Source: European Medicines Agency (EU) Revision Year: 2023 Publisher: Viatris Healthcare Limited, Damastown Industrial Park, Mulhuddart, Dublin 15, Dublin, Ireland
hypertriglyceridaemia
<60 mL/min/1.73 m²)
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 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).
There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use. IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment; positive antiHMG CoA reductase antibody; muscle biopsy showing necrotizing myopathy; and improvement with immunosuppressive agents. Additional neuromuscular and serologic testing may be necessary. Treatment with immunosuppressive agents may be required. Consider risk of IMNM carefully prior to initiation of another statin. If therapy is initiated with another statin, monitor for signs and symptoms of IMNM.
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 sections 4.3 and 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 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.
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:
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.
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 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.
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.
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.
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.
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.
In few cases, statins have been reported to induce de novo or aggravate pre-existing myasthenia gravis or ocular myasthenia (see section 4.8). Cholib should be discontinued in case of aggravation of symptoms. Recurrences when the same or a different statin was (re-) administered have been reported.
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’.
This medicinal product contains sunset yellow FCF (E110) that may cause allergic reactions.
No interaction studies have been performed with Cholib.
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), cobicistat and nefazodone.
Combination with itraconazole, ketoconazole, posaconazole, HIV protease inhibitors (e.g. nelfinavir), cobicistat, 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.
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).
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).
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.
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).
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).
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.
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 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.
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.
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.
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.
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.
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.
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.
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 Cobicistat | 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 |
As simvastatin is contraindicated during pregnancy (see hereafter), Cholib is contraindicated during pregnancy (see section 4.3).
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 is contraindicated during pregnancy. Safety in pregnant women has not been established. Maternal treatment with simvastatin may reduce the foetal levels of mevalonate which is a precursor of cholesterol biosynthesis. For these reasons, simvastatin must not be used in women who are pregnant, trying to become pregnant or suspect they are pregnant. Treatment with simvastatin must be suspended for the duration of pregnancy or until it has been determined that the woman is not pregnant.
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).
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.
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.
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.
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 |
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 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 | ||
| Myasthenia gravis | not known | ||
| Eye disorders | Vision blurred, visual impairment | rare | |
| Ocular myasthenia | not known | ||
| 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 syndrome, toxic epidermal necrolysis, etc.) | not known | |
| 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** Immune-mediated necrotizing myopathy (see section 4.4) | rare | ||
| Tendinopathy | 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 |
* 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).
* 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).
** 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).
*** 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: 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.
***** 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 suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
Not applicable.
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