Rosufen

Each film-coated tablet contains: Fenofibrate, BP 160 mg and Rosuvastatin (as calcium), Ph. Eur. 10 mg.
Fenofibrate, BP 160 mg and Rosuvastatin (as calcium), Ph. Eur. 20 mg.

Lipid Modifying Agent.
Pharmacology: Pharmacodynamics: Rosuvastatin: Rosuvastatin is a selective and competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts 3-hydroxy-3-methylglutaryl coenzyme A to mevalonate, a precursor for cholesterol. The primary site of action of rosuvastatin is the liver, the target organ for cholesterol lowering. Rosuvastatin increases the number of hepatic LDL receptors on the cell-surface, enhancing uptake and catabolism of LDL and it inhibits the hepatic synthesis of VLDL, thereby reducing the total number of VLDL and LDL particles.
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 increases the lipolysis and elimination of atherogenic triglyceride-rich particles from plasma by activating lipoprotein lipase and reducing production of apoprotein CIII. Activation of PPARα also induces an increase in the synthesis of apoproteins AI and AII.
The previously stated effects of fenofibrate on lipoproteins lead to a reduction in very low- and low density fractions (VLDL and LDL) containing apoprotein B and an increase in the high density lipoprotein fraction (HDL) containing apoprotein AI and AII.
In addition, through modulation of the synthesis and the catabolism of VLDL fractions fenofibrate increases the LDL clearance and reduces small dense LDL, the levels of which are elevated in the atherogenic lipoprotein phenotype, a common disorder in patients at risk for coronary heart disease.
Pharmacokinetics: Rosuvastatin: Absorption: Maximum rosuvastatin plasma concentrations are achieved approximately 5 hours after oral administration. The absolute bioavailability is approximately 20%.
Distribution: Rosuvastatin is taken up extensively by the liver which is the primary site of cholesterol synthesis and LDL-C clearance. The volume of distribution of rosuvastatin is approximately 134 L. Approximately 90% of rosuvastatin is bound to plasma proteins, mainly to albumin.
Metabolism: Rosuvastatin undergoes limited metabolism (approximately 10%). In vitro metabolism studies using human hepatocytes indicate that rosuvastatin is a poor substrate for cytochrome P450-based metabolism. CYP2C9 was the principal isoenzyme involved, with 2C19, 3A4 and 2D6 involved to a lesser extent. The main metabolites identified are the N-desmethyl and lactone metabolites. The N-desmethyl metabolite is approximately 50% less active than rosuvastatin whereas the lactone form is considered clinically inactive. Rosuvastatin accounts for greater than 90% of the circulating HMG-CoA reductase inhibitor activity.
Excretion: Approximately 90% of the rosuvastatin dose is excreted unchanged in the faeces (consisting of absorbed and non-absorbed active substance) and the remaining part is excreted in urine. Approximately 5% is excreted unchanged in urine. The plasma elimination half-life is approximately 19 hours. The elimination half-life does not increase at higher doses. The geometric mean plasma clearance is approximately 50 litres/hour (coefficient of variation 21.7%). As with other HMG-CoA reductase inhibitors, the hepatic uptake of rosuvastatin involves the membrane transporter OATP-C. This transporter is important in the hepatic elimination of rosuvastatin.
Fenofibrate: Absorption: Maximum plasma concentrations (Cmax) occur within 4 to 5 hours after oral administration. Plasma concentrations are stable during continuous treatment in any given individual. The absorption of fenofibrate is increased when administered with food.
Distribution: Fenofibric acid is strongly bound to plasma albumin (more than 99%). Plasma half-life: The plasma elimination half-life of fenofibric acid is approximately 20 hours.
Metabolism and excretion: No unchanged fenofibrate can be detected in the plasma where the principal metabolite is fenofibric acid. 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.

Rosuvastatin and Fenofibrate combination is indicated as an adjunct to diet to reduce elevated total-C, LDL-C, apo B and TG levels and to increase HDL-C in these patients.
Lipid altering agents should be used in addition to diet restricted in saturated fat and cholesterol only when the response to diet and other non-pharmacological measures has been inadequate.

The recommended dosage of Rosuvastatin and Fenofibrate combination is one tablet once daily orally administered after dinner. Or as prescribed by the physician.

Rosuvastatin: There is no specific treatment in the event of overdose. In the event of overdose, the patient should be treated symptomatically and supportive measures instituted as required. Liver function and CK levels should be monitored. Hemodialysis is unlikely to be of benefit.
Fenofibrate: No case of overdosage has been reported. No specific antidote is known. If an overdose is suspected, treat symptomatically and institute appropriate supportive measures as required. Fenofibrate cannot be eliminated by hemodialysis.

Rosuvastatin + Fenofibrate tablet is contraindicated in patients with: known hypersensitivity to either component of the product; hepatic or severe renal dysfunction, including primary biliary cirrhosis, and patients with unexplained persistent liver function abnormality; unexplained persistent elevations of serum transaminases exceeding three times the upper limit of normal; pre-existing gall bladder disease; pregnancy and lactation.

Liver function: As with other lipid lowering agents, increases have been reported in transaminase levels in some patients. In the majority of cases these elevations were transient, minor and asymptomatic. It is recommended that transaminase levels be monitored every 3 months during the first 12 months of treatment. Attention should be paid to patients who develop increase in transaminase levels and therapy should be discontinued if ASAT and ALAT levels increase to more than 3 times the upper limit of the normal range or 100 IU.
Pancreatitis: Pancreatitis has been reported in patients taking fenofibrate. This occurrence may represent a failure of efficacy in patients with severe hypertriglyceridemia, a direct drug effect, or a secondary phenomenon mediated through biliary tract stone or sludge formation, resulting in the obstruction of the common bile duct.
Muscle: Muscle toxicity, including very rare cases of rhabdomyolysis, has been reported with administration of fibrates and other lipid-lowering agents. The incidence of this disorder increases in cases of hypoalbuminaemia and previous renal insufficiency. Muscle toxicity should be suspected in patients presenting diffuse myalgia, myositis, muscular cramps and weakness and/or marked increases in CPK (levels exceeding 5 times the normal range). In such cases treatment with fenofibrate should be stopped.
Patients with pre-disposing factors for myopathy and/or rhabdomyolysis, including age above 70 years old, personal or familial history of hereditary muscular disorders, renal impairment, hypothyroidism and high alcohol intake, may be at an increased risk of developing rhabdomyolysis. For these patients, the putative benefits and risks of fenofibrate therapy should be carefully weighed up.
The risk of muscle toxicity may be increased if the drug is administered with another fibrate or an HMG-CoA reductase inhibitor, especially in cases of pre-existing muscular disease. Consequently, the co-prescription of fenofibrate with a statin should be reserved to patients with severe combined dyslipidaemia and high cardiovascular risk without any history of muscular disease.
This combination therapy should be used with caution and patients should be monitored closely for signs of muscle toxicity.
For hyperlipidaemic patients taking oestrogens or contraceptives containing oestrogens it should be ascertained whether the hyperlipidaemia is of primary or secondary nature (possible elevation of lipid values caused by oral oestrogens).
Renal function: Fenofibrate is contraindicated in severe renal impairment.
Fenofibrate should be used with caution in patients with mild to moderate renal insufficiency. Dose should be adjusted in patients whose estimated glomerular filtration rate is 30 to 59 mL/min/1.73 m². 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 therapy and tended to return to baseline following discontinuation of treatment.
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.
Creatine Kinase Measurement: Creatine Kinase (CK) should not be measured following strenuous exercise or in the presence of a plausible alternative cause of CK increase which may confound interpretation of the result. If CK levels are significantly elevated at baseline (>5xULN) a confirmatory test should be carried out within 5 - 7 days. If the repeat test confirms a baseline CK >5xULN, treatment should not be started.
Protease inhibitors: Increased systemic exposure to rosuvastatin has been observed in subjects receiving rosuvastatin concomitantly with various protease inhibitors in combination with ritonavir. Consideration should be given both to the benefit of lipid lowering by use of Rosuvastatin in HIV patients receiving protease inhibitors and the potential for increased rosuvastatin plasma concentrations when initiating and up titrating Rosuvastatin doses in patients treated with protease inhibitors. The concomitant use with certain protease inhibitors is not recommended unless the dose of Rosuvastatin is adjusted.
Interstitial lung disease: Exceptional cases of interstitial lung disease have been reported with some statins, especially with long-term therapy. 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, statin 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.
Effects on Ability to Drive and Use Machine: Studies determine the effect of Rosuvastatin and Fenofibrate combination on the ability to drive and use machines have not been conducted. However, when driving vehicles or operating machines, it should be taken into account that dizziness may occur during treatment.

Pregnancy: Rosuvastatin is contraindicated in pregnancy and lactation.
Women of child bearing potential should use appropriate contraceptive measures.
Since cholesterol and other products of cholesterol biosynthesis are essential for the development of the foetus, the potential risk from inhibition of HMG-CoA reductase outweighs the advantage of treatment during pregnancy. Animal studies provide limited evidence of reproductive toxicity. If a patient becomes pregnant during use of this product, treatment should be discontinued immediately.
There are no adequate data from the use of fenofibrate in pregnant women. Animal studies have not demonstrated any teratogenic effects. Embryotoxic effects have been shown at doses in the range of maternal toxicity. The potential risk for humans is unknown. Therefore, fenofibrate 160 mg tablets should only be used after a careful benefit/risk assessment.
Lactation: Rosuvastatin is excreted in the milk of rats. There are no data with respect to excretion in milk in humans.
There are no data on the excretion of fenofibrate and/or its metabolites into breast milk. Consequently, fenofibrate 160mg tablets should not be used in nursing mothers.

Rosuvastatin: The adverse reactions seen with Rosuvastatin are generally mild and transient. In controlled clinical trials, less than 4% of Rosuvastatin-treated patients were withdrawn due to adverse reactions.
Tabulated list of adverse reactions: Based on data from clinical studies and extensive post-marketing experience, the following table presents the adverse reaction profile for rosuvastatin. Adverse reactions listed as follows are classified according to frequency and system organ class (SOC).
The frequencies of adverse reactions are ranked according to the following convention: Common (≥/100 to <1/10); Uncommon (≥1/1,000 to <1/100); Rare (≥1/10,000 to <1/1000); Very rare (<1/10,000); Not known (cannot be estimated from the available data). (See table.)

Click on icon to see table/diagram/image

As with other HMG-CoA reductase inhibitors, the incidence of adverse drug reactions tends to be dose dependent.
Fenofibrate: The frequencies of adverse events are ranked according top the following: Very common (> 1/10), Common (> 1/100, < 1/10), Uncommon (> 1/1,000, < 1/100), Rare (>1/10,000, < 1/1,000), very rare (< 1/10,000) including isolated reports.
Gastrointestinal: Common: Digestive, gastric or intestinal disorