Cholib (Fenofibrate_Simvastatin)

Uses

Fenofibrate is used for an adjunct to diet and other non pharmacological treatment (e.g. exercise, weight reduction) for the following:

• Treatment of severe hypertriglyceridemia with or without low HDL cholesterol.
• Mixed hyperlipidemia when a statin is contraused or not tolerated.
• Mixed hyperlipidemia in patients at high cardiovascular risk in addition to a statin when triglycerides and HDL cholesterol are not adequately controlled

Primary hypercholesterolemia (type IIa and IIb) in patients who have not responded adequately to diet and other appropriate measures. Coronary heart disease and elevated plasma cholesterol level.

Cholib (Fenofibrate_Simvastatin) is also used to associated treatment for these conditions: Mixed Dyslipidemias, Primary Hypercholesterolemia, Severe Hypertriglyceridemia, Severe Fredrickson Type IV Hypertriglyceridemia, Severe Fredrickson Type V HypertriglyceridemiaCardiovascular Events, Diabetes Mellitus, Heterozygous Familial Hypercholesterolemia, High Cholesterol, Homozygous Familial Hypercholesterolemia, Mixed Hyperlipidemia, History of coronary heart disease cardiovascular event, History of stroke or other cerebrovascular disease cardiovascular event

How Cholib (Fenofibrate_Simvastatin) works

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.

Simvastatin is a prodrug in which the 6-membered lactone ring of simvastatin is hydrolyzed in vivo 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.

Dosage

Cholib (Fenofibrate_Simvastatin) dosage

The dose is one 200 mg capsule per day. Dosage should be individualized according to patient response, and should be increased sequentially if necessary following repeat serum triglyceride estimations at 4 to 8 week intervals. Patients should be placed on an appropriate triglyceride-lowering diet before receiving fenofibrate, and should continue this diet during treatment with fenofibrate. Fenofibrate should be given with meals, thereby optimizing the bioavailability of the medication.

The patient should be placed on a standard cholesterol lowering diet before receiving Simvastatin and should continue on this during treatment with Simvastatin. The usual starting dose is 10 mg/day given as a single dose in the evening. Adjustment of dosage, if required, should be made at intervals of not less than four weeks, to a maximum of 40 mg daily given as a single dose in the evening. If LDL-cholesterol levels fall below 2 mmol/L or total plasma cholesterol levels fall below 3.5 mmol/L consideration should be given to reducing the dose of Simvastatin. In hypercholesterolemia, the recommended starting dose is 5-10 mg once a day in the evening and the recommended dosing range is 5-40 mg per day as a single dose in the evening. In patients with coronary heart disease and hypercholesterolemia, the starting dose should be 20 mg once a day in the evening. Because Simvastatin does not undergo significant renal excretion, modification of dosage should not be necessary in patients with renal insufficiency. Safety and effectiveness in children and adolescents have not been established.

Side Effects

Digestive: hepatitis, cholelithiasis, cholecystitis, hepatomegaly

Musculoskeletal: myalgia, myasthenia, rhabdomyolysis

Skin and appendages: photosensitivity, eczema

Cardiovascular: peripheral edema, angina, palpitations, tachycardia, and migraine

Simvastatin is generally well tolerated. Headache, fatigue, insomnia, gastrointestinal effects like nausea, constipation or diarrhoea, flatulence, dyspepsia, abdominal cramps and muscular effects like myalgia, myositis and myopathy have been reported. Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have been associated with Simvastatin therapy. Hepatitis, pancreatitis, rash, Angio-oedema have also been reported. No potentially life threatening effects have been reported.

Toxicity

The oral LD₅₀ in rats is >2g/kg and in mice is 1600mg/kg. The oral TDLO in rats is 9mg/kg.

Treat patients with supportive care including monitoring of vital signs and observing clinical status. Recent overdose may be treated with inducing vomiting or gastric lavage. Due to fenofibrate's extensive protein binding, hemodialysis is not expected to be useful.

Precaution

Increased risk of cholelithiasis, pancreatitis, skeletal muscle effects. Patient at risk of rhabdomyolysis. Renal impairment. Pregnancy.

• If there is a history of liver disease
• Who take high alcohol
• Liver function test should be done before and during treatment
• If serum transaminase rises three times the upper limit of normal, treatment should be discontinued
• Avoid pregnancy during and for one month after treatment

Interaction

Oral Anticoagulants: Caution should be exercised when anticoagulants are given in conjunction with fenofibrate. The dosage of the anticoagulants should be reduced to maintain the prothrombin time at the desired level to prevent bleeding complications.

Resins: Since bile acid sequestrants may bind other drugs given concurrently, patients should take fenofibrate at least 1 hour before or 4-6 hours after a bile acid binding resin to avoid impending its absorption.

Cyclosporine: Because cyclosporine can produce nephrotoxicity with decreases in creatinine clearance and rises in serum creatinine, and because renal excretion is the primary elimination route of fibrate drugs including fenofibrate, there is a risk that an interaction will lead to deterioration.

Digoxin: Concomitant administration of Simvastatin and Digoxin in normal volunteers resulted in a slight elevation (less than 0.3 µgm/ml) in drug concentrations in plasma compared to concomitant administration of placebo and Digoxin.

Coumarin derivatives: Slightly enhance the anticoagulant effect of Warfarin (mean changes in p rothrombin time less than two seconds) in normal volunteers maintained in a state of low therapeutic anticoagulation.

Others: In clinical studies, Simvastatin was used concomitantly with ACE inhibitors, beta-blockers, calcium channel blockers, diuretics and NSAIDs without evidence of clinically significant adverse interactions.

Volume of Distribution

The volume of distribution of fenofibrate is 0.89L/kg, and can be as high as 60L.

Rat studies indicate that when radiolabeled simvastatin was administered, simvastatin-derived radioactivity crossed the blood-brain barrier.

Elimination Route

A single 300mg oral dose of fenofibrate reaches a C_max of 6-9.5mg/L with a T_max of 4-6h in healthy, fasting volunteers.

Peak plasma concentrations of both active and total inhibitors were attained within 1.3 to 2.4 hours post-dose. While the recommended therapeutic dose range is 10 to 40 mg/day, there was no substantial deviation from linearity of AUC with an increase in dose to as high as 120 mg. Relative to the fasting state, the plasma profile of inhibitors was not affected when simvastatin was administered immediately before a test meal.

In a pharmacokinetic study of 17 healthy Chinese volunteers, the major PK parameters were as follows: Tmax 1.44 hours, Cmax 9.83 ug/L, t1/2 4.85 hours, and AUC 40.32ug·h/L.

Simvastatin undergoes extensive first-pass extraction in the liver, the target organ for the inhibition of HMG-CoA reductase and the primary site of action. This tissue selectivity (and consequent low systemic exposure) of orally administered simvastatin has been shown to be far greater than that observed when the drug is administered as the enzymatically active form, i.e. as the open hydroxyacid.

In animal studies, after oral dosing, simvastatin achieved substantially higher concentrations in the liver than in non-target tissues. However, because simvastatin undergoes extensive first-pass metabolism, the bioavailability of the drug in the systemic system is low. In a single-dose study in nine healthy subjects, it was estimated that less than 5% of an oral dose of simvastatin reached the general circulation in the form of active inhibitors.

Genetic differences in the OATP1B1 (Organic-Anion-Transporting Polypeptide 1B1) hepatic transporter encoded by the SCLCO1B1 gene (Solute Carrier Organic Anion Transporter family member 1B1) have been shown to impact simvastatin pharmacokinetics. Evidence from pharmacogenetic studies of the c.521T>C single nucleotide polymorphism (SNP) showed that simvastatin plasma concentrations were increased on average 3.2-fold for individuals homozygous for 521CC compared to homozygous 521TT individuals. The 521CC genotype is also associated with a marked increase in the risk of developing myopathy, likely secondary to increased systemic exposure. Other statin drugs impacted by this polymorphism include rosuvastatin, pitavastatin, atorvastatin, lovastatin, and pravastatin.

For patients known to have the above-mentioned c.521CC OATP1B1 genotype, a maximum daily dose of 20mg of simvastatin is recommended to avoid adverse effects from the increased exposure to the drug, such as muscle pain and risk of rhabdomyolysis.

Evidence has also been obtained with other statins such as rosuvastatin that concurrent use of statins and inhibitors of Breast Cancer Resistance Protein (BCRP) such as elbasvir and grazoprevir increased the plasma concentration of these statins. Further evidence is needed, however a dose adjustment of simvastatin may be necessary. Other statin drugs impacted by this polymorphism include fluvastatin and atorvastatin.

Half Life

Fenofibric acid, the active metabolite of fenofibrate, has a half life of 23 hours. Fenofibrate has a half life of 19-27 hours in healthy subjects and up to 143 hours in patients with renal failure.

4.85 hours

Clearance

The oral clearance of fenofibrate is 1.1L/h in young adults and 1.2L/h in the elderly.

Elimination Route

5-25% of a dose of fenofibrate is eliminated in the feces, while 60-88% is eliminated in the urine. 70-75% of the dose recovered in the urine is in the form of fenofibryl glucuronide and 16% as fenofibric acid.

Following an oral dose of 14C-labeled simvastatin in man, 13% of the dose was excreted in urine and 60% in feces.

Pregnancy & Breastfeeding use

Pregnancy Category C. Fenofibrate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing mothers: Fenofibrate should not be used in nursing mothers. Because of the potential for tumorigenicity seen in animal studies, a decision should be made whether to discontinue nursing or to discontinue the drug.

Category X: Studies in animals or human beings have demonstrated foetal abnormalities or there is evidence of foetal risk based on human experience or both, and the risk of the use of the drug in pregnant women clearly outweighs any possible benefit. The drug is contraindicated in women who are or may become pregnant.

Contraindication

Fenofibrate is contraindicated in patients with-

• Hypersensitivity to fenofibrate or any component of this medication.
• Known photoallergy or phototoxic reaction during treatment with fibrates or ketoprofen.
• Severe liver dysfunction, gallbladder disease, biliary cirrhosis, severe renal disorders.
• Chronic or acute pancreatitis with the exception of acute pancreatitis due to severe hypertriglyceridemia.
• Pregnancy and lactation.

Simvastatin should not be used in-

• Active liver disease
• Pregnant and breast feeding mother
• Women of child bearing age unless they have been adequately protected by contraception
• Hypersensitivity to any component of the preparation
• Patients with the homozygous familial hypercholesterolemia who have a complete absence of LDL receptors

Special Warning

Geriatrics: This indicates that a similar dosage regimen can be used in the elderly, without increasing accumulation of the drug or metabolites.

Pediatrics: No data are available. Fenofibrate is not indicated for use in the pediatric population.

Gender: No pharmacokinetic difference between male and female has been observed for fenofibrate.

Renal insufficiency: The dosage of fenofibrate should be minimized in patients who have severe renal impairment, while no modification of dosage is required in patients having moderate renal impairment.

Hepatic insufficiency: No pharmacokinetic study has been conducted in patients having hepatic insufficiency.

Acute Overdose

There are no data available on overdose. No antidote is available. General measures should be adopted and liver function should be monitored.

Storage Condition

Store at cool & dry place. Protect from light and moisture.

Store in a cool, dry place, Away from light keep out of reach of children.

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