertension) should be monitored both clinically and biochemically according to national guidelines.

 

Veno-thromboembolic 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% 48/4900 patients) versus fenofibrate 1.4% (67/4895); 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.

Excipients

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

As this medicinal product contains sucrose, patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

This medicinal product contains sunset yellow FCF (E110) that may cause allergic reactions.