Cholib

Fenofibrate, simvastatin.

Cholib 145 mg/20 mg 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).
Excipients/Inactive Ingredients: Tablet core: Butylhydroxyanisole (E320), Lactose monohydrate, Sodium laurilsulfate, Pregelatinised (maize) starch, Docusate sodium, Sucrose, Citric acid monohydrate (E330), Hypromellose (E464), Crospovidone (E1202), Magnesium stearate (E572), Silicified microcrystalline cellulose (comprised of cellulose, microcrystalline and colloidal anhydrous silica), Ascorbic acid (E300).
Film-coating: Partially hydrolysed (E1203) poly (vinyl alcohol), Titanium dioxide (E171), Talc (E553b), Lecithin (derived from soya bean (E322)), Xanthan gum (E415), Iron oxide red (E172), Iron oxide yellow (E172), Sunset yellow FCF (E110).

Pharmacotherapeutic group: Lipid modifying substances, HMG-CoA reductase inhibitors in combination with other lipid modifying substances. ATC code: C10BA04.
Pharmacology: Pharmacodynamics: Mechanism of action: Fenofibrate: Fenofibrate is a fibric acid derivative whose lipid modifying effects reported in humans are mediated via activation of Peroxisome Proliferator Activated Receptor type alpha (PPARα).
Through activation of PPARα, fenofibrate activates lipoprotein lipase production and reduces production of apoprotein CIII. Activation of PPARα also induces an increase in the synthesis of apoproteins AI and AII.
Simvastatin: Simvastatin, which is an inactive lactone, is hydrolyzed in the liver to the corresponding active betahydroxyacid form which has a potent activity in inhibiting HMG-CoA reductase (3 hydroxy-3 methylglutaryl CoA reductase). This enzyme catalyses the conversion of HMG-CoA to mevalonate, an early and rate-limiting step in the biosynthesis of cholesterol.
Cholib 145 mg/20 mg film-coated tablet contains fenofibrate and simvastatin, which have different modes of action as described previously.
Pharmacodynamic effects: Fenofibrate: Studies with fenofibrate on lipoprotein fractions show decreases in levels of LDL and VLDL cholesterol (VLDL-C). HDL-C levels are frequently increased. LDL and VLDL triglycerides are reduced. The overall effect is a decrease in the ratio of low and very low-density lipoproteins to high-density lipoproteins.
Fenofibrate also has a uricosuric effect leading to reduction in uric acid levels of approximately 25%.
Simvastatin: Simvastatin has been shown to reduce both normal and elevated LDL-C concentrations. LDL is formed from very-low-density protein (VLDL) and is catabolised predominantly by the high affinity LDL receptor. The mechanism of the LDL lowering effect of simvastatin may involve both reduction of VLDL-C concentration and induction of the LDL receptor, leading to reduced production and increased catabolism of LDL-C. Apolipoprotein B also falls substantially during treatment with simvastatin. In addition, simvastatin moderately increases HDL-C and reduces plasma TG.
As a result of these changes the ratios of TC to HDL-C and LDL-C to HDL-C are reduced.
The respective effects of simvastatin and fenofibrate are complementary.
Clinical efficacy and safety: Four pivotal clinical studies were carried out in the clinical program. Overall, 7,583 subjects with mixed dyslipidemia entered a 6 week statin run-in period. Of these, 2,474 subjects were randomized for 24 weeks treatment, 1,237 subjects received fenofibrate and simvastatin co-administration and 1,230 subjects received statin monotherapy all administered in the evening. Statin type and dose used: (See Table 1.)

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Study 0501 evaluated 2 different doses of fenofibrate-simvastatin combination compared to simvastatin 40 mg for a 24 week double-blind period. The primary efficacy criterion was superiority of the combination fenofibrate 145 and simvastatin 20 mg versus simvastatin 40 mg on TG decrease and HDL-C increase and non-inferiority for LDL-C decrease at 12 weeks. (See Table 2.)

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After the first 12 weeks of treatment, the combination of fenofibrate 145 mg and simvastatin 20 mg showed superiority over simvastatin 40 mg for TG reduction and HDL-C increase but did not meet the criteria for non-inferiority on LDL-C. The combination of fenofibrate 145 mg with simvastatin 20 mg demonstrated statistically significant superiority on apoA1 increase and fibrinogen decrease compared to simvastatin 40 mg.
Supportive study: The Action to Control Cardiovascular Risk in Diabetes (ACCORD) lipid trial was a randomized placebo-controlled study of 5,518 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.
Pharmacokinetics: The geometric mean ratios and 90% CIs for the comparison of AUC, AUC(0-t) and Cmax of the active metabolites, fenofibric acid and simvastatin acid, of the fixed dose combination Cholib 145 mg/20 mg film-coated tablets and the co-administration of the separate 145 mg fenofibrate and 20 mg simvastatin tablets as used in the clinical program, were all within the 80-125% bioequivalence interval.
The geomean maximum plasma level (Cmax) of the inactive parent simvastatin was 2.7 ng/mL for the fixed dose combination Cholib 145 mg/20 mg film-coated tablets and 3.9 ng/mL for the co-administration of the separate 145 mg fenofibrate and 20 mg simvastatin tablets as used in the clinical program.
The geometric mean ratios and 90% CIs for the comparison of plasma exposure (AUC and AUC (0-t)) to simvastatin after administration of the fixed dose combination Cholib 145 mg/20 mg film-coated tablet and after co-administration of the separate 145 mg fenofibrate and 20 mg simvastatin tablets as used in the clinical program, were within the 80-125% bioequivalence interval.
Absorption: Maximum plasma concentrations (Cmax) of fenofibrate occur within 2 to 4 hours after oral administration. Plasma concentrations are stable during continuous treatment in any given individual.
Fenofibrate is water-insoluble and must be taken with food to facilitate absorption. The use of micronised fenofibrate and NanoCrystal technology for the formulation of the fenofibrate 145 mg tablet enhances its absorption.
Contrarily to previous fenofibrate formulations, the maximum plasma concentration and overall exposure of this formulation is independent from food intake.
A food-effect study involving administration of this formulation of fenofibrate 145 mg tablets to healthy male and female subjects under fasting conditions and with a high fat meal indicated that exposure (AUC and Cmax) to fenofibric acid is not affected by food.
Therefore, fenofibrate in Cholib 145 mg/20 mg film-coated tablet may be taken without regard to meals.
Kinetic studies following the administration of a single dose and continuous treatment have demonstrated that the drug does not accumulate.
Simvastatin is an inactive lactone which is readily hydrolyzed in vivo to the corresponding betahydroxyacid, a potent inhibitor of HMG-CoA reductase. Hydrolysis takes place mainly in the liver; the rate of hydrolysis in human plasma is very slow.
Simvastatin is well absorbed and undergoes extensive hepatic first-pass extraction. The extraction in the liver is dependent on the hepatic blood flow. The liver is the primary site of action of the active form. The availability of the beta-hydroxyacid to the systemic circulation following an oral dose of simvastatin was found to be less than 5% of the dose. Maximum plasma concentration of active inhibitors is reached approximately 1-2 hours after administration of simvastatin. Concomitant food intake does not affect the absorption.
The pharmacokinetics of single and multiple doses of simvastatin showed that no accumulation of medicinal product occurred after multiple dosing.
Distribution: Fenofibric acid is strongly bound to plasma albumin (more than 99%). The protein binding of simvastatin and its active metabolite is > 95%.
Biotransformation and Elimination: After oral administration, fenofibrate is rapidly hydrolyzed by esterases to the active metabolite fenofibric acid. No unchanged fenofibrate can be detected in the plasma. Fenofibrate is not a substrate for CYP 3A4. No hepatic microsomal metabolism is involved.
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 elderly patients, the fenofibric acid apparent total plasma clearance is not modified.
Kinetic studies following the administration of a single dose and continuous treatment have demonstrated that the drug does not accumulate. Fenofibric acid is not eliminated by hemodialysis.
Mean plasma half-life: the plasma elimination half-life of fenofibric acid is approximately 20 hours.
Simvastatin is a substrate of CYP3A4 and of the efflux transporter BCRP. Simvastatin is taken up actively into the hepatocytes by the transporter OATP1B1. The major metabolites of simvastatin present in human plasma are the betahydroxyacid and four additional active metabolites. Following an oral dose of radioactive simvastatin to man, 13% of the radioactivity was excreted in the urine and 60% in the faeces within 96 hours. The amount recovered in the faeces represents absorbed medicinal product equivalents excreted in bile as well as unabsorbed medicinal product. Following an intravenous injection of the beta-hydroxyacid metabolite, its half-life averaged 1.9 hours. An average of only 0.3% of the intravenous dose was excreted in urine as inhibitors.
Effects of repeated administration of fenofibrate on the pharmacokinetics of single or multiple doses of simvastatin have been investigated in two small studies (n=12) followed by a larger one (n=85) in healthy subjects.
In one study the AUC of the simvastatin acid (SVA), a major active metabolite of simvastatin, was reduced by 42% (90% CI 24%-56%) when a single dose of 40 mg simvastatin was combined with repeated administration of fenofibrate 160 mg. In the other study [Bergman et al, 2004] repeated coadministration of both simvastatin 80 mg and fenofibrate 160 mg led to a reduction in the AUC of the SVA of 36% (90% CI 30%-42%). In the larger study a reduction of 21% (90% CI 14%-27%) in AUC of SVA was observed after repeated co-administration of simvastatin 40 mg and fenofibrate 145 mg in the evening. This was not significantly different from the 29% (90% CI 22%-35%) reduction in AUC of SVA observed when co-administration was 12 hours apart: simvastatin 40 mg in the evening and fenofibrate 145 mg in the morning.
Whether fenofibrate had an effect on other active metabolites of simvastatin was not investigated. The exact mechanism of interaction is not known. In the available clinical data, the effect on LDL-C reduction was not considered to be significantly different to simvastatin monotherapy when LDL-C is controlled at the time of initiating treatment.
The repeated administration of simvastatin 40 or 80 mg, the highest dose registered, did not affect the plasma levels of fenofibric acid at steady state.
Special populations: Carriers of the SLCO1B1 gene c.521T>C allele have lower OATP1B1 activity. The mean exposure (AUC) of the main active metabolite, simvastatin acid is 120% in heterozygote carriers (CT) of the C allele and 221% in homozygote (CC) carriers relative to that of patients who have the most common genotype (TT). The C allele has a frequency of 18% in the European population. In patients with SLCO1B1 polymorphism there is a risk of increased exposure of simvastatin, which may lead to an increased risk of rhabdomyolysis (see Precautions).
Toxicology: Preclinical safety data: No preclinical studies have been performed with the fixed dose combination Cholib 145 mg/20 mg film-coated tablet.
Fenofibrate: Acute toxicity studies have yielded no relevant information about specific toxicity of fenofibrate.
In a three-month oral nonclinical study in the rat species with fenofibric acid, the active metabolite of fenofibrate, toxicity for the skeletal muscles (particularly those rich in type I-slow oxidative-myofibres) and cardiac degeneration, anemia and decreased body weight were seen at exposure levels ≥50-fold the human exposure for the skeletal toxicity and >15 fold for the cardiomyotoxicity.
Reversible ulcers and erosions in the gastro-intestinal tract occurred in dogs treated during 3 months at exposures approximately 7-fold the clinical AUC.
Studies on mutagenicity of fenofibrate have been negative.
In rats and mice, liver tumours have been found in carcinogenicity studies, which are attributable to peroxisome proliferation. These changes are specific to rodents and have not been observed in other species at comparable dose levels. This is of no relevance to therapeutic use in man.
Studies in mice, rats and rabbits did not reveal any teratogenic effect. Embryotoxic effects were observed at doses in the range of maternal toxicity. Prolongation of the gestation period and difficulties during delivery were observed at high doses.
No effects on fertility were detected in non-clinical reproductive toxicity studies conducted with fenofibrate. However reversible hypospermia and testicular vacuolation and immaturity of the ovaries were observed in a repeat-dose toxicity study with fenofibric acid in young dogs.
Simvastatin: Based on conventional animal studies regarding pharmacodynamics, repeated dose toxicity, genotoxicity and carcinogenicity, there are no other risks for the patient than may be expected on account of the pharmacological mechanism. At maximally tolerated doses in both the rat and the rabbit, simvastatin produced no fetal malformations, and had no effects on fertility, reproductive function or neonatal development.

Cholib 145 mg/20 mg film-coated tablet 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 145 mg/20 mg film-coated tablet 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 Interactions).
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 145 mg/20 mg film-coated tablet is contraindicated (see Contraindications).
Patients with renal impairment: Cholib 145 mg/20 mg film-coated tablet is contraindicated in patients with moderate to severe renal insufficiency whose estimated glomerular filtration rate is < 60 mL/min/1.73 m² (see Contraindications). Cholib 145 mg/20 mg film-coated tablet 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 Precautions).
Patients with hepatic impairment: Cholib 145 mg/20 mg film-coated tablet has not been studied in patients with hepatic impairment and is therefore contraindicated in this population (see Contraindications).
Paediatric population: Cholib 145 mg/20 mg film-coated tablet is contraindicated in children and adolescents up to 18 years old (see Contraindications).
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 Pharmacology: Pharmacokinetics under Actions).

No specific antidote is known. If an overdose is suspected, symptomatic treatment and appropriate supportive measures should be provided as required.
Fenofibrate: Only anecdotal cases of fenofibrate overdose have been received. In the majority of cases no overdose symptoms were reported. Fenofibrate cannot be eliminated by haemodialysis.
Simvastatin: A few cases of simvastatin overdose have been reported; the maximum dose taken was 3.6 g. All patients recovered without sequelae. There is no specific treatment in the event of overdose. In this case, symptomatic and supportive measures should be adopted.

Hypersensitivity to the active substances, peanut, soya or to any of the excipients listed in Description (see also Precautions).
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 Interactions).
Concomitant administration of glecaprevir/pibrentasvir (see Interactions).
Paediatric population (age below 18 years).
Pregnancy and breast-feeding (see Use in Pregnancy & Lactation).
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 Precautions).

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 Pharmacology: Pharmacokinetics under Actions).
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 145 mg/20 mg film-coated tablet is administered with another fibrate, statin, niacin, fusidic acid or other specific concomitant substances (for specific interactions see Interactions). Physicians contemplating combined therapy with Cholib 145 mg/20 mg film-coated tablet 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 Interactions).
Simvastatin is a substrate of the Breast Cancer Resistant Protein (BCRP) efflux transporter. Concomitant administration of products that are inhibitors of BCRP (e.g., elbasvir and grazoprevir) may lead to increased plasma concentrations of simvastatin and an increased risk of myopathy; therefore, a dose adjustment of simvastatin should be considered depending on the prescribed dose. Co-administration of elbasvir and grazoprevir with simvastatin has not been studied; however, the dose of simvastatin should not exceed 20 mg daily in patients receiving concomitant medication with products containing elbasvir or grazoprevir (see Interactions).
Cholib 145 mg/20 mg film-coated tablet 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 Interactions). 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 145 mg/20 mg film-coated tablet 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 145 mg/20 mg film-coated tablet 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 145 mg/20 mg film-coated tablet therapy should be discontinued.
Cholib 145 mg/20 mg film-coated tablet should be used with caution in patients who consume substantial quantities of alcohol.
Pancreatitis: Pancreatitis has been reported in patients taking fenofibrate (see Contraindications and Adverse Reactions). 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 145 mg/20 mg film-coated tablet is contraindicated in moderate to severe renal impairment (see Contraindications).
Cholib 145 mg/20 mg film-coated tablet 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 Dosage & Administration).
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 > 200μmol/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 Adverse Reactions). 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 145 mg/20 mg tablet 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.
Effects on ability to drive and use machines: Fenofibrate has no or negligible influence on the ability to drive and use machines. Dizziness has been reported rarely in post-marketing experience with simvastatin. This adverse reaction should be taken into account when driving vehicles or using machines under Cholib 145 mg/20 mg film-coated tablet therapy.

Pregnancy: As simvastatin is contraindicated during pregnancy (see hereafter), Cholib 145 mg/20 mg film-coated tablet is contraindicated during pregnancy (see Contraindications).
Fenofibrate: There are no adequate data from the use of fenofibrate in pregnant women. Animal studies have shown embryo-toxic effects at doses in the range of maternal toxicity (see Pharmacology: Toxicology: Preclinical safety data under Actions). The potential risk for humans is unknown. Therefore, fenofibrate should only be used during pregnancy after a careful benefit/risk assessment.
Simvastatin: Simvastatin is contraindicated during pregnancy. Safety in pregnant women has not been established. Maternal treatment with simvastatin may reduce the foetal levels of mevalonate which is a precursor of cholesterol biosynthesis. For these reasons, simvastatin must not be used in women who are pregnant, trying to become pregnant or suspect they are pregnant. Treatment with simvastatin must be suspended for the duration of pregnancy or until it has been determined that the woman is not pregnant.
Breast-feeding: It is unknown whether fenofibrate, simvastatin and/or their metabolites are excreted in human milk. Therefore, Cholib 145 mg/20 mg film-coated tablet is contraindicated during breast-feeding (see Contraindications).
Fertility: Reversible effects on fertility have been observed in animals (see Pharmacology: Toxicology: Preclinical safety data under Actions). There are no clinical data on fertility from the use of Cholib 145 mg/20 film-coated mg tablet.

Summary of the safety profile: The most commonly reported adverse drug reactions (ADRs) during Cholib 145 mg/20 mg film-coated tablet therapy are increased blood creatinine, upper respiratory tract infection, increased platelet count, gastroenteritis and increased alanine-aminotransferase.
Tabulated list of adverse reactions: During four double blind clinical trials of 24-week duration 1,237 patients have received treatment with co-administered fenofibrate and simvastatin. In a pooled analysis of these four trials, the rate of discontinuation due to treatment emergent adverse reactions was 5.0% (51 subjects on 1012) after 12 weeks of treatment with fenofibrate and simvastatin 145 mg/20 mg per day and 1.8% (4 subjects on 225) after 12 weeks of treatment with fenofibrate and simvastatin 145 mg/40 mg per day.
Treatment emergent adverse reactions reported in patients receiving co-administration of fenofibrate and simvastatin occurring are listed as follows by system organ class and frequency.
The adverse reactions of Cholib 145 mg/20 mg film-coated tablet are in line with what is known from its two active substances: fenofibrate and simvastatin.
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) and not known (cannot be estimated from the available data).
Adverse reactions observed with the co-administration of fenofibrate and simvastatin (Cholib 145 mg/20 mg film-coated tablet). (See Table 3.)

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Description of selected adverse reactions: Blood creatinine increased: 10% of patient 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.
Additional information on the individual active substances of the fixed dose combination: Additional adverse reactions associated with the use of medicinal products containing simvastatin or fenofibrate observed in clinical trials and postmarketing experience that may potentially occur with Cholib 145 mg/20 mg tablet are listed as follows. (See Table 4.)

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Description of selected adverse reactions: Pancreatitis: * In the FIELD study, a randomised 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).
Thromboembolism: * In the FIELD study, a statistically significant increase was reported in the incidence of pulmonary embolism (0.7% [32/4900 patients] in the placebo group versus 1.1% [53/4895 patients] 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 patients]; p=0.074).
Myopathy: ** In a clinical trial, myopathy occurred commonly in patients treated with simvastatin 80 mg/day compared to patients treated with 20 mg/day (1.0% vs 0.02%, respectively).
Hypersensitivity syndrome: *** An apparent hypersensitivity syndrome has been reported rarely which has included some of the following features: angioedema, lupus-like syndrome, polymyalgia rheumatica, dermatomyositis, vasculitis, thrombocytopenia, eosinophilia, erythrocyte sedimentation rate (ESR) increased, arthritis and arthralgia, urticaria, photosensitivity, fever, flushing, dyspnoea and malaise.
Diabetes mellitus: **** Diabetes mellitus: 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.
Increased blood homocysteine level: ***** In the FIELD study the average increase in blood homocysteine level in patients treated with fenofibrate was 6.5 μmol/L, and was reversible on discontinuation of fenofibrate treatment.
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.

No interaction studies have been performed with Cholib 145 mg/20 mg film-coated tablet.
Interactions relevant to monotherapies: Inhibitors of CYP 3A4: Simvastatin is a substrate of cytochrome P450 3A4.
Potent inhibitors of cytochrome P450 3A4 increase the risk of myopathy and rhabdomyolysis by increasing the concentration of HMG-CoA reductase inhibitory activity in plasma during simvastatin therapy. Such inhibitors include itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors (e.g. nelfinavir), cobicistat and nefazodone.
Combination with itraconazole, ketoconazole, posaconazole, HIV protease inhibitors (e.g. nelfinavir), cobicistat, erythromycin, clarithromycin, telithromycin and nefazodone is contraindicated (see Contraindications). If treatment with itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin or telithromycin is unavoidable, therapy with Cholib 145 mg/20 mg film-coated tablet must be suspended during the course of treatment. Caution should be exercised when combining Cholib 145 mg/20 mg film-coated tablet with certain other less potent CYP 3A4 inhibitors: fluconazole, verapamil, or diltiazem (see Contraindications and Precautions).
Danazol: The risk of myopathy and rhabdomyolysis is increased by concomitant administration of danazol with simvastatin. The dose of simvastatin should not exceed 10 mg daily in patients taking danazol.
Therefore, the co-administration of Cholib 145 mg/20 mg film-coated tablets with danazol is contraindicated (see Contraindications).
Ciclosporin: The risk of myopathy/rhabdomyolysis is increased by concomitant administration of ciclosporin with simvastatin. Although the mechanism is not fully understood, ciclosporin has been shown to increase the plasma exposure (AUC) to simvastatin acid, presumably due in part to inhibition of CYP 3A4 and OATP-1B1 transporter. Because the dose of simvastatin should not exceed 10 mg daily in patients taking ciclosporin, the co-administration of Cholib 145 mg/20 mg tablet with ciclosporin is contraindicated (see Contraindications).
Amiodarone, amlodipine, diltiazem and verapamil: The risk of myopathy and rhabdomyolysis is increased by concomitant use of amiodarone, amlodipine, diltiazem or verapamil with simvastatin 40 mg per day.
In a clinical trial, myopathy was reported in 6% of patients receiving simvastatin 80 mg and amiodarone, versus 0.4% in patients on simvastatin 80 mg only.
Concomitant administration of amlodipine and simvastatin caused a 1.6-fold increase in exposure of simvastatin acid.
Concomitant administration of diltiazem and simvastatin caused a 2.7-fold increase in exposure of simvastatin acid, presumable due to inhibition of CYP 3A4.
Concomitant administration of verapamil and simvastatin resulted in a 2.3-fold increase in plasma exposure to simvastatin acid, presumably due, in part, to inhibition of CYP 3A4.
Therefore, the dose of Cholib 145 mg/20 mg film-coated tablet should not exceed 145 mg/20 mg daily in patients taking amiodarone, amlodipine, diltiazem or verapamil.
Inhibitors of Breast Cancer Resistant Protein (BCRP): Concomitant administration of medicinal products that are inhibitors of BCRP, including products containing elbasvir or grazoprevir, may lead to increased plasma concentrations of simvastatin and an increased risk of myopathy (see Precautions).
Other statins and fibrates: Gemfibrozil increases the AUC of simvastatin acid by 1.9-fold, possibly due to inhibition of the glucuronidation pathway. The risk of myopathy and rhabdomyolysis is significantly increased by concomitant use of gemfibrozil with simvastatin. The risk of rhabdomyolysis is also increased in patients concomitantly receiving other fibrates or statins. Therefore, the co-administration of Cholib 145 mg/20 mg tablet with gemfibrozil, other fibrates, or statins is contraindicated (see Contraindications).
Niacin (nicotinic acid): Cases of myopathy/rhabdomyolysis have been associated with concomitant administration of statins and niacin (nicotinic acid) at lipid-modifying doses (≥ 1 g/day), knowing that niacin and statins can cause myopathy when given alone.
Physicians contemplating combined therapy with Cholib 145 mg/20 mg film-coated tablet 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.
Fusidic acid: The risk of myopathy including rhabdomyolysis may be increased by the concomitant administration of systemic fusidic acid with statins. Co-administration of this combination may cause increased plasma concentrations of both agents. The mechanism of this interaction (whether it is pharmacodynamics or pharmacokinetic, or both) is yet unknown. There have been reports of rhabdomyolysis (including some fatalities) in patients receiving this combination.
If treatment with fusidic acid is necessary, Cholib 145 mg/20 mg film-coated tablet treatment should be discontinued throughout the duration of the fusidic acid treatment. (Also see Precautions).
Grapefruit juice: Grapefruit juice inhibits CYP 3A4. Concomitant intake of large quantities (over 1 liter daily) of grapefruit juice and simvastatin resulted in a 7-fold increase in plasma exposure to simvastatin acid. Intake of 240 mL of grapefruit juice in the morning and simvastatin in the evening also resulted in a 1.9-fold increase in plasma exposure to simvastatin acid. Intake of grapefruit juice during treatment with Cholib should therefore be avoided.
Colchicine: There have been reports of myopathy and rhabdomyolysis with the concomitant administration of colchicine and simvastatin in patients with renal insufficiency. Therefore, close clinical monitoring of such patients taking colchicine and Cholib 145 mg/20 mg film-coated tablet is advised.
Vitamin K antagonists: Fenofibrate and simvastatin enhance effects of Vitamin K antagonists and may increase the risk of bleeding. It is recommended that the dose of those oral 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. INR should be determined before starting Cholib and frequently enough during early therapy to ensure that no significant alteration of INR occurs. Once a stable INR has been documented, it can be monitored at the intervals usually recommended for patients on those oral anticoagulants. If the dose of Cholib 145 mg/20 mg film-coated tablet is changed or discontinued, the same procedure should be repeated. Cholib 145 mg/20 mg film-coated tablet therapy has not been associated with bleeding in patients not taking anticoagulants.
Glitazones: Some cases of reversible paradoxical reduction of HDL-C have been reported during concomitant administration of fenofibrate and glitazones. Therefore it is recommended to monitor HDL-C if Cholib 145 mg/20 mg tablet is co-administered with a glitazone and stopping either therapy if HDL-C is too low.
Rifampicin: Because rifampicin is a potent CYP 3A4 inducer that interferes with simvastatin metabolism, patients undertaking long-term rifampicin therapy (e.g. treatment of tuberculosis) may experience loss of efficacy of simvastatin. In normal volunteers, the plasma exposure to simvastatin acid was decreased by 93% with concomitant administration of rifampicin.
Effects on the pharmacokinetics of other medicinal products: Fenofibrate and simvastatin are not CYP 3A4 inhibitors or inducers. Therefore, Cholib 145 mg/20 mg film-coated tablet is not expected to affect plasma concentrations of substances metabolised via CYP 3A4.
Fenofibrate and simvastatin are not inhibitors of CYP 2D6, CYP 2E1, or CYP 1A2. Fenofibrate is a mild to moderate inhibitor of CYP 2C9 and a weak inhibitor of CYP 2C19 and CYP 2A6.
Patients receiving co-administration of Cholib 145 mg/20 mg film-coated tablet and drugs metabolised by CYP 2C19, CYP 2A6, or especially CYP 2C9 with a narrow therapeutic index should be carefully monitored and, if necessary, dose adjustment of these drugs is recommended.
Interaction between simvastatin and fenofibrate: Effects of repeated administration of fenofibrate on the pharmacokinetics of single or multiple doses of simvastatin have been investigated in two small studies (n=12) followed by a larger one (n= 85) in healthy subjects.
In one study the AUC of the simvastatin acid (SVA), a major active metabolite of simvastatin, was reduced by 42% (90% CI 24%-56%) when a single dose of 40 mg simvastatin was combined with repeated administration of fenofibrate 160 mg. In the other study [Bergman et al, 2004] repeated coadministration of both simvastatin 80 mg and fenofibrate 160 mg led to a reduction in the AUC of the SVA of 36% (90% CI 30%-42%). In the larger study a reduction of 21% (90% CI 14%-27%) in AUC of SVA was observed after repeated co-administration of simvastatin 40 mg and fenofibrate 145 mg in the evening. This was not significantly different from the 29% (90% CI 22%-35%) reduction in AUC of SVA observed when co-administration was 12 hours apart: simvastatin 40 mg in the evening and fenofibrate 145 mg in the morning.
Whether fenofibrate had an effect on other active metabolites of simvastatin was not investigated. The exact mechanism of interaction is not known. In the available clinical data, the effect on LDL-C reduction was not considered to be significantly different to simvastatin monotherapy when LDL-C is controlled at the time of initiating treatment.
The repeated administration of simvastatin 40 or 80 mg, the highest dose registered, did not affect the plasma levels of fenofibric acid at steady state.
Prescribing recommendations for interacting substances are summarised in the table as follows (see also Dosage & Administration and Contraindications). (See Table 5.)

Click on icon to see table/diagram/image

Incompatibilities: Not applicable.
Special precautions for disposal and other handling: Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Shelf life: 2 years.
Store below 30°C.

Dyslipidaemic Agents

C10BA04 - simvastatin and fenofibrate ; Belongs to the class of HMG CoA reductase inhibitors in combination with other lipid modifying agents. Used in the treatment of hyperlipidemia.

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