Cholib

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
 
 



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1. NAME OF THE MEDICINAL PRODUCT 
 
Cholib 145 mg/20 mg film-coated tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
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. 
 
 
3. PHARMACEUTICAL FORM 
 
Film-coated tablet (tablet). 
 
Oval, biconvex, tan coloured, film-coated tablet, with bevelled edges and 145/20 on one side. The 
diameter dimensions are 19.3 x 9.3 mm approximately and the tablet weight is about 734 mg. 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
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. 
 
4.2 Posology and method of administration 
 
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). 
 



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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). 
 
Concomitant therapy  
In patients taking products containing elbasvir or grazoprevir concomitantly with Cholib the dose of 
simvastatin should not exceed 20 mg/day. (See sections 4.4 and 4.5.) 
 
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). 
 
4.3 Contraindications 
 
• 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) 
• Concomitant administration of glecaprevir/ pibrentasvir (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) 

 
4.4 Special warnings and precautions for use 
 
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. 
 



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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). 
 
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 section 4.5). 
 
The risk of myopathy is increased by high levels of HMG CoA reductase inhibitory activity in plasma 
(i.e., elevated simvastatin and simvastatin acid plasma levels), which may be due, in part, to 
interacting drugs that interfere with simvastatin metabolism and/or transporter pathways (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. 



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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. 
 



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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. 



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This medicine contains less than 1 mmol sodium (23 mg) per one tablet, that is to say essentially 
‘sodium-free’. 
 
This medicinal product contains sunset yellow FCF (E110) that may cause allergic reactions. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
No interaction studies have been performed with Cholib. 
 
Interactions relevant to monotherapies 
Inhibitors of CYP 3A4 
Simvastatin is a substrate of cytochrome P450 3A4. 
 
Multiple mechanisms may contribute to potential interactions with HMG Co-A reductase inhibitors. 
Drugs or herbal products that inhibit certain enzymes (e.g. CYP3A4) and/or transporter (e.g. 
OATP1B) pathways may increase simvastatin and simvastatin acid plasma concentrations and may 
lead to an increased risk of myopathy/rhabdomyolysis. 
 
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), and nefazodone. 
 
Combination with itraconazole, ketoconazole, posaconazole, HIV protease inhibitors (e.g. nelfinavir), 
erythromycin, clarithromycin, telithromycin and nefazodone is contraindicated (see section 4.3). If 
treatment with itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin or 
telithromycin is unavoidable, therapy with Cholib must be suspended during the course of treatment. 
Caution should be exercised when combining Cholib with certain other less potent 
 
CYP 3A4 inhibitors: fluconazole, verapamil, or diltiazem (see sections 4.3 and 4.4). 
 
Consult the prescribing information of all concomitantly used drugs to obtain further 
information about their potential interactions with simvastatin and/or the potential for enzyme 
or transporter alterations and possible adjustments to dose and regimens. 
 
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 with danazol is contraindicated (see section 4.3). 
 
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 with ciclosporin is contraindicated (see 
section 4.3). 
 
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. 
 



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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 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 sections 4.2 and 4.4). 
 
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 
with gemfibrozil, other fibrates, or statins is contraindicated (see section 4.3). 
 
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 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 treatment should be discontinued throughout the 
duration of the fusidic acid treatment. (Also see section 4.4). 
 
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 is advised. 
 



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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 is changed or discontinued, the same procedure should be 
repeated. Cholib 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 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 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 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 
co-administration 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. 
 



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Prescribing recommendations for interacting substances are summarised in the table below (see also 
sections 4.2 and 4.3). 
 
Interacting substances Prescribing recommendations 
Potent CYP 3A4 inhibitors: 
Itraconazole 
Ketoconazole 
Fluconazole 
Posaconazole 
Erythromycin 
Clarithromycin 
Telithromycin 
HIV protease inhibitors (e.g. nelfinavir) 
Nefazodone 

Contraindicated with Cholib 

Danazol 
Ciclosporin Contraindicated with Cholib  

Gemfibrozil, Other statins and fibrates Contraindicated with Cholib 
Amiodarone 
Verapamil 
Diltiazem 
Amlodipine 

Do not exceed one Cholib 145 mg/20 mg per day, 
unless clinical benefit outweigh the risk 

Elbasvir 
Grazoprevir Do not exceed one Cholib 145 mg/20 mg per day 

Glecaprevir 
Pibrentasvir Contraindicated with Cholib 

Niacin (nicotinic acid) ≥ 1 g/day 

Avoid with Cholib unless clinical benefit 
outweigh the risk 
Monitor patients for any signs and symptoms of 
muscle pain, tenderness or weakness 

Fusidic acid 
Patients should be closely monitored. Temporary 
suspension of Cholib treatment may be 
considered 

Grapefruit juice Avoid when taking Cholib 

Vitamin K antagonists  Adjust the dose of these oral anticoagulants according to INR monitoring 

Glitazones Monitor HDL-C and stop either therapy (glitazone or Cholib) if HDL-C is too low 
 
4.6 Fertility, pregnancy and lactation 
 
Pregnancy 
 
Cholib 
As simvastatin is contraindicated during pregnancy (see hereafter), Cholib is contraindicated during 
pregnancy (see section 4.3). 
 
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 section 5.3). 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 



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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 is contraindicated during breast-feeding (see section 4.3). 
 
Fertility 
Reversible effects on fertility have been observed in animals (see section 5.3). 
There are no clinical data on fertility from the use of Cholib. 
 
4.7 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 therapy. 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
The most commonly reported adverse drug reactions (ADRs) during Cholib 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 below by system organ class and frequency. 
 
The adverse reactions of Cholib 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) 
 
System Organ Class Adverse reactions Frequency 

Infections and infestations Upper respiratory tract infection, Gastroenteritis Common 

Blood and lymphatic 
disorders Platelet count increased Common 

Hepatobiliary disorders Alanine- aminotransferase increased Common 

Skin and subcutaneous tissue 
disorders Dermatitis and eczema Uncommon 

Investigations Blood creatinine increased (see sections 4.3 and 4.4) very common 

 



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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 are listed below. Frequency categories are based on information available from simvastatin and 
fenofibrate Summary of Product Characteristics available in the EU. 
 
System Organ Class Adverse reactions 

(fenofibrate) 
Adverse reactions 
(simvastatin) 

Frequency 

Blood and lymphatic 
system disorders 

Haemoglobin decreased 
White blood cell count 
decreased 

 rare 

 Anaemia rare 
Immune system disorders Hypersensitivity  rare 

 Anaphylaxis very rare 
Metabolism and nutrition 
disorders 

 Diabetes Mellitus**** not known 

Psychiatric disorders  Insomnia very rare 
Sleep disorder, including 
nightmares, depression 

not known 

Nervous system disorders Headache  uncommon 
 Paresthesia, dizziness, 

peripheral neuropathy 
rare 

Memory impairment/ 
Memory loss 

rare 

Eye disorders  Vision blurred, visual 
impairment 

rare 

Vascular disorders Thromboembolism 
(pulmonary embolism, 
deep vein thrombosis)* 

 uncommon 

Respiratory, thoracic and 
mediastinal disorders 

 Interstitial lung disease not known 

Gastrointestinal disorders Gastrointestinal signs and 
symptoms (abdominal pain, 
nausea, vomiting, 
diarrhoea, flatulence) 

 common 

Pancreatitis* uncommon 
 Constipation, dyspepsia rare 

Hepatobiliary disorders Transaminases increased  common 
Cholelithiasis uncommon 
Complications of 
cholelithiasis (e.g. 
cholecystitis, cholangitis, 
biliary colic etc) 

not known 

 Gamma-glutamyltransferase 
increase 

rare 

Hepatitis/jaundice 
Hepatic failure 

very rare 

Skin and subcutaneous 
tissue disorders 

Severe cutaneous reactions 
(e.g erythema multiforme, 
Ste vens-Johnson 

 not known 

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13 

System Organ Class Adverse reactions 
(fenofibrate) 

Adverse reactions 
(simvastatin) 

Frequency 

syndrome, toxic epidermal 
necrolysis, etc.) 
Cutaneous hypersensitivity 
(e.g. Rash, pruritus, 
urticaria) 

 uncommon 

Alopecia rare 
Photosensitivity reactions rare 
 Hypersensitivity syndrome 

*** 
rare 

 Lichenoid drug eruptions very rare 
Musculoskeletal, 
connective tissue 
disorders 

Muscle disorders (e.g. 
myalgia, myositis, 
muscular spasms and 
weakness) 

 uncommon 

Rhabdomyolysis with or 
without renal failure 
(see section 4.4), 

 rare 

 Myopathy** 
Tendinopathy 
Immune-mediated 
necrotizing myopathy (see 
section 4.4) 

rare 
unkown 

 Muscle rupture very rare 
Reproductive system and 
breast disorders 

Sexual dysfunction  uncommon 
 Erectile dysfunction not known 
 Gynecomastia very rare 

General disorders and 
administration site 
conditions 

 Asthenia rare 

Investigations Blood homocysteine level 
increased (see 
section 4.4)***** 

 very 
common 

Blood urea increased rare 
 Blood alkaline phosphatase 

increased 
rare 

Blood creatine 
phosphokinase level 
increase 

rare 

Glycosylated haemoglobin 
increased 

not known 

Blood glucose increased not known 
 
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 thromboses 
(placebo: 1.0% [48/4900 patients] versus fenofibrate 1.4% [67/4895 patients]; p=0.074). 



14 

 
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 via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
Cholib 
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. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Lipid modifying substances, HMG-CoA reductase inhibitors in 
combination with other lipid modifying substances, ATC code: C10BA04 
 
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). 
 

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15 

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 
beta-hydroxyacid 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: 
Cholib contains fenofibrate and simvastatin, which have different modes of action as described above. 
 
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. 
 
Cholib 
The respective effects of simvastatin and fenofibrate are complementary. 
 
Clinical efficacy and safety 
 
Cholib 
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: 
 
  Week 0 to Week 12 Week 12 to Week 24 
Stud
y 

Statin 6 weeks 
run-in 

Statin 
monotherapy 

Fenofibrate/Simvas
tatin in 
combination 

Statin 
monotherapy 

Fenofibrate/Simvas
tatin in 
combination 

0501 simvastatin 
20 mg 

simvastatin 40 
mg 

simvastatin 20 mg simvastatin 40 
mg 

simvastatin 40 mg 

0502 simvastatin 40 
mg 

simvastatin 40 
mg 

simvastatin 40 mg simvastatin 40 
mg 

simvastatin 40 mg 

0503 atorvastatin 10 
mg 

atorvastatin 10 
mg 

simvastatin 20 mg atorvastatin 20 
mg 

simvastatin 40 mg 

0504 pravastatin 40 
mg 

pravastatin 40 
mg 

simvastatin 20 mg pravastatin 40 
mg 

simvastatin 40 mg 



16 

 
Cholib 145/40 
Study 0502 was evaluated a constant dose of fenofibrate-simvastatin combination and statin 
comparator throughout the 24 week double-blind period. The primary efficacy criterion was 
superiority of the combination fenofibrate 145 and simvastatin 40 mg versus simvastatin 40 mg on TG 
and LDL-C decrease and HDL-C increase at 12 weeks. 
 
At 12 weeks and 24 weeks the combination of fenofibrate 145 mg and simvastatin 40 mg (F145/S40) 
showed superiority over simvastatin 40 mg (S40) for TG reduction and HDL-C increase. 
 
The combination F145/S40 showed superiority over S40 for LDL-C reduction only at 24 weeks from 
a non-significant additional 1.2% reduction of LDL-C at 12 weeks to a statistically significant 7.2% 
reduction at 24 weeks. 
 

TG, LDL-C and HDL-C Percent Change from Baseline to 12 and 24 Weeks 
Full Analysis Subject Sample 

Lipid  
parameter 
(mmol/L) 

Feno 145+Simva 40 
(N=221) 

Simva 40 
(N=219) 

Treatment 
Comparison* 

P-value 

After 12 weeks % Change Mean (SD)   
TG  -27.18 (36.18) -0.74 (39.54) -28.19 

(-32.91, -23.13) 
<0.001 

LDL-C  -6.34 (23.53) -5.21 (22.01) -1.24 
(-5.22, 2.7) 

0.539 

HDL-C  5.77 (15.97) -0.75 (12.98) 6.46 
(3.83, 9.09) 

<0.001 

After 24 weeks % Change Mean (SD)   
TG -22.66 (43.87) 1.81 (36.64) -27.56 

(-32.90, -21.80) 
<0.001 

LDL-C  -3.98 (24.16) 3.07 (30.01) -7.21 
(-12.20, -2.21) 

0.005 

HDL-C  5.08 (16.10) 0.62 (13.21) 4.65 
(1.88, 7.42) 

0.001 

*Treatment Comparison consists of the difference between the LS-means for Feno 145 + Simva 40 an
d Simva 40, as well as the corresponding 95% CI. 
 
The results on the biological parameters of interest at 24 weeks are presented in the table below. 
F145/S40 demonstrated statistically significant superiority on all parameters except on 
ApoA1 increase. 
 

ANCOVA (analysis of covariance) of Percent Change in TC, non-HDL-C, ApoAI, ApoB, 
ApoB/ApoAI and fibrinogen from Baseline to 24 Weeks – Full Analysis Subject Sample 

Parameter Treatment 
Group 

N Means (SD) Treatment 
Comparison* 

P-value 

TC (mmol/L) Feno 145 + 
Simva 40 
Simva 40 

213 
203 

-4.95 (18.59) 
1.69 (20.45) 

 
-6.76 (-10.31, -3.20) 

 
<0.001 

Non-HDL-C 
(mmol/L) 

Feno 145 + 
Simva 40 
Simva 40 

213 
203 

-7.62 (23.94) 
2.52 (26.42) 

 
-10.33 (-14.94, -5.72) 

 
<0.001 

Apo AI (g/L) Feno 145 + 
Simva  40 
Simva 40 

204 
194 

5.79 (15.96) 
4.02 (13.37) 

 
2.34 (-0.32, 4.99) 

 
0.084 

Apo B (g/L) Feno 145 + 
Simva 40 
Simva 40 

204 
194 

-2.95 (21.88) 
6.04 (26.29) 

 
-9.26 (-13.70, -4.82) 

 
<0.001 



17 

ANCOVA (analysis of covariance) of Percent Change in TC, non-HDL-C, ApoAI, ApoB, 
ApoB/ApoAI and fibrinogen from Baseline to 24 Weeks – Full Analysis Subject Sample 

Parameter Treatment 
Group 

N Means (SD) Treatment 
Comparison* 

P-value 

Apo B/Apo AI Feno 145 + 
Simva 40 
Simva 40 

204 
194 

-4.93 (41.66) 
3.08 (26.85) 

 
-8.29 (-15.18, -1.39) 

 
0.019 

Fibrinogen* (g/L) Feno 145 + 
Simva 40 
Simva 40 

202 
192 

-29 (0.04) 
0.01 (0.05) 

 
-0.30 (-0.41, -0.19) 

 
<0.001 

*Treatment Comparison consists of the difference between the LS-means for Feno 145 + Simva 40 an
d Simva 40, as well as the corresponding 95% CI. LS (less square mean) SD (standard deviation) 
 
Cholib 145/20 
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. 
 

Mean Percent Change from Baseline to 12 Weeks 
Full Analysis Subject Sample 

Parameter Feno 145+Simva 
20 
(N=493) 
Mean (SD) 

Simva 40 
(N=505) 
Mean (SD) 

Treatment 
Comparison* 

P-value 

TG (mmol/L) -28.20 (37.31) -4.60 (40.92) -26.47 (-30.0, -22.78) <0.001 
LDL-C (mmol/L) -5.64 (23.03) -10.51 (22.98) 4.75 (2.0, 7.51) NA 
HDL-C (mmol/L) 7.32 (15.84) 1.64 (15.76) 5.76 (3.88, 7.65) <0.001 
TC (mmol/L) -6.00 (15.98) -7.56 (15.77) 1.49 (-0.41, 3.38) 0.123 
Non-HDL-C 
(mmol/L) 

-9.79 (21.32) -9.79 (20.14) -0.11 (-2.61,2.39) 0.931 

Apo AI (g/L) 3.97 (13.15) 0.94 (13.03) 2.98 (1.42,4.55) <0.001 
Apo B (g/L) -6.52 (21.12) -7.97 (17.98) 1.22 (-1.19,3.63) 0.320 
Apo B/Apo AI -8.49 (24.42) -7.94 (18.96) -0.73 (-3.44,1.97) 0.595 
Fibrinogen (g/L) -0.31 (0.70) -0.02 (0.70) -0.32 (-0.40,-0.24) < 0.001 
*Treatment Comparison: difference between the LS Means for Feno 145 + Simva 20 and Simva 40, 
as well as the associated 95% confidence interval 
 
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 



18 

(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. 
 
Paediatric population 
The European Medicines Agency has waived the obligation to submit the results of studies with 
Cholib in all subsets of the paediatric population in combined dyslipidaemia (see section 4.2 for 
information on paediatric use). 
 
5.2 Pharmacokinetic properties 
 
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 
tablet 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 tablet 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 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 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 
beta-hydroxyacid, 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 



19 

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 CYP 3A4 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 beta-hydroxyacid 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 
co-administration 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. 
 



20 

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 section 4.4). 
 
5.3 Preclinical safety data 
 
No preclinical studies have been performed with the fixed dose combination Cholib. 
 
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. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Tablet core: 
 
Butylhydroxyanisole (E320) 
Lactose monohydrate 
Sodium laurilsulfate 
Starch, pregelatinised (maize) 
Docusate sodium 



21 

Sucrose 
Citric acid monohydrate (E330) 
Hypromellose (E464) 
Crospovidone (E1202) 
Magnesium stearate (E572) 
Silicified microcrystalline cellulose (comprised of cellulose, microcrystalline and silica, 
colloidal anhydrous) 
Ascorbic acid (E300) 
 
Film-coating: 
 
Poly (vinyl alcohol), partially hydrolysed (E1203) 
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) 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
2 years. 
 
6.4 Special precautions for storage 
 
Store below 30°C. 
 
6.5 Nature and contents of container 
 
Alu/Alu blisters 
Pack sizes: 10, 30 and 90 film-coated tablets. 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal 
 
Any unused medicinal product or waste material should be disposed of in accordance with 
local requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
 
Mylan IRE Healthcare Ltd 
Unit 35/36 Grange Parade,  
Baldoyle Industrial Estate,  
Dublin 13 
Ireland 
 
 



22 

8. MARKETING AUTHORISATION NUMBERS 
 
EU/1/13/866/001-002 
EU/1/13/866/005 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 26 August 2013 
Date of latest renewal: 16 May 2018 
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 
 
 

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


23 

1. NAME OF THE MEDICINAL PRODUCT 
 
Cholib 145 mg/40 mg film-coated tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
One film-coated tablet contains 145 mg of fenofibrate and 40 mg of simvastatin. 
 
Excipient(s) with known effect: 
One film-coated tablet contains, 194.7 mg of lactose (as monohydrate), 145 mg of sucrose and 0.8 mg 
of lecithin (derived from soya bean (E322)). 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Film-coated tablet (tablet). 
 
Oval, biconvex, brick red coloured, film-coated tablet, with bevelled edges and 145/40 on one side. 
The diameter dimensions are 19.3 x 9.3 mm approximately and the tablet weight is about 840 mg. 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
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. 
 
4.2 Posology and method of administration 
 
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). 
 



24 

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). 
 
Concomitant therapy  
In patients taking products containing elbasvir or grazoprevir concomitantly with Cholib the dose of 
simvastatin should not exceed 20 mg/day. (See sections 4.4 and 4.5.) 
 
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). 
 
4.3 Contraindications 
 
• 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) 
• Concomitant administration of glecaprevir, pibrentasvir, elbasvir or grazoprevir (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) 

Concomitant administration of amiodarone, verapamil, amlodipine or diltiazem (see section 4.5) 
4.4 Special warnings and precautions for use 
 
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 



25 

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). 
 
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 section 4.5). 
 
The risk of myopathy is increased by high levels of HMG CoA reductase inhibitory activity in plasma 
(i.e., elevated simvastatin and simvastatin acid plasma levels), which may be due, in part, to 
interacting drugs that interfere with simvastatin metabolism and/or transporter pathways (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. 
 



26 

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). 
 



27 

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 medicine contains less than 1 mmol sodium (23 mg) per one tablet, that is to say essentially 
‘sodium-free’. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
No interaction studies have been performed with Cholib. 
 
Interactions relevant to monotherapies 
Inhibitors of CYP 3A4 
Simvastatin is a substrate of cytochrome P450 3A4. 
 



28 

Multiple mechanisms may contribute to potential interactions with HMG Co-A reductase inhibitors. 
Drugs or herbal products that inhibit certain enzymes (e.g. CYP3A4) and/or transporter (e.g. 
OATP1B) pathways may increase simvastatin and simvastatin acid plasma concentrations and may 
lead to an increased risk of myopathy/rhabdomyolysis. 
 
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), and nefazodone. 
 
Combination with itraconazole, ketoconazole, posaconazole, HIV protease inhibitors (e.g. nelfinavir), 
erythromycin, clarithromycin, telithromycin and nefazodone is contraindicated (see section 4.3). 
If treatment with itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin or 
telithromycin is unavoidable, therapy with Cholib must be suspended during the course of 
treatment. Caution should be exercised when combining Cholib with certain other less potent 
 
CYP 3A4 inhibitors: fluconazole, verapamil, or diltiazem (see sections 4.3 and 4.4). 
 
Consult the prescribing information of all concomitantly used drugs to obtain further 
information about their potential interactions with simvastatin and/or the potential for enzyme 
or transporter alterations and possible adjustments to dose and regimens. 
 
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 with danazol is contraindicated (see section 4.3). 
 
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 with ciclosporin is contraindicated (see 
section 4.3). 
 
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 should not exceed 145 mg/20 mg daily in patients taking amiodarone, 
amlodipine, diltiazem or verapamil. 
 



29 

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 sections 4.2 and 4.4). 
 
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 
with gemfibrozil, other fibrates, or statins is contraindicated (see section 4.3). 
 
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 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 treatment should be discontinued throughout the 
duration of the fusidic acid treatment. (Also see section 4.4). 
 
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 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 is changed or discontinued, the same procedure should be 
repeated. Cholib therapy has not been associated with bleeding in patients not taking anticoagulants. 
 



30 

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 
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 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 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 
co-administration 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. 
 



31 

Prescribing recommendations for interacting substances are summarised in the table below (see also 
sections 4.2 and 4.3). 
 
Interacting substances Prescribing recommendations 
Potent CYP 3A4 inhibitors: 
Itraconazole 
Ketoconazole 
Fluconazole 
Posaconazole 
Erythromycin 
Clarithromycin 
Telithromycin 
HIV protease inhibitors (e.g. nelfinavir) 
Nefazodone 

Contraindicated with Cholib 

Danazol 
Ciclosporin Contraindicated with Cholib  

Gemfibrozil, Other statins and fibrates Contraindicated with Cholib 
Amiodarone 
Verapamil 
Diltiazem 
Amlodipine 

Contraindicated with Cholib 145 mg/40 mg 

Elbasvir  
Grazoprevir Contraindicated with Cholib 145 mg/40 mg 

Glecaprevir 
Pibrentasvir Contraindicated with Cholib 

Niacin (nicotinic acid) ≥ 1 g/day  

Avoid with Cholib unless clinical benefit 
outweigh the risk 
Monitor patients for any signs and symptoms of 
muscle pain, tenderness or weakness 

Fusidic acid 
Patients should be closely monitored. Temporary 
suspension of Cholib treatment may be 
considered 

Grapefruit juice Avoid when taking Cholib 

Vitamin K antagonists  Adjust the dose of these oral anticoagulants according to INR monitoring 

Glitazones Monitor HDL-C and stop either therapy (glitazone or Cholib) if HDL-C is too low 
 
4.6 Fertility, pregnancy and lactation 
 
Pregnancy 
 
Cholib 
As simvastatin is contraindicated during pregnancy (see hereafter), Cholib is contraindicated during 
pregnancy (see section 4.3). 
 
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 section 5.3). 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 



32 

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 is contraindicated during breast-feeding (see section 4.3). 
 
Fertility 
Reversible effects on fertility have been observed in animals (see section 5.3). 
There are no clinical data on fertility from the use of Cholib. 
 
4.7 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 therapy. 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
The most commonly reported adverse drug reactions (ADRs) during Cholib 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 below by system organ class and frequency. 
 
The adverse reactions of Cholib 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) 
 
System Organ Class Adverse reactions Frequency 

Infections and infestations Upper respiratory tract infection, Gastroenteritis Common 

Blood and lymphatic 
disorders Platelet count increased Common 

Hepatobiliary disorders Alanine- aminotransferase increased Common 

Skin and subcutaneous tissue 
disorders Dermatitis and eczema Uncommon 

Investigations Blood creatinine increased (see sections 4.3 and 4.4) very common 

 



33 

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 are listed below. Frequency categories are based on information available from simvastatin and 
fenofibrate Summary of Product Characteristics available in the EU. 
 
System Organ Class Adverse reactions 

(fenofibrate) 
Adverse reactions 
(simvastatin) 

Frequenc
y 

Blood and lymphatic 
system disorders 

Haemoglobin decreased 
White blood cell count 
decreased 

 rare 

 Anaemia rare 
Immune system disorders Hypersensitivity  rare 

 Anaphylaxis very rare 
Metabolism and nutrition 
disorders 

 Diabetes Mellitus**** not 
known 

Psychiatric disorders  Insomnia very rare 
Sleep disorder, including 
nightmares, depression 

not 
known 

Nervous system disorders Headache  uncommo
n 

 Paresthesia, dizziness, 
peripheral neuropathy 

rare 

Memory 
impairment/Memory loss 

rare 

Eye disorders  Vision blurred, visual 
impairment 

rare 

Vascular disorders Thromboembolism 
(pulmonary embolism, 
deep vein thrombosis)* 

 uncommo
n 

Respiratory, thoracic and 
mediastinal disorders 

 Interstitial lung disease not 
known 

Gastrointestinal disorders Gastrointestinal signs and 
symptoms (abdominal pain, 
nausea, vomiting, 
diarrhoea, flatulence) 

 common 

Pancreatitis* uncommo
n 

 Constipation, dyspepsia rare 
Hepatobiliary disorders Transaminases increased  common 

Cholelithiasis uncommo
n 

Complications of 
cholelithiasis (e.g. 
cholecystitis, cholangitis, 
biliary colic etc) 

not 
known 

 Gamma-glutamyltransferase 
increase 

rare 

Hepatitis/jaundice 
Hepatic failure 

very rare 

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34 

System Organ Class Adverse reactions 
(fenofibrate) 

Adverse reactions 
(simvastatin) 

Frequenc
y 

Skin and subcutaneous 
tissue disorders 

Severe cutaneous reactions 
(e.g erythema multiforme, 
Ste vens-Johnson 
syndrome, toxic epidermal 
necrolysis, etc.) 

 not 
known 

Cutaneous hypersensitivity 
(e.g. Rash, pruritus, 
urticaria) 

 uncommo
n 

Alopecia rare 
Photosensitivity reactions rare 
 Hypersensitivity syndrome 

*** 
rare 

 Lichenoid drug eruptions very rare 
Musculoskeletal, 
connective tissue 
disorders 

Muscle disorders (e.g. 
myalgia, myositis, muscular 
spasms and weakness) 

 uncommo
n 

Rhabdomyolysis with or 
without renal failure 
(see section 4.4), 

 rare 

 Myopathy** 
Tendinopathy 
Immune-mediated 
necrotizing myopathy (see 
section 4.4) 

rare 
unkown 

 Muscle rupture very rare 
Reproductive system and 
breast disorders 

Sexual dysfunction  uncommo
n 

 Erectile dysfunction not 
known 

 Gynecomastia very rare 
General disorders and 
administration site 
conditions 

 Asthenia rare 

Investigations Blood homocysteine level 
increased (see 
section 4.4)***** 

 very 
common 

Blood urea increased rare 
 Blood alkaline phosphatase 

increased 
rare 

Blood creatine 
phosphokinase level 
increase 

rare 

Glycosylated haemoglobin 
increased 

not 
known 

Blood glucose increased not 
known 

 
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). 
 



35 

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 thromboses 
(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 via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
Cholib 
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. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Lipid modifying substances, HMG-CoA reductase inhibitors in 
combination with other lipid modifying substances, ATC code: C10BA04 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc
http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc
http://www.whocc.no/atc_ddd_index/?code=C10BA
http://www.whocc.no/atc_ddd_index/?code=C10BA
http://www.whocc.no/atc_ddd_index/?code=C10BA
http://www.whocc.no/atc_ddd_index/?code=C10BA


36 

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 
beta-hydroxyacid 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: 
Cholib contains fenofibrate and simvastatin, which have different modes of action as described above. 
 
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. 
 
Cholib 
The respective effects of simvastatin and fenofibrate are complementary. 
 
Clinical efficacy and safety 
 
Cholib 
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. 
 
 
 
 
 
 
 



37 

 
Statin type and dose used: 
 
  Week 0 to Week 12 Week 12 to Week 24 
Stud
y 

Statin 6 weeks 
run-in 

Statin 
monotherapy 

Fenofibrate/Simvas
tatin in 
combination 

Statin 
monotherapy 

Fenofibrate/Simvas
tatin in 
combination 

0501 simvastatin 
20 mg 

simvastatin 40 
mg 

simvastatin 20 mg simvastatin 40 
mg 

simvastatin 40 mg 

0502 simvastatin 40 
mg 

simvastatin 40 
mg 

simvastatin 40 mg simvastatin 40 
mg 

simvastatin 40 mg 

0503 atorvastatin 10
 mg 

atorvastatin 10
 mg 

simvastatin 20 mg atorvastatin 20
 mg 

simvastatin 40 mg 

0504 pravastatin 40 
mg 

pravastatin 40 
mg 

simvastatin 20 mg pravastatin 40 
mg 

simvastatin 40 mg 

 
Cholib 145/40 
Study 0502 was evaluated a constant dose of fenofibrate-simvastatin combination and statin 
comparator throughout the 24 week double-blind period. The primary efficacy criterion was 
superiority of the combination fenofibrate 145 and simvastatin 40 mg versus simvastatin 40 mg on 
TG and LDL-C decrease and HDL-C increase at 12 weeks. 
 
At 12 weeks and 24 weeks the combination of fenofibrate 145 mg and simvastatin 40 mg (F145/S40) 
showed superiority over simvastatin 40 mg (S40) for TG reduction and HDL-C increase. 
 
The combination F145/S40 showed superiority over S40 for LDL-C reduction only at 24 weeks from 
a non-significant additional 1.2% reduction of LDL-C at 12 weeks to a statistically significant 7.2% 
reduction at 24 weeks. 
 

TG, LDL-C and HDL-C Percent Change from Baseline to 12 and 24 Weeks 
Full Analysis Subject Sample 

Lipid parameter 
(mmol/L) 

Feno 145+Simva 40 
(N=221) 

Simva 40 
(N=219) 

Treatment 
Comparison* 

P-value 

After 12 weeks % Change Mean (SD)   
TG  -27.18 (36.18) -0.74 (39.54) -28.19 

(-32.91, -23.13) 
<0.001 

LDL-C  -6.34 (23.53) -5.21 (22.01) -1.24 
(-5.22, 2.7) 

0.539 

HDL-C  5.77 (15.97) -0.75 (12.98) 6.46 
(3.83, 9.09) 

<0.001 

After 24 weeks % Change Mean (SD)   
TG -22.66 (43.87) 1.81 (36.64) -27.56 

(-32.90, -21.80) 
<0.001 

LDL-C  -3.98 (24.16) 3.07 (30.01) -7.21 
(-12.20, -2.21) 

0.005 

HDL-C  5.08 (16.10) 0.62 (13.21) 4.65 
(1.88, 7.42) 

0.001 

*Treatment Comparison consists of the difference between the LS-means for Feno 145 + Simva 40 an
d Simva 40, as well as the corresponding 95% CI. 
 



38 

The results on the biological parameters of interest at 24 weeks are presented in the table below. 
F145/S40 demonstrated statistically significant superiority on all parameters except on 
ApoA1 increase. 
 

ANCOVA (analysis of covariance) of Percent Change in TC, non-HDL-C, ApoAI, ApoB, 
ApoB/ApoAI and fibrinogen from Baseline to 24 Weeks – Full Analysis Subject Sample 

Parameter Treatment 
Group 

N Means (SD) Treatment 
Comparison* 

P-value 

TC (mmol/L) Feno 145 +  
Simva 40 
Simva 40 

213 
203 

-4.95 (18.59) 
1.69 (20.45) 

 
-6.76 (-10.31, -3.20) 

 
<0.001 

Non-HDL-C 
(mmol/L) 

Feno 145 +  
Simva 40 
Simva 40 

213 
203 

-7.62 (23.94) 
2.52 (26.42) 

 
-10.33 (-14.94, -
5.72) 

 
<0.001 

Apo AI (g/L) Feno 145 +  
Simva 40 
Simva 40 

204 
194 

5.79 (15.96) 
4.02 (13.37) 

 
2.34 (-0.32, 4.99) 

 
0.084 

Apo B (g/L) Feno 145 +  
Simva 40 
Simva 40 

204 
194 

-2.95 (21.88) 
6.04 (26.29) 

 
-9.26 (-13.70, -4.82) 

 
<0.001 

Apo B/Apo AI Feno 145 +  
Simva 40 
Simva 40 

204 
194 

-4.93 (41.66) 
3.08 (26.85) 

 
-8.29 (-15.18, -1.39) 

 
0.019 

Fibrinogen* (g/L) Feno 145 +  
Simva 40 
Simva 40 

202 
192 

-29 (0.04) 
0.01 (0.05) 

 
-0.30 (-0.41, -0.19) 

 
<0.001 

*Treatment Comparison consists of the difference between the LS-means for Feno 145 + Simva 40 an
d Simva 40, as well as the corresponding 95% CI. LS (less square mean) SD (standard deviation) 
 
Cholib 145/20 
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. 
 

Mean Percent Change from Baseline to 12 Weeks 
Full Analysis Subject Sample 

Parameter Feno 145+Simva 20 
(N=493) 
Mean (SD) 

Simva 40 
(N=505) 
Mean (SD) 

Treatment 
Comparison* 

P-value 

TG (mmol/L) -28.20 (37.31) -4.60 (40.92) -26.47 (-30.0, -
22.78) 

<0.001 

LDL-C (mmol/L) -5.64 (23.03) -10.51 
(22.98) 

4.75 (2.0, 7.51) NA 

HDL-C (mmol/L) 7.32 (15.84) 1.64 (15.76) 5.76 (3.88, 7.65) <0.001 
TC (mmol/L) -6.00 (15.98) -7.56 (15.77) 1.49 (-0.41, 3.38) 0.123 
Non-HDL-C (mmol/L) -9.79 (21.32) -9.79 (20.14) -0.11 (-2.61,2.39) 0.931 
Apo AI (g/L) 3.97 (13.15) 0.94 (13.03) 2.98 (1.42,4.55) <0.001 
Apo B (g/L) -6.52 (21.12) -7.97 (17.98) 1.22 (-1.19,3.63) 0.320 
Apo B/Apo AI -8.49 (24.42) -7.94 (18.96) -0.73 (-3.44,1.97) 0.595 
Fibrinogen (g/L) -0.31 (0.70) -0.02 (0.70) -0.32 (-0.40,-0.24) < 0.001 
*Treatment Comparison: difference between the LS Means for Feno 145 + Simva 20 and Simva 40, 
as well as the associated 95% confidence interval 
 
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 



39 

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. 
 
Paediatric population 
The European Medicines Agency has waived the obligation to submit the results of studies with 
Cholib in all subsets of the paediatric population in combined dyslipidaemia (see section 4.2 for 
information on paediatric use). 
 
5.2 Pharmacokinetic properties 
 
The geometric mean ratios and 90% CIs for the comparison of AUC, AUC(0-t) and Cmax for fenofibric 
acid, simvastatin and simvastatin acid of the fixed dose combination Cholib 145 mg/40 mg tablet and 
the co-administration of the separate 145 mg fenofibrate and 40 mg simvastatin tablets as used in the 
clinical program, were all 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 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. 
 



40 

Simvastatin is an inactive lactone which is readily hydrolyzed in vivo to the corresponding 
beta-hydroxyacid, 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 CYP 3A4 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 beta-hydroxyacid 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 
co-administration 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. 
 



41 

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 section 4.4). 
 
5.3 Preclinical safety data 
 
No preclinical studies have been performed with the fixed dose combination Cholib. 
 
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. 
 
 



42 

6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Tablet core: 
 
Butylhydroxyanisole (E320) 
Lactose monohydrate 
Sodium laurilsulfate 
Starch, pregelatinised (maize) 
Docusate sodium 
Sucrose 
Citric acid monohydrate (E330) 
Hypromellose (E464) 
Crospovidone (E1202) 
Magnesium stearate (E572) 
Silicified microcrystalline cellulose (comprised of cellulose, microcrystalline and silica, 
colloidal anhydrous) 
Ascorbic acid (E300) 
 
Film-coating: 
 
Poly (vinyl alcohol), partially hydrolysed (E1203) 
Titanium dioxide (E171) 
Talc (E553b) 
Lecithin (derived from soya bean (E322)) 
Xanthan gum (E415) 
Iron oxide red (E172) 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
2 years. 
 
6.4 Special precautions for storage 
 
Store below 30°C. 
 
6.5 Nature and contents of container 
 
Alu/Alu blisters 
Pack sizes: 10, 30 and 90 film-coated tablets. 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal 
 
Any unused medicinal product or waste material should be disposed of in accordance with 
local requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
 
Mylan IRE Healthcare Ltd 



43 

Unit 35/36 Grange Parade,  
Baldoyle Industrial Estate,  
Dublin 13 
Ireland 
 
 
8. MARKETING AUTHORISATION NUMBERS 
 
EU/1/13/866/003-004 
EU/1/13/866/006 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 26 August 2013 
Date of latest renewal: 16 May 2018 
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 
 

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


44 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 
 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
AUTHORISATION 

 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
 



45 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer(s) responsible for batch release 
 
Mylan Laboratories SAS 
Route de Belleville - Lieu-dit Maillard 
01400 Châtillon-sur-Chalaronne 
France 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal product subject to medical prescription. 
 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
• Periodic safety update reports (PSURs) 
 
The marketing authorisation holder shall submit the first periodic safety update report for this 
product within six months following authorisation. Subsequently, the marketing authorisation 
holder shall submit periodic safety update reports for this product in accordance with the 
requirements set out in the list of Union reference dates (EURD list) provided for under 
Article 107c(7) of Directive 2001/83/EC and published on the European medicines web-portal. 
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
• Risk management plan (RMP) 
 
The marketing authorisation holder (MAH) shall perform the required pharmacovigilance 
activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the 
marketing authorisation and any agreed subsequent updates of the RMP. 
 
An updated RMP should be submitted: 

• At the request of the European Medicines Agency; 
• Whenever the risk management system is modified, especially as the result of new 

information being received that may lead to a significant change to the benefit/risk 
profile or as the result of an important (pharmacovigilance or risk minimisation) 
milestone being reached. 

 
If the submission of a PSUR and the update of a RMP coincide, they can be submitted at the 
same time. 
 



46 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
 



47 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 



48 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Cholib 145 mg/20 mg film-coated tablets 
fenofibrate/simvastatin 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains 145 mg of fenofibrate and 20 mg of simvastatin 
 
 
3. LIST OF EXCIPIENTS 
 
Contains: lactose, sucrose, lecithin (derived from soya bean (E322)), sunset yellow FCF (E110). 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
10 film-coated tablets 
30 film-coated tablets 
90 film coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use 
Oral use 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store below 30°C. 
 
 



49 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
  
Mylan IRE Healthcare Ltd 
Unit 35/36 Grange Parade,  
Baldoyle Industrial Estate,  
Dublin 13 
Ireland 
 
 
 
12. MARKETING AUTHORISATION NUMBERS 
 
EU/1/13/866/001 10 film-coated tablets 
EU/1/13/866/002 30 film-coated tablets 
EU/1/13/866/005 90 film coated tablets 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Cholib 145 mg/20 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
<2D barcode carrying the unique identifier included.> 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
< PC: {number} [product code] 
SN: {number} [serial number] 
NN: {number} [national reimbursement number or other national number identifying the medicinal 
product]> 



50 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTERS 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Cholib 145 mg/20 mg tablets 
fenofibrate/simvastatin 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Mylan 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 



51 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Cholib 145 mg/40 mg film-coated tablets 
fenofibrate/simvastatin 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains 145 mg of fenofibrate and 40 mg of simvastatin 
 
 
3. LIST OF EXCIPIENTS 
 
Contains: lactose, sucrose, lecithin (derived from soya bean (E322)) 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
10 film-coated tablets 
30 film-coated tablets 
90 film coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral use 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the reach and sight of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store below 30°C. 
 
 



52 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Mylan IRE Healthcare Ltd 
Unit 35/36 Grange Parade,  
Baldoyle Industrial Estate,  
Dublin 13 
Ireland 
 
 
 
12. MARKETING AUTHORISATION NUMBERS 
 
EU/1/13/866/003 10 film-coated tablets 
EU/1/13/866/004 30 film-coated tablets 
EU/1/13/866/006 90 film coated tablets 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Cholib 145 mg/40 mg  
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
<2D barcode carrying the unique identifier included.> 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
< PC: {number} [product code] 
SN: {number} [serial number] 
NN: {number} [national reimbursement number or other national number identifying the medicinal 
product]> 
 



53 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTERS 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Cholib 145 mg/40 mg tablets 
fenofibrate/simvastatin 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Mylan 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 



54 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



55 

Package leaflet: Information for the user 
 

Cholib 145 mg/20 mg film-coated tablets 
 

fenofibrate/simvastatin 
 

Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you. 
 
• Keep this leaflet. You may need to read it again. 
• If you have any further questions, ask your doctor or pharmacist. 
• This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even  

if their signs of illness are the same as yours. 
• If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. 
 
What is in this leaflet 
 
1. What Cholib is and what it is used for 
2. What you need to know before you take Cholib 
3. How to take Cholib 
4. Possible side effects 
5. How to store Cholib 
6. Contents of the pack and other information 
 
 
1. What Cholib is and what it is used for 
 
Cholib contains two different active substances: fenofibrate (belongs to the group called ‘fibrates’) 
and simvastatin (belongs to the group called ‘statins’). They are both used to lower levels of total 
cholesterol, “bad” cholesterol (LDL cholesterol), and fatty substances called triglycerides in the blood. 
In addition, they both raise levels of “good” cholesterol (HDL cholesterol). 
 
What should I know about cholesterol and triglycerides? 
 
Cholesterol is one of several fats found in your blood. Your total cholesterol is made up mainly of 
LDL and HDL cholesterol. 
 
LDL cholesterol is often called ‘bad’ cholesterol because it can build up in the walls of your arteries 
and form plaque. Over time, this plaque build-up can lead to a clogging of your arteries. 
 
 
HDL cholesterol is often called ‘good’ cholesterol because it helps keep the ‘bad’ cholesterol from 
building up in the arteries and because it protects against heart disease. 
 
Triglycerides are another fat in your blood. They may raise your risk of having heart problems. 
 
In most people, there are no signs of cholesterol or triglycerides problems at first. Your doctor can 
measure your lipids with a simple blood test. Visit your doctor regularly to keep track of your lipids 
level. 
 
Cholib is used in adults at high risk of problems like heart attack and stroke who have high blood 
levels of 2 types of fats (triglycerides and LDL cholesterol). It is given to lower triglycerides and 
increase the good cholesterol (HDL cholesterol) in patients whose bad cholesterol (LDL cholesterol) 
is already controlled with simvastatin alone in a dose of 20 mg. 
 



56 

You must continue a low fat diet or other measures (e.g. exercise, weight reduction) during treatment 
with Cholib. 
 
 
2. What you need to know before you take use Cholib 
 
Do not take Cholib: 
 
• If you are allergic to fenofibrate or simvastatin or any of the other ingredients of Cholib 

(listed in section 6) 
• If you are allergic to peanut, arachis oil, soya lecithin or related substances 
• If while taking other medicines, you have had an allergic reaction or skin damage from sunlight 

or UV light (these medicines include other fibrates and an anti-inflammatory medicine called 
“ketoprofen”) 

• If you have liver or gallbladder problems 
• If you have pancreatitis (inflamed pancreas which causes abdominal pain), which is not caused 

by high levels of fats in the blood 
• If you have moderate or severe kidney problems 
• If you have a history of muscle problems during treatment to lower the level of fats in the blood 

with either of the active substances in this medicine, or with other statins (such as atorvastatin, 
pravastatin or rosuvastatin) or fibrates (such as bezafibrate or gemfibrozil) 

• If you are already taking the following medicines: 
o danazol (a man-made hormone used to treat endometriosis) 
o ciclosporin (a medicine often used in organ transplant patients) 
o itraconazole, ketoconazole, fluconazole or posaconazole (medicines for fungal infections) 
o HIV protease inhibitors such as indinavir, nelfinavir, ritonavir and saquinavir (medicines 

used for HIV infection and AIDS) 
o glecaprevir or pibrentasvir (used to treat hepatitis C virus infection) 
o erythromycin, clarithromycin, or telithromycin (medicines for bacterial infections) 
o nefazodone (a medicine for depression) 

• If you are already being treated and will continue your treatment with: 
o a fibrate (e.g. gemfibrozil) 
o a statin (medicines to lower the levels of fats in the blood, e.g. simvastatin, atorvastatin) 

• If you are under 18 years of age 
• If you are pregnant or breast-feeding 

 
Do not take Cholib if any of the above applies to you. Check with your doctor or pharmacist if you are 
not sure. 
 
Warnings and precautions: 
 
Talk to your doctor or pharmacist before taking Cholib if: 
 
• you have an underactive thyroid gland (hypothyroidism) 
• you are due to have an operation. You may need to stop taking Cholib for a short time. 
• you drink large amounts of alcohol (more than 21 units (210 mL) a week of pure alcohol) 
• you have chest pain and are feeling breathless. These may be signs of a blood clot in the lung 

(pulmonary embolism) 
• you have severe lung disease 
• you have kidney disease 
• you or a close family member have a muscle problem which runs in the family 
• you are taking or, in the last 7 days, have taken or been given a medicine called fusidic acid 

(a medicine for bacterial infection)  
• you are taking hepatitis C antiviral agents such as elbasvir or grazoprevir (used to treat hepatitis 

C virus infection) 
 



57 

 
If any of the above applies to you, talk to your doctor or pharmacist before taking Cholib. Check with 
your doctor or pharmacist if you are not sure. 
 
Also tell your doctor or pharmacist if you have a muscle weakness that is constant. Additional tests 
and medicines may be needed to diagnose and treat this. 
 
Your doctor should do a blood test before you start taking Cholib. This is to check how well your liver 
is working. 
 
Your doctor may also want you to have blood tests to check how well your liver is working after you 
start taking Cholib. 
 
While you are on this medicine your doctor will monitor you closely if you have diabetes or are at risk 
of developing diabetes. You are likely to be at risk of developing diabetes if you have high levels of 
sugars and fats in your blood, are overweight and have high blood pressure. 
 
Your doctor may do a blood test to check your muscles before and after starting treatment. 
 
Children and adolescents 
 
Cholib must not be given to children and adolescents (age below 18 years). 
 
Other medicines and Cholib: 
 
It is particularly important to tell your doctor or pharmacist if you are taking, have recently taken or 
might take any other medicines. This also concerns medicines obtained without a prescription 
including herbal medicines. 
 
Tell your doctor or pharmacist if you are taking any of the following medicines: 
 
o danazol (a man-made hormone used to treat endometriosis) 
o ciclosporin (a medicine often used in organ transplant patients) 
o itraconazole, ketoconazole, fluconazole or posaconazole (medicines for fungal infections) 
o HIV protease inhibitors such as indinavir, nelfinavir, ritonavir and saquinavir (medicines used 

for HIV infection and AIDS) 
o glecaprevir or pibrentasvir (used to treat hepatitis C virus infection) 
o erythromycin, clarithromycin, or telithromycin (medicines for bacterial infections) 
o nefazodone (a medicine for depression) 
o a fibrate (e.g. fenofibrate, gemfibrozil) 
o a statin (e.g. simvastatin, atorvastatin) 
 
Do not take Cholib if any of the above applies to you. Check with your doctor or pharmacist if you are 
not sure. 
 
In particular tell your doctor or pharmacist if you are taking any of the following medicines 
(taking Cholib with any of these medicines can increase the risk of muscle problems): 
 
• high doses of at least 1 gram per day of niacin (nicotinic acid) or a treatment containing niacin 

(medicine for lowering fat levels in the blood) 
• colchicine (a medicine used to treat gout) 
 
Do not take fusidic acid (a medicine for bacterial infections) while using this medicine. 
 
As well as the medicines listed previously, tell your doctor or pharmacist if you are taking, have 
recently taken or might take any of the following medicines: 
 



58 

• anticoagulants such as warfarin, fluindione, phenprocoumone or acenocoumarol 
(medicines to prevent blood clots) 

• pioglitazone (a particular class of medicines to treat diabetes) 
• rifampicin (a medicine used to treat tuberculosis) 
• elbasvir or grazoprevir (used to treat hepatitis C virus infection) 
 
If any of the above applies to you, talk to your doctor or pharmacist before taking Cholib. Check with 
your doctor or pharmacist if you are not sure. 
 
Cholib with food and drink 
 
Grapefruit juice contains one or more components that alter how the body uses Cholib. Do not 
consume grapefruit juice with Cholib as it may increase your risk of muscle problems. 
 
Pregnancy and breast-feeding 
 
• Do not take Cholib if you are pregnant, trying to get pregnant or think you may be pregnant. 

If you get pregnant while taking Cholib, stop taking it immediately and contact your doctor. 
• Do not take Cholib if you are breast-feeding or plan to breast-feed your baby, because it is not 

known if the medicine passes into breast milk. 
 
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 
your doctor or pharmacist for advice before taking this medicine. 
 
Driving and using machines 
 
Cholib is not expected to affect you being able to drive or use tools or machines. However, it should 
be taken into account that some people get dizzy after taking Cholib. 
 
Important information about some of the ingredients of Cholib 
 
Cholib contains types of sugars called lactose and sucrose. If you have been told by your doctor that 
you have an intolerance to some sugars, talk to your doctor before taking this medicine. 
 
Cholib contains soya lecithin. If you are allergic to peanut, soya or arachis oil do not use Cholib. 
 
Cholib contains sunset yellow FCF (E110) that may cause allergic reactions. 
 
 
3. How to take Cholib 
 
Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor 
or pharmacist if you are not sure. 
 
Your doctor will determine the appropriate strength for you, depending on your condition, your 
current treatment and your personal risk status. 
The usual dose is one tablet per day. 
You can take Cholib with or without food. 
Swallow the tablet with a glass of water. 
Do not crush or chew the tablet. 
 
You should continue a low-fat diet or other measures (e.g. exercise, weight reduction) whilst 
taking Cholib. 
 



59 

If you take more Cholib than you should 
 
If you have taken more Cholib than you should or if someone else has taken your medicine, tell your 
doctor or pharmacist or contact your nearest hospital 
 
If you forget to take Cholib 
 
Do not take a double dose to make up for a forgotten tablet. Take the next tablet at your regular time 
on the next day. If you are worried about this, talk to your doctor or pharmacist. 
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
 
4. Possible side effects 
 
Like all medicines, Cholib can cause side effects, although not everybody gets them. 
 
• Unexplained muscle pain, tenderness, or weakness may be sign of muscle break down. 

Therefore please contact your doctor immediately if you experience these symptoms. This is 
because on rare occasions, there have been cases of serious muscle problems including muscle 
breakdown resulting in kidney damage; and very rare deaths have occurred. Compared to a 
fibrate or a statin alone, the risk of muscle breakdown is increased when you take 
these 2 medicines together, as in Cholib. It is higher in female patients or in patients 65 years or 
older. 

 
Some patients have experienced the following serious side effects whilst taking fenofibrate or 
simvastatin (both active substances in Cholib): 
 
• hypersensitivity (allergic) reactions including swelling of the face, tongue and throat which may 

cause difficulty in breathing (angioedema) (rare) 
• a serious allergic reaction which causes difficulty in breathing or dizziness (anaphylaxis) (very 

rare) 
• Hypersensitivity reaction to Cholib with symptoms like: pain or inflammation of the joints, 

inflammation of blood vessels, unusual bruising, skin eruptions and swelling, hives, skin 
sensitivity to the sun, fever, flushing, shortness of breath and feeling unwell, lupus-like disease 
picture (including rash, joint disorders, and effects on white blood cells) 

• cramps or painful, tender or weak muscles, muscle rupture - these may be signs of muscle 
inflammation or breakdown, which can cause kidney damage or even death 

• stomach pain - this may be a sign that your pancreas is inflamed (pancreatitis) 
• chest pain and feeling breathless - these may be signs of a blood clot in the lung 

(pulmonary embolism) 
• pain, redness or swelling in the legs - these may be signs of a blood clot in the leg 

(deep vein thrombosis) 
• yellowing of the skin and whites of the eyes (jaundice), or an increase in liver enzymes - these 

may be signs of an inflamed liver (hepatitis and hepatic failure) 
• increased sensitivity of your skin to sunlight, sun lamps and sunbeds 
• rash that may occur on the skin or sores in the mouth (lichenoid drug eruptions) 
 
If any of the previously listed serious side effects happen, stop taking Cholib and tell your doctor 
immediately or go to the emergency room at your nearest hospital - you may need urgent medical 
treatment. 
 
Some patients have experienced the following side effects whilst taking Cholib, fenofibrate 
or simvastatin: 
 



60 

Very common side effects (may affect more than 1 in 10 people): 
 
• Increase in the blood level of “creatinine” (substance excreted by the kidneys) 
• Increase in blood levels of “homocysteine” (too much of this amino acid in the blood is related 

to a higher risk of coronary heart disease, stroke and peripheral vascular disease, although a 
causal link has not been established) 
 

Common side effects (may affect up to 1 in 10 people): 
 
• increase in blood platelets count 
• elevations in blood tests of liver function (transaminases) 
• digestive disturbances (stomach pain, nausea, vomiting, diarrhoea and flatulence) 
• infection of the upper respiratory tract 
 
Uncommon side effects (may affect up to 1 in 100 people): 
 
• muscle problems 
• gallstones 
• rashes, itching, red patches on the skin 
• headache 
• sexual difficulties 
 
Rare side effects (may affect up to 1 in 1,000 people): 
 
• low red blood cell count (anaemia) 
• numbness or weakness of the arms and legs 
• confusion 
• feeling dizzy 
• feeling exhausted (astenia) 
• increase in “urea” - produced by the kidneys - shown in tests 
• increase in “gamma-glutamyltransferase” - produced by the liver - shown in tests 
• increase in “alkaline phosphatase” - produced by the bile system - shown in tests 
• increase in “creatine phosphokinase” - produced by the muscle - shown in tests 
• drop in haemoglobin (that carries oxygen in blood) and white blood cells- shown in tests 
• trouble sleeping 
• poor memory or memory loss 
• hair loss 
• constipation 
• dyspepsia 
• blurred vision; impaired vision 
 
Very rare side effect (may affect up to 1 in 10,000 people): 
• gynecomastia (breast enlargement in men) 
 
 
The following side effects have also been reported but the frequency cannot be estimated from the 
available information (frequency not known): 
 
• severe allergic skin rash with blisters 
• complications of gall stones such as colic because of stones in bile duct, infection of the bile 

ducts or gall bladder 
• diabetes mellitus 
• erectile dysfunction 
• feeling depressed 
• sleep disturbances including nightmares 



61 

• specific lung disease with difficulties breathing (called interstitial lung disease) 
• muscle weakness that is constant 
• increase in “glycosylated haemoglobin” and blood glucose levels - markers for blood glucose 

control in diabetes mellitus - shown in tests 
 
Reporting of side effects 
 
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 
listed in Appendix V. By reporting side effects you can help provide more information on the safety of 
this medicine. 
 
 
5. How to store Cholib 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use Cholib after the expiry date which is stated on the carton and the blister after EXP. 
The expiry date refers to the last day of that month. 
 
Store below 30°C. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Cholib contains 
 
The active substances are fenofibrate and simvastatin. Each tablet contains 145 mg of fenofibrate 
and 20 mg of simvastatin. 
 
This medicine contains less than 1 mmol sodium (23 mg) per one tablet, that is to say essentially 
‘sodium-free’. 
 
The other ingredients are: 
 
Tablet core: 
Butylhydroxyanisole (E320), lactose monohydrate, sodium laurilsulfate, starch, pregelatinised (maize), 
docusate sodium, sucrose, citric acid monohydrate (E330), hypromellose (E464), crospovidone 
(E1202), magnesium stearate (E572), silicified microcrystalline cellulose (comprised of cellulose, 
microcrystalline and silica, colloidal anhydrous), ascorbic acid (E300). 
 
Film-coat: 
Poly (vinyl alcohol), partially hydrolysed (E1203), 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). 
 
What Cholib looks like and contents of the pack 
 
 
Oval, biconvex, tan coloured, film-coated tablet, with bevelled edges and 145/20 on one side. The 
diameter dimensions are 19.3 x 9.3 mm approximately and the tablet weight is about 734 mg. 
 
The tablets are provided in carton boxes with blisters containing 10, 30 or 90 tablets. 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc
http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


62 

Not all pack sizes may be marketed. 
 
Marketing Authorisation Holder and Manufacturer 
 
Marketing Authorisation Holder: 
Mylan IRE Healthcare Ltd, Unit 35/36 Grange Parade, Baldoyle Industrial Estate, Dublin 13 – Ireland. 
 
Manufacturer: 
Mylan Laboratories SAS, Route de Belleville - Lieu-dit Maillard, 01400 Châtillon-sur-
Chalaronne - France. 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien 
Mylan EPD  
Tel/Tél: + 32 2 658 61 00 
 

Ireland 
Mylan IRE Healthcare Ltd 
Tel: +44 (0) 1707 853000 
 

Norge 
Mylan Healthcare Norge AS 
Tlf: + 47 66 75 33 00 
 

България 
Майлан ЕООД  
Teл.: + 359 2 4455 400 
 

Ísland 
 Icepharma hf. 
Sími: +354 540 8000 

Österreich 
Mylan Österreich GmbH 
Tel: + 43 1 891 24 -0 
 

Česká republika 
Mylan Healthcare CZ s.r.o. 
Tel: +420 222 004 400 
 

Italia 
Mylan Italia S.r.l. 
Tel: + 39 (0) 2 61246921 

Polska 
Mylan Healthcare Sp. z o.o. 
Tel: +48 22 546 64 00 

Danmark 
Mylan Denmark ApS 
Tlf. +45 28 11 69 32 

Κύπρος 
Βαρνάβας Χατζηπαναγής Λτδ 
(Varnavas Hadjipanayis Ltd) 
Τηλ: +357 22207700 
 

Portugal 
BGP Products, Unipessoal, Lda. 
Tel : +351 214 127 256  
 

Deutschland 
Mylan Healthcare GmbH 
(Troisdorf) 
Tel: +49 511 4754 3400 
 

Latvija 
Mylan Healthcare SIA 
Tel: + 371 67 605 580 
 

România 
BGP Products S.R.L. 
Tel: +40 372 579 000 
 

Eesti 
BGP Products Switzerland GmbH 
Eesti filiaal 
Tel: + 372 6363052 
 

Lietuva 
BGP Products UAB 
Tel: +370 52 051 288 
 

Slovenija 
Mylan Healthcare d.o.o. 
Tel: + 386 (0)123 63 180 

Ελλάδα 
BGP ΠΡΟΪΟΝΤΑ Μ.Ε.Π.Ε. 
Τηλ.: +30 210 9891 777 

Luxembourg/Luxemburg 
Mylan EPD sprl-bvba 
Tel/Tél: + 32 2 658 6100 
 

Slovenská republika 
BGP Products s.r.o. 
Tel: +421 2 40 20 38 00 

España 
Mylan pharmaceuticals S.L. 
+34 91 669 93 00 

Magyarország 
Mylan EPD Kft 
Tel: +36 1 465 2100 

Suomi/Finland 
Mylan Finland Oy 
Puh/Tel: +358 20 720 9555 
 

France 
Mylan Medical SAS  
Tél: + 33 (0)1 56 64 10 70 
 
 

Malta 
V.J. Salomone Pharma 
Limited  Tel: +356-22-98 31 43 
 

Sverige 
BGP Products AB 
Tel: +46 8 555 227 07 
 

Hrvatska 
Mylan Hrvatska d.o.o. 
Tel: + 385 (0)1 2350 599 

Nederland 
Mylan Healthcare B.V. 
Tel: +31 (0)20 426 33 00 

United Kingdom 
Mylan Products Ltd 
Tel: +44 (0) 170 785 3000 

tel:+49
tel:+49
tel:+370
tel:+370


63 

  
 
This leaflet was last revised in <{MM/YYYY}>: 
 
Other sources of information 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu. 
 

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


64 

Package leaflet: Information for the user 
 

Cholib 145 mg/40 mg film-coated tablets 
 

fenofibrate/simvastatin 
 

Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you. 
 
• Keep this leaflet. You may need to read it again. 
• If you have any further questions, ask your doctor or pharmacist. 
• This medicine has been prescribed for you. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 
• If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. 
 
What is in this leaflet 
 
1. What Cholib is and what it is used for 
2. What you need to know before you take Cholib 
3. How to take Cholib 
4. Possible side effects 
5. How to store Cholib 
6. Contents of the pack and other information 
 
 
1. What Cholib is and what it is used for 
 
Cholib contains two different active substances: fenofibrate (belongs to the group called ‘fibrates’) 
and simvastatin (belongs to the group called ‘statins’). They are both used to lower levels of total 
cholesterol, “bad” cholesterol (LDL cholesterol), and fatty substances called triglycerides in the blood. 
In addition, they both raise levels of “good” cholesterol (HDL cholesterol). 
 
What should I know about cholesterol and triglycerides? 
Cholesterol is one of several fats found in your blood. Your total cholesterol is made up mainly of 
LDL and HDL cholesterol. 
LDL cholesterol is often called ‘bad’ cholesterol because it can build up in the walls of your arteries 
and form plaque. Over time, this plaque build-up can lead to a clogging of your arteries. 
HDL cholesterol is often called ‘good’ cholesterol because it helps keep the ‘bad’ cholesterol from 
building up in the arteries and because it protects against heart disease. 
Triglycerides are another fat in your blood. They may raise your risk of having heart problems. 
In most people, there are no signs of cholesterol or triglycerides problems at first. Your doctor can 
measure your lipids with a simple blood test. Visit your doctor regularly to keep track of your lipids 
level. 
 
Cholib is used in adults at high risk of problems like heart attack and stroke who have high blood 
levels of 2 types of fats (triglycerides and LDL cholesterol). It is given to lower triglycerides and 
increase the good cholesterol (HDL cholesterol) in patients whose bad cholesterol (LDL cholesterol) is 
already controlled with simvastatin alone in a dose of 40 mg. 
 
You must continue a low fat diet or other measures (e.g. exercise, weight reduction) during treatment 
with Cholib. 
 
 



65 

2. What you need to know before you take use Cholib 
 
Do not take Cholib: 
 
• If you are allergic to fenofibrate or simvastatin or any of the other ingredients of Cholib 

(listed in section 6) 
• If you are allergic to peanut, arachis oil, soya lecithin or related substances 
• If while taking other medicines, you have had an allergic reaction or skin damage from sunlight 

or UV light (these medicines include other fibrates and an anti-inflammatory medicine called 
“ketoprofen”) 

• If you have liver or gallbladder problems 
• If you have pancreatitis (inflamed pancreas which causes abdominal pain), which is not caused 

by high levels of fats in the blood 
• If you have moderate or severe kidney problems 
• If you have a history of muscle problems during treatment to lower the level of fats in the blood 

either of the active substances in this medicine, or with other statins (such as atorvastatin, 
pravastatin or rosuvastatin) or fibrates (such as bezafibrate or gemfibrozil) 

• If you are already taking the following medicines: 
o danazol (a man-made hormone used to treat endometriosis) 
o ciclosporin (a medicine often used in organ transplant patients) 
o itraconazole, ketoconazole, fluconazole or posaconazole (medicines for fungal infections) 
o HIV protease inhibitors such as indinavir, nelfinavir, ritonavir and saquinavir (medicines 

used for HIV infection and AIDS) 
o erythromycin, clarithromycin, or telithromycin (medicines for bacterial infections) 
o nefazodone (a medicine for depression) 
o amiodarone (a medicine for an irregular heartbeat) or verapamil (a medicine for high 

blood pressure, chest pain associated with heart disease, or other heart conditions) 
o hepatitis C antiviral agents such as elbasvir, grazoprevir, glecaprevir or pibrentasvir (used 

to treat hepatitis C virus infection) 
• If you are already being treated and will continue your treatment with: 

o a fibrate (e.g. gemfibrozil) 
• a statin (medicines to lower the levels of fats in the blood, e.g. simvastatin, atorvastatin)If you 

are under 18 years of age 
• If you are pregnant or breast-feeding 

 
Do not take Cholib if any of the above applies to you. Check with your doctor or pharmacist if you are 
not sure. 
 
Warnings and precautions: 
 
Talk to your doctor or pharmacist before taking Cholib if: 
• you have an underactive thyroid gland (hypothyroidism) 
• you are due to have an operation. You may need to stop taking Cholib for a short time 
• you drink large amounts of alcohol (more than 21 units (210 mL) a week of pure alcohol) 
• you have chest pain and are feeling breathless. These may be signs of a blood clot in the lung 

(pulmonary embolism) 
• you have severe lung disease 
• you have kidney disease 
• you or a close family member have a muscle problem which runs in the family 
• you are taking or, in the last 7 days, have taken or been given a medicine called fusidic acid (a 

medicine for bacterial infection) 
• you are taking hepatitis C antiviral agents such as elbasvir or grazoprevir (used to treat hepatitis 

C virus infection) 
 
If any of the above applies to you, talk to your doctor or pharmacist before taking Cholib. Check with 
your doctor or pharmacist if you are not sure. 



66 

 
Also tell your doctor or pharmacist if you have a muscle weakness that is constant. Additional tests 
and medicines may be needed to diagnose and treat this. 
 
Your doctor should do a blood test before you start taking Cholib. This is to check how well your liver 
is working. 
 
Your doctor may also want you to have blood tests to check how well your liver is working after you 
start taking Cholib. 
 
While you are on this medicine your doctor will monitor you closely if you have diabetes or are at risk 
of developing diabetes. You are likely to be at risk of developing diabetes if you have high levels of 
sugars and fats in your blood, are overweight and have high blood pressure. 
 
Your doctor may do a blood test to check your muscles before and after starting treatment. 
 
Children and adolescents 
 
Cholib must not be given to children and adolescents (age below 18 years). 
 
Other medicines and Cholib: 
 
It is particularly important to tell your doctor or pharmacist if you are taking, have recently taken 
or might take any other medicines. This also concerns medicines obtained without a prescription 
including herbal medicines. 
 
Tell your doctor or pharmacist if you are taking any of the following medicines: 
• danazol (a man-made hormone used to treat endometriosis) 
• ciclosporin (a medicine often used in organ transplant patients) 
• itraconazole, ketoconazole, fluconazole or posaconazole (medicines for fungal infections) 
• HIV protease inhibitors such as indinavir, nelfinavir, ritonavir and saquinavir 

(medicines used for HIV infection and AIDS) 
• elbasvir, grazoprevir, glecaprevir or pibrentasvir (used to treat hepatitis C virus 

infection)erythromycin, clarithromycin, or telithromycin (medicines for bacterial infections) 
• nefazodone (a medicine for depression) 
• amiodarone (a medicine for an irregular heartbeat) or verapamil (a medicine for high 

blood pressure, chest pain associated with heart disease, or other heart conditions) 
• a fibrate (e.g. fenofibrate, gemfibrozil) 
• a statin (e.g. simvastatin, atorvastatin) 
 
Do not take Cholib if any of above applies to you. Check with your doctor or pharmacist if you are not 
sure. 
 
In particular tell your doctor or pharmacist if you are taking any of the following medicines (taking 
Cholib with any of these medicines can increase the risk of muscle problems): 
• high doses of at least 1 gram per day of niacin (nicotinic acid) or a treatment containing niacin 

(medicine for lowering fat levels in the blood) 
• colchicine (a medicine used to treat gout). 

 
Do not take fusidic acid (a medicine for bacterial infections) while using this medicine. 
 
As well as the medicines listed previously, tell your doctor or pharmacist if you are taking, have 
recently taken or might take any of the following medicines: 
• anticoagulants such as warfarin, fluindione, phenprocoumone or acenocoumarol 

(medicines to prevent blood clots) 
• pioglitazone (a particular class of medicines to treat diabetes) 



67 

• rifampicin (a medicine used to treat tuberculosis). 
 

If any of the above applies to you, talk to your doctor or pharmacist before taking Cholib. Check with 
your doctor or pharmacist if you are not sure. 
 
Cholib with food and drink 
 
Grapefruit juice contains one or more components that alter how the body uses Cholib. Do not 
consume grapefruit juice with Cholib as it may increase your risk of muscle problems. 
 
Pregnancy and breast-feeding 
 
• Do not take Cholib if you are pregnant, trying to get pregnant or think you may be pregnant. 

If you get pregnant while taking Cholib, stop taking it immediately and contact your doctor. 
• Do not take Cholib if you are breast-feeding or plan to breast-feed your baby, because it is not 

known if the medicine passes into breast milk. 
 
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 
your doctor or pharmacist for advice before taking this medicine. 
 
Driving and using machines 
 
Cholib is not expected to affect you being able to drive or use tools or machines. However, it should 
be taken into account that some people get dizzy after taking Cholib. 
 
Important information about some of the ingredients of Cholib 
 
Cholib contains types of sugars called lactose and sucrose. If you have been told by your doctor that 
you have an intolerance to some sugars, talk to your doctor before taking this medicine. 
 
Cholib contains soya lecithin. If you are allergic to peanut, soya or arachis oil do not use Cholib. 
 
 
3. How to take Cholib 
 
Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor 
or pharmacist if you are not sure. 
 
Your doctor will determine the appropriate strength for you, depending on your condition, your 
current treatment and your personal risk status. 
The usual dose is one tablet per day. 
You can take Cholib with or without food. 
Swallow the tablet with a glass of water. 
Do not crush or chew the tablet. 
 
You should continue a low-fat diet or other measures (e.g. exercise, weight reduction) whilst taking 
Cholib. 
 
If you take more Cholib than you should 
 
If you have taken more Cholib than you should or if someone else has taken your medicine, tell your 
doctor or pharmacist or contact your nearest hospital 
 
If you forget to take Cholib 
 
Do not take a double dose to make up for a forgotten tablet. Take the next tablet at your regular time 
on the next day. If you are worried about this, talk to your doctor or pharmacist. 



68 

 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
 
4. Possible side effects 
 
Like all medicines, Cholib can cause side effects, although not everybody gets them. 
 
• Unexplained muscle pain, tenderness, or weakness may be sign of muscle break down. 

Therefore please contact your doctor immediately if you experience these symptoms. This is 
because on rare occasions, there have been cases of serious muscle problems including muscle 
breakdown resulting in kidney damage; and very rare deaths have occurred. Compared to a 
fibrate or a statin alone, the risk of muscle breakdown is increased when you take 
these 2 medicines together, as in Cholib. It is higher in female patients or in patients 65 years or 
older. 

 
Some patients have experienced the following serious side effects whilst taking fenofibrate or 
simvastatin (both active substances in Cholib): 
 
• hypersensitivity (allergic) reactions including swelling of the face, tongue and throat which may 

cause difficulty in breathing (angioedema) (rare) 
• a serious allergic reaction which causes difficulty in breathing or dizziness (anaphylaxis) (very 

rare) 
• Hypersensitivity reaction to Cholib with symptoms like: pain or inflammation of the joints, 

inflammation of blood vessels, unusual bruising, skin eruptions and swelling, hives, skin 
sensitivity to the sun, fever, flushing, shortness of breath and feeling unwell, lupus-like disease 
picture (including rash, joint disorders, and effects on white blood cells) 

• cramps or painful, tender or weak muscles, muscle rupture - these may be signs of muscle 
inflammation or breakdown, which can cause kidney damage or even death 

• stomach pain - this may be a sign that your pancreas is inflamed (pancreatitis) 
• chest pain and feeling breathless - these may be signs of a blood clot in the lung (pulmonary 

embolism) 
• pain, redness or swelling in the legs - these may be signs of a blood clot in the leg (deep vein 

thrombosis) 
• yellowing of the skin and whites of the eyes (jaundice), or an increase in liver enzymes - these 

may be signs of an inflamed liver (hepatitis and hepatic failure). 
• increased sensitivity of your skin to sunlight, sun lamps and sunbeds 
• rash that may occur on the skin or sores in the mouth (lichenoid drug eruptions) 
 
If any of the previously listed serious side effects happen, stop taking Cholib and tell your doctor 
immediately or go to the emergency room at your nearest hospital - you may need urgent medical 
treatment. 
 
Some patients have experienced the following side effects whilst taking Cholib, fenofibrate or 
simvastatin: 
 
Very common side effects (may affect more than 1 in 10 people): 
 
• Increase in the blood level of “creatinine” (substance excreted by the kidneys) 
• Increase in blood levels of “homocysteine” (too much of this amino acid in the blood is related 

to a higher risk of coronary heart disease, stroke and peripheral vascular disease, although a 
causal link has not been established) 

 
Common side effects (may affect up to 1 in 10 people): 
 
• increase in blood platelets count 



69 

• elevations in blood tests of liver function (transaminases) 
• digestive disturbances (stomach pain, nausea, vomiting, diarrhoea and flatulence) 
• infection of the upper respiratory tract 
 
Uncommon side effects (may affect up to 1 in 100 people): 
 
• muscle problems 
• gallstones 
• rashes, itching, red patches on the skin. 
• headache 
• sexual difficulties 
 
Rare side effects (may affect up to 1 in 1,000 people): 

• low red blood cell count (anaemia) 
• numbness or weakness of the arms and legs 
• confusion 
• feeling dizzy 
• feeling exhausted (astenia) 
• increase in “urea” - produced by the kidneys - shown in tests 
• increase in “gamma-glutamyltransferase” - produced by the liver - shown in tests 
• increase in “alkaline phosphatase” - produced by the bile system - shown in tests 
• increase in “creatine phosphokinase” - produced by the muscle - shown in tests 
• drop in haemoglobin (that carries oxygen in blood) and white blood cells- shown in tests. 
• trouble sleeping 
• poor memory or memory loss 
• hair loss 
• constipation 
• dyspepsia 
• blurred vision; impaired vision 
 
Very rare side effect (may affect up to 1 in 10,000 people): 
• gynecomastia (breast enlargement in men) 
 
 
The following side effects have also been reported but the frequency cannot be estimated from the 
available information (frequency not known): 

• severe allergic skin rash with blisters 
• complications of gall stones such as colic because of stones in bile duct, infection of the bile 

ducts or gall bladder 
• diabetes mellitus 
• erectile dysfunction 
• feeling depressed 
• sleep disturbances including nightmares 
• specific lung disease with difficulties breathing (called interstitial lung disease) 
• muscle weakness that is constant 
• increase in “glycosylated haemoglobin” and blood glucose levels - (markers for blood glucose 

control in diabetes mellitus - shown in tests 
 
Reporting of side effects 
 
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 



70 

listed in Appendix V. By reporting side effects you can help provide more information on the safety 
of this medicine. 
 
 
5. How to store Cholib 
 
Keep this medicine out of the sight and reach of children. 
Do not use Cholib after the expiry date which is stated on the carton and the blister after EXP. 
The expiry date refers to the last day of that month. 
 
Store below 30°C. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how 
to throw away medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Cholib contains 
 
The active substances are fenofibrate and simvastatin. Each tablet contains 145 mg of fenofibrate 
and 40 mg of simvastatin. 
 
This medicine contains less than 1 mmol sodium (23 mg) per one tablet, that is to say essentially 
‘sodium-free’. 
 
The other ingredients are: 
 
Tablet core: 
Butylhydroxyanisole (E320), lactose monohydrate, sodium laurilsulfate, starch, pregelatinised 
(maize), docusate sodium, sucrose, citric acid monohydrate (E330), hypromellose (E464), 
crospovidone (E1202), magnesium stearate (E572), silicified microcrystalline cellulose (comprised of 
cellulose, microcrystalline and silica, colloidal anhydrous), ascorbic acid (E300). 
 
Film-coat: 
Poly (vinyl alcohol), partially hydrolysed (E1203), titanium dioxide (E171), talc (E553b), lecithin 
(derived from soya bean (E322)), xanthan gum (E415), iron oxide red (E172). 
 
What Cholib looks like and contents of the pack 
 
Oval, biconvex, brick red coloured, film-coated tablet, with bevelled edges and 145/40 on one side. 
The diameter dimensions are 19.3 x 9.3 mm approximately and the tablet weight is about 840 mg. 
 
The tablets are provided in carton boxes with blisters containing 10,30 or 90 tablets. 
 
Not all pack sizes may be marketed. 
 
Marketing Authorisation Holder and Manufacturer 
 
Marketing Authorisation Holder: 
 Mylan IRE Healthcare Ltd, Unit 35/36 Grange Parade, Baldoyle Industrial Estate, Dublin 13 - 
Ireland. 
 
Manufacturer: 
Mylan Laboratories SAS, Route de Belleville - Lieu-dit Maillard,  01400 Châtillon-sur-
Chalaronne - France. 
 

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71 

 
 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
 
België/Belgique/Belgien 
Mylan EPD  
Tel/Tél: + 32 2 658 61 00 
 

 
Ireland 
Mylan IRE Healthcare Ltd 
Tel: +44 (0) 1707 853000 
 

 
Norge 
Mylan Healthcare Norge AS 
Tlf: + 47 66 75 33 00 
 

България 
Майлан ЕООД  
Teл.: + 359 2 4455 400 
 

Ísland 
 Icepharma hf. 
Sími: +354 540 8000 

Österreich 
Mylan Österreich GmbH 
Tel: + 43 1 891 24 -0 
 

Česká republika 
Mylan Healthcare CZ s.r.o. 
Tel: +420 222 004 400 
 

Italia 
Mylan Italia S.r.l. 
Tel: + 39 (0) 2 61246921 

Polska 
Mylan Healthcare Sp. z o.o. 
Tel: +48 22 546 64 00 

Danmark 
Mylan Denmark ApS 
Tlf. +45 28 11 69 32 

Κύπρος 
Βαρνάβας Χατζηπαναγής Λτδ 
(Varnavas Hadjipanayis Ltd) 
Τηλ: +357 22207700 

Portugal 
BGP Products, Unipessoal, Lda. 
Tel : +351 214 127 256  
 

Deutschland 
Mylan Healthcare GmbH 
(Troisdorf) 
Tel: +49 511 4754 3400 
 

Latvija 
Mylan Healthcare SIA 
Tel: + 371 67 605 580 
 

România 
BGP Products S.R.L. 
Tel: +40 372 579 000 
 

Eesti 
BGP Products Switzerland 
GmbH Eesti filiaal 
Tel: + 372 6363052 
 

Lietuva 
BGP Products UAB 
Tel: +370 52 051 288 
 

Slovenija 
Mylan Healthcare d.o.o. 
Tel: + 386 (0)123 63 180 

Ελλάδα 
BGP ΠΡΟΪΟΝΤΑ Μ.Ε.Π.Ε. 
Τηλ.: +30 210 9891 777 

Luxembourg/Luxemburg 
Mylan EPD sprl-bvba 
Tel/Tél: + 32 2 658 6100 
 

Slovenská republika 
BGP Products s.r.o. 
Tel: +421 2 40 20 38 00 

España 
Mylan pharmaceuticals S.L. 
+34 91 669 93 00 

Magyarország 
Mylan EPD Kft 
Tel: +36 1 465 2100 

Suomi/Finland 
Mylan Finland Oy 
Puh/Tel: +358 20 720 9555 
 

France 
Mylan Medical SAS  
Tél: + 33 (0)1 56 64 10 70 
 
 

Malta 
V.J. Salomone Pharma 
Limited  Tel: +356-22-98 31 43 
 

Sverige 
BGP Products AB 
Tel: +46 8 555 227 07 
 

Hrvatska 
Mylan Hrvatska d.o.o. 
Tel: + 385 (0)1 2350 599 
 

Nederland 
Mylan Healthcare B.V. 
Tel: +31 (0)20 426 33 00 

United Kingdom 
Mylan Products Ltd 
Tel: +44 (0) 170 785 3000 

 
 

tel:+49
tel:+49
tel:+370
tel:+370


72 

This leaflet was last revised in <{MM/YYYY}>. 
 
Other sources of information 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu. 
 
 

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

	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET