(simvastatin · DailyMed)
CHOLIB 145/20
FENOFIBRATE , SIMVASTATIN
What it does
Fenofibrate is a medication used to lower cholesterol and fat levels in the blood.
Commonly used for: high cholesterol (hyperlipidemia), high triglycerides
Read more in plain English ↓Plain-language summary for general understanding - not medical advice. Always follow your pharmacist/doctor.
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Sourcing - Kenya onlyRegistration & product details
Source: South African Health Products Regulatory Authority · fetched 2026-04-15 21:30:28 · updated 2026-10-18 04:02:35
Drug Interactions
128Pharmacodynamic Warnings
Simvastatin appears in TABLE 1: Drugs that cause hepatotoxicity
Severe (11)
Pravastatin - increases risk of rhabdomyolysis
Fenofibrate is predicted to increase the risk of rhabdomyolysis when given with statins (pravastatin). Avoid.
Simvastatin - increases exposure
Cobicistat is predicted to increase the exposure to statins (simvastatin). Avoid.
Simvastatin - increases exposure
Idelalisib is predicted to increase the exposure to statins (simvastatin). Avoid.
Simvastatin - increases exposure
Letermovir is predicted to increase the exposure to statins (rosuvastatin, simvastatin). Avoid.
Simvastatin - increases exposure
Clarithromycin is predicted to increase the exposure to statins (simvastatin). Avoid.
Moderate (40)
Fluvastatin - increases risk of rhabdomyolysis
Fenofibrate is predicted to increase the risk of rhabdomyolysis when given with statins (fluvastatin). Use with caution and adjust fenofibrate dose, p. 218.
Simvastatin - increases exposure
Dronedarone moderately increases the exposure to statins (simvastatin). Monitor and adjust dose.
Simvastatin - increases exposure
Fluconazole is predicted to increase the exposure to statins (atorvastatin, simvastatin). Monitor and adjust dose. Also see TABLE 1 p. 1517.
Simvastatin - increases exposure
Isavuconazole is predicted to increase the exposure to statins (simvastatin). Monitor and adjust dose.
Simvastatin - decreases exposure
Cenobamate is predicted to decrease the exposure to statins (simvastatin). Adjust dose.
Unknown (77)
Daptomycin - increases risk of rhabdomyolysis
Statins are predicted to increase the risk of rhabdomyolysis when given with daptomycin. Daratumumab → see monoclonal antibodies Darbepoetin alfa → see TABLE 5 p. 1518 (thromboembolism), TABLE 16 p. 1
Daptomycin - increases risk of rhabdomyolysis e
Statins are predicted to increase the risk of rhabdomyolysis when given with daptomycin.
Simvastatin - decreases exposure
Enzalutamide is predicted to decrease the exposure to statins (atorvastatin, simvastatin).
Simvastatin - increases concentration
Darolutamide is predicted to increase the concentration of statins (pravastatin, simvastatin).
Simvastatin - decreases exposure
Apalutamide is predicted to decrease the exposure to statins (simvastatin). Avoid or monitor.
Data from BNF 85 (British National Formulary). This is not a substitute for professional medical advice. Matched via: exact
About fenofibrate
Fenofibrate is a medication used to lower cholesterol and fat levels in the blood.
What it treats
- high cholesterol (hyperlipidemia)
- high triglycerides
How it works
It helps reduce the amount of fat in the blood by increasing the breakdown of fats and decreasing their production in the liver.
Who it's for
This medicine is for adults who have high cholesterol or triglycerides that may not be controlled by diet alone.
AI-assisted summary grounded in BNF data - general information only, not medical advice. Always confirm with your pharmacist or doctor.
About simvastatin
Simvastatin is a medication that helps lower cholesterol levels in the blood.
What it treats
- high cholesterol (hyperlipidemia)
- preventing heart disease
- reducing the risk of strokes
How it works
It works by blocking a substance your body needs to make cholesterol, which helps lower overall cholesterol levels.
Who it's for
Simvastatin is for adults who have high cholesterol or are at risk of heart disease.
Drug class
Statins
Cautions
- • Avoid using with other drugs that can harm the liver.
AI-assisted summary grounded in BNF data - general information only, not medical advice. Always confirm with your pharmacist or doctor.
Clinical monograph: Fenofibrate
BNF-referencedFenofibrate is a synthetic fibrate used primarily for the treatment of hyperlipidaemia, particularly in patients with high serum triglyceride levels. It functions by activating peroxisome proliferator-activated receptor alpha (PPARα), which enhances lipolysis, reduces triglycerides, and has variable effects on LDL cholesterol. Fenofibrate is indicated for patients who cannot tolerate statins or as an adjunct therapy in severe cases of hypertriglyceridaemia.
Indications
- Mixed hyperlipidaemia
- Severe hypertriglyceridaemia
- Familial hypercholesterolaemia (under expert advice)
Dosage
Children: For children aged 4–14 years, the dosage is one 67 mg capsule per 20 kg body weight daily, with a maximum of four 67 mg capsules per day
Adults: Initially 200 mg daily, increased if necessary to a maximum of 267 mg daily, or 100 mg to 160 mg daily depending on the formulation and patient needs.
Mechanism of action
Fenofibrate activates PPARα, a nuclear receptor that regulates gene transcription involved in lipid metabolism. This activation increases lipolysis, enhances the activity of lipoprotein lipase, and reduces apoprotein C-III levels. The resultant effect is an alteration in lipid homeostasis, leading to decreased triglyceride levels and improved lipid profiles. Fenofibrate also exhibits anti-inflammatory properties by suppressing the production of inflammatory cytokines.
Pharmacodynamics
Fenofibrate is effective in treating primary hypercholesterolemia, mixed dyslipidemia, and severe hypertriglyceridemia. Its long half-life of 19-27 hours allows for once-daily dosing, making it convenient for patients. The therapeutic index is wide, but caution is advised due to the risks of rhabdomyolysis and myopathy, especially when used with statins.
Pharmacokinetics
Fenofibrate is absorbed after oral administration, with peak plasma concentrations occurring approximately 4-5 hours post-dose. It is extensively protein-bound and undergoes metabolism in the liver, converting to its active form. The elimination half-life is between 19 to 27 hours, and it is primarily excreted via urine. Dose adjustments may be necessary in cases of renal impairment.
Contra-indications
- Gall bladder disease
- Severe hepatic impairment
- Concurrent use of a statin in patients with risk factors for myopathy
- Hypoalbuminaemia
- Nephrotic syndrome
- Photosensitivity to fibrates
Adverse effects
- Alopecia
- Diarrhoea
- Dizziness
- Drowsiness
- Fatigue
- Gastrointestinal discomfort
- Headache
- Myalgia
- Nausea
- Skin reactions
- Vertigo
- Rhabdomyolysis
- Pancreatitis
- Hepatic disorders
- Sexual dysfunction
- Fatigue
- Interstitial lung disease
Interactions
- Fenofibrate + statins (increased risk of rhabdomyolysis)
- Fenofibrate + pravastatin (severe interaction, increases risk of rhabdomyolysis)
- Fenofibrate + fluvastatin (moderate interaction, increases risk of rhabdomyolysis)
- Fenofibrate + ketoprofen (photosensitivity)
Precautions
- Correct hypothyroidism before initiating treatment
- Monitor liver function and creatine kinase when fibrates are used in combination with a statin
- Use caution in patients with risk factors for myopathy or severe hypertriglyceridaemia
Pregnancy
Manufacturers advise avoiding use due to potential toxicity based on animal studies.
Breast-feeding
Manufacturer advises avoiding use as fenofibrate is present in milk in animal studies.
Storage
Store in a cool, dry place, away from direct sunlight.
Formulations
- Modified-release tablets (200 mg)
- Tablets (100 mg)
- Micronised capsules (67 mg)
- Micronised capsules (200 mg)
- Micronised capsules (267 mg)
AI-synthesized from BNF references - general information only, not a substitute for professional medical advice or the current BNF. Verify doses with a pharmacist.
