Simvastatin and Fenofibrate interacts in the following cases:
Fenofibrate/simvastatin 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.
Do not exceed 145 mg of fenofibrate and 20 mg of simvastatin per day, unless clinical benefit outweigh the risk.
Do not exceed 145 mg of fenofibrate and 20 mg of simvastatin per day.
As simvastatin is contraindicated during pregnancy (see hereafter), fenofibrate/simvastatin combination is contraindicated during pregnancy.
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. 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, fenofibrate/simvastatin combination is contraindicated during breast-feeding.
Reversible effects on fertility have been observed in animals. There are no clinical data on fertility from the use of fenofibrate/simvastatin.
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 fenofibrate/simvastatin therapy.
The most commonly reported adverse drug reactions (ADRs) during fenofibrate/simvastatin 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 fenofibrate/simvastatin 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:
| 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 | 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 fenofibrate/simvastatin 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 | rare | ||
| Myopathy** Immune-mediated necrotizing myopathy | 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***** | 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.
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