Clinical monograph: Simvastatin
BNF-referencedSimvastatin is a member of the statin class of drugs, primarily used as an antilipemic agent to lower cholesterol levels in patients with hyperlipidaemia. It works by inhibiting HMG-CoA reductase, an enzyme crucial for cholesterol biosynthesis, ultimately reducing low-density lipoprotein (LDL) and triglyceride levels while increasing high-density lipoprotein (HDL) levels. This drug is part of a comprehensive strategy to reduce the risk of cardiovascular events and manage associated conditions such as atherosclerosis.
Mechanism of action
Simvastatin is a prodrug that is hydrolyzed in vivo to its active metabolite, which resembles HMG-CoA. This metabolite competes with HMG-CoA for the active site of HMG-CoA reductase, thereby inhibiting cholesterol synthesis. The reduction in hepatic cholesterol concentrations enhances the upregulation of LDL receptors, facilitating increased clearance of LDL from the bloodstream. Additionally, simvastatin inhibits the synthesis of very low-density lipoprotein (VLDL), contributing to its lipid-lowering effects. Beyond its cholesterol-lowering properties, simvastatin has been shown to exert vasculoprotective effects, known as pleiotropic effects.
Pharmacodynamics
Simvastatin effectively lowers total cholesterol, LDL cholesterol, apolipoprotein B, non-HDL cholesterol, and triglyceride levels, while increasing HDL cholesterol concentrations. Elevated levels of LDL and triglycerides are associated with an increased risk of atherosclerosis and cardiovascular diseases (CVD). By modulating these lipid levels, simvastatin reduces cardiovascular morbidity and mortality. The balance of cholesterol levels, particularly the total cholesterol to HDL ratio, serves as a predictive marker for coronary artery disease, with statins like simvastatin demonstrating significant cost-effectiveness in CVD management.
Pharmacokinetics
Simvastatin is administered orally and exhibits a peak plasma concentration within 1 to 2 hours post-dose. It is extensively metabolized in the liver, primarily by CYP3A4, with a half-life of approximately 1 to 2 hours. The drug's bioavailability is approximately 5% due to extensive first-pass metabolism. Simvastatin and its metabolites are primarily excreted via bile, with only a small fraction eliminated through urine. The pharmacokinetic profile necessitates caution in patients with renal impairment, particularly for higher doses.
Contra-indications
- Active liver disease
- Pregnancy
- Hypersensitivity to simvastatin or any component of the formulation
Adverse effects
- Myopathy
- Rhabdomyolysis
- Hepatic enzyme abnormalities
- Gastrointestinal disturbances
- Headache
- Dizziness
- Sleep disturbances
- Skin rash
- Increased creatine kinase levels
Interactions
- Cobicistat (severe increase in exposure)
- Idelalisib (severe increase in exposure)
- Letermovir (severe increase in exposure)
- Clarithromycin (severe increase in exposure)
- Erythromycin (severe increase in exposure)
- Ribociclib (severe increase in exposure)
- Dronedarone (moderate increase in exposure)
- Fluconazole (moderate increase in exposure)
- Isavuconazole (moderate increase in exposure)
- Cenobamate (moderate decrease in exposure)
- Amiodarone (max 20 mg daily)
- Amlodipine (max 20 mg daily)
- Verapamil (max 20 mg daily)
- Diltiazem (max 20 mg daily)
- Bezafibrate (max 10 mg daily)
- Ciprofibrate (max 10 mg daily)
- Lomitapide (max 40 mg daily)
- Ticagrelor (max 20 mg daily)
- Elbasvir with grazoprevir (max 20 mg daily)
- Bempedoic acid (max 20 mg daily with concurrent use)
Precautions
- Use with caution in patients with renal impairment
- Monitor liver function tests before and during treatment
- Consider routine monitoring of renal function
- Counsel patients regarding the risk of myopathy and rhabdomyolysis
- Assess for any potential drug interactions prior to initiation
Pregnancy
Manufacturer advises avoiding use during pregnancy due to potential risks.
Breast-feeding
Manufacturer advises avoiding use during breastfeeding due to lack of safety data.
Storage
Store at room temperature, away from moisture and
AI-synthesized from BNF references - general information only, not a substitute for professional medical advice or the current BNF. Verify doses with a pharmacist.
Molecular reference: Fenofibrate
PubChem CID 3339Molecular formula: C20H21ClO4
Mechanism of action
Fenofibrate activates peroxisome proliferator activated receptor alpha (PPARα), increasing lipolysis, activating lipoprotein lipase, and reducing apoprotein C-III. PPARα is a nuclear receptor and its activation alters lipid, glucose, and amino acid homeostasis. Activation of PPARα activates transcription of gene transcription and translation that generates peroxisomes filled with hydrogen peroxide, reactive oxygen species, and hydroxyl radicals that also participate in lipolysis. This mechanism of increased lipid metabolism is also associated with increased oxidative stress on the liver. In rare cases this stress can lead to cirrhosis and chronic active hepatitis. Fenofibrate is a synthetic ligand for the nuclear receptor peroxisome proliferator-activated receptor (PPAR) alpha and has been widely used in the treatment of metabolic disorders, especially hyperlipemia, due to its lipid-lowering effect. The molecular mechanism of lipid-lowering is relatively well defined: an activated PPARalpha forms a PPAR-RXR heterodimer and this regulates the transcription of genes involved in energy metabolism by binding to PPAR response elements in their promoter regions, so-called "trans-activation". In addition, fenofibrate also has anti-inflammatory and anti-athrogenic effects in vascular endothelial and smooth muscle cells. /There is/ limited information about the anti-inflammatory mechanism of fenofibrate; however, "trans-repression" which suppresses production of inflammatory cytokines and adhesion molecules probably contributes to this mechanism. Furthermore, there are reports that fenofibrate affects endothelial cells in a PPARalpha-independent manner. In order to identify PPARalpha-dependently and PPARalpha-independently regulated transcripts, ... microarray data from human endothelial cells treated with fenofibrate, and with and without siRNA-mediated knock-down of PPARalpha /were obtained/. ... Dynamic Bayesian transcriptome networks /were used/ to reveal PPARalpha-dependent and -independent pathways. Transcriptome network analysis identified growth differentiation factor 15 (GDF15) as a hub gene having PPARalpha-independently regulated transcripts as its direct downstream children. This result suggests that GDF15 may be PPARalpha-independent master-regulator of fenofibrate action in human endothelial cells. The effects of fenofibric acid seen in clinical practice have been explained in vivo in transgenic mice and in vitro in human hepatocyte cultures by the activation of peroxisome proliferator activated receptor a (PPARa). Through this mechanism, fenofibrate increases lipolysis and elimination of triglyceride-rich particles from plasma by activating lipoprotein lipase and reducing production of apoprotein C-III (an inhibitor of lipoprotein lipase activity). The resulting fall in triglycerides produces an alteration in the size and composition of LDL from small, dense particles (which are thought to be atherogenic due to their susceptibility to oxidation), to large buoyant particles. These larger particles have a greater affinity for cholesterol receptors and are catabolized rapidly. Activation of PPARa also induces an increase in the synthesis of apoproteins A-I, A-II and HDL-cholesterol. ... /This study/ investigated whether fenofibrate affects serum levels of retinol-binding protein-4 (RBP4), an adipocytokine that has recently been shown to link obesity and insulin resistance. Fenofibrate treatment significantly decreased serum RBP4 levels of dyslipidemic patients, which correlated with reduced body weight and increased insulin sensitivity. ... the effect of fenofibrate on RBP4 expression in obese rats /were also examined/. Fenofibrate greatly decreased RBP4 mRNA levels in adipose tissue but not in the liver, which correlated with decreased serum RBP4 levels and increased insulin sensitivity in obese rats. Consistent with a direct effect on RBP4 expression, fenofibrate treatment significantly reduced the mRNA expression levels
Pharmacodynamics
Fenofibrate is a fibrate that activates peroxisome proliferator activated receptor alpha (PPARα) to alter lipid metabolism and treat primary hypercholesterolemia, mixed dyslipidemia, and severe hypertriglyceridemia. Fenofibrate requires once daily dosing and has a half life of 19-27 hours so its duration of action is long. Fenofibrate capsules are given at a dose of 50-150mg daily so the therapeutic index is wide. Patients should be counselled about the risk of rhabdomyolysis, myopathy, and cholelithiasis when taking fibrates.
Source: PubChem (NCBI) · pathways from PathBank, Reactome, WikiPathways & PharmGKB.
Molecular reference: Simvastatin
PubChem CID 54454Molecular formula: C25H38O5
Mechanism of action
Simvastatin is a prodrug in which the 6-membered lactone ring of simvastatin is hydrolyzed <i>in vivo</i> to generate the beta,delta-dihydroxy acid, an active metabolite structurally similar to HMG-CoA (hydroxymethylglutaryl CoA). Once hydrolyzed, simvastatin competes with HMG-CoA for HMG-CoA reductase, a hepatic microsomal enzyme, which catalyzes the conversion of HMG-CoA to mevalonate, an early rate-limiting step in cholesterol biosynthesis. Simvastatin acts primarily in the liver, where decreased hepatic cholesterol concentrations stimulate the upregulation of hepatic low density lipoprotein (LDL) receptors which increases hepatic uptake of LDL. Simvastatin also inhibits hepatic synthesis of very low density lipoprotein (VLDL). The overall effect is a decrease in plasma LDL and VLDL. At therapeutic doses, the HMG-CoA enzyme is not completely blocked by simvastatin activity, thereby allowing biologically necessary amounts of mevalonate to remain available. As mevalonate is an early step in the biosynthetic pathway for cholesterol, therapy with simvastatin would also not be expected to cause any accumulation of potentially toxic sterols. In addition, HMG-CoA is metabolized readily back to acetyl-CoA, which participates in many biosynthetic processes in the body. In vitro and in vivo animal studies also demonstrate that simvastatin exerts vasculoprotective effects independent of its lipid-lowering properties, also known as the pleiotropic effects of statins. This includes improvement in endothelial function, enhanced stability of atherosclerotic plaques, reduced oxidative stress and inflammation, and inhibition of the thrombogenic response. Statins have also been found to bind allosterically to β2 integrin function-associated antigen-1 (LFA-1), which plays an important role in leukocyte trafficking and in T cell activation. Simvastatin is a prodrug and is hydrolyzed to its active beta-hydroxyacid form, simvastatin acid, after administration. Simvastatin is a specific inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the enzyme that catalyzes the conversion of HMG-CoA to mevalonate, an early and rate limiting step in the biosynthetic pathway for cholesterol. In addition, simvastatin reduces VLDL and TG and increases HDL-C. The HDL-associated enzyme paraoxonase protects LDLs from oxidative stress. 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) appear to favorably influence the atherosclerotic process by different mechanisms. The present study examined the influence of simvastatin on paraoxonase expression and serum paraoxonase levels. Simvastatin upregulated in a dose-dependent manner the activity of the promoter of the paraoxonase gene in expression cassettes transfected into HepG2 cells. Upregulation could be blocked by mevalonate and other intermediates of the cholesterol biosynthetic pathway. Simvastatin increased nuclear factors, notably sterol regulatory element-binding protein-2, capable of binding to the paraoxonase promoter; this was also blocked by mevalonate. Sterol regulatory element-binding protein-2 upregulated promoter activity in vitro. Patients treated with statin showed a significant increase in serum concentrations and activities of paraoxonase. The data indicate that simvastatin can modulate expression in vitro of the antioxidant enzyme paraoxonase and is associated with increased serum paraoxonase concentration and activity. It is consistent with effects of simvastatin treatment, which have the potential to influence beneficially antiatherogenic mechanisms at the HDL level. The study provides evidence for 1 molecular mechanism by which paraoxonase gene expression could be regulated. ... We report in this work that, unexpectedly, simvastatin enhances LPS-induced IL-12p40 production by murine macrophages, and that it does so by activating the IL-12p40 promoter. Mutational analysis and dominant-negative expression studies indicate that both C/EBP and AP-1 transcri
Pharmacodynamics
Simvastatin is an oral antilipemic agent which inhibits HMG-CoA reductase. It is used to lower total cholesterol, low density lipoprotein-cholesterol (LDL-C), apolipoprotein B (apoB), non-high density lipoprotein-cholesterol (non-HDL-C), and trigleride (TG) plasma concentrations while increasing HDL-C concentrations. High LDL-C, low HDL-C and high TG concentrations in the plasma are associated with increased risk of atherosclerosis and cardiovascular disease. The total cholesterol to HDL-C ratio is a strong predictor of coronary artery disease and high ratios are associated with higher risk of disease. Increased levels of HDL-C are associated with lower cardiovascular risk. By decreasing LDL-C and TG and increasing HDL-C, rosuvastatin reduces the risk of cardiovascular morbidity and mortality. Elevated cholesterol levels, and in particular, elevated low-density lipoprotein (LDL) levels, are an important risk factor for the development of CVD. Use of statins to target and reduce LDL levels has been shown in a number of landmark studies to significantly reduce the risk of development of CVD and all-cause mortality. Statins are considered a cost-effective treatment option for CVD due to their evidence of reducing all-cause mortality including fatal and non-fatal CVD as well as the need for surgical revascularization or angioplasty following a heart attack. Evidence has shown that even for low-risk individuals (with <10% risk of a major vascular event occurring within 5 years) statins cause a 20%-22% relative reduction in major cardiovascular events (heart attack, stroke, coronary revascularization, and coronary death) for every 1 mmol/L reduction in LDL without any significant side effects or risks. **Skeletal Muscle Effects** Simvastatin occasionally causes myopathy manifested as muscle pain, tenderness or weakness with creatine kinase (CK) above ten times the upper limit of normal (ULN). Myopathy sometimes takes the form of rhabdomyolysis with or without acute renal failure secondary to myoglobinuria, and rare fatalities have occurred. Predisposing factors for myopathy include advanced age (≥65 years), female gender, uncontrolled hypothyroidism, and renal impairment. Chinese patients may also be at increased risk for myopathy. In most cases, muscle symptoms and CK increases resolved when treatment was promptly discontinued. In a clinical trial database of 41,413 patients, the incidence of myopathy was approximately 0.03% and 0.08% at 20 and 40 mg/day, respectively, while the risk of myopathy with simvastatin 80 mg (0.61%) was disproportionately higher than that observed at the lower doses. It's therefore recommended that the 80mg dose of simvastatin should be used only in patients who have been taking simvastatin 80 mg chronically (e.g., for 12 months or more) without evidence of muscle toxicity. As well, patients already stabilized on simvastatin 80mg should be monitored closely for evidence of muscle toxicity; if they need to be initiated on an interacting drug that is contraindicated or is associated with a dose cap for simvastatin, that patient should be switched to an alternative statin with less potential for the drug-drug interaction. The risk of myopathy during treatment with simvastatin may be increased with concurrent administration of interacting drugs such as [fenofibrate], [niacin], [gemfibrozil], [cyclosporine], and strong inhibitors of the CYP3A4 enzyme. Cases of myopathy, including rhabdomyolysis, have been reported with HMG-CoA reductase inhibitors coadministered with [colchicine], and caution should therefore be exercised when prescribing these two medications together. **Liver Enzyme Abnormalities** Persistent increases (to more than 3X the ULN) in serum transaminases have occurred in approximately 1% of patients who received simvastatin in clinical studies. When drug treatment was interrupted or discontinued in these patients, the transaminase levels usually fell slowly to pretreatment levels. The in
Biological pathways
Source: PubChem (NCBI) · pathways from PathBank, Reactome, WikiPathways & PharmGKB.
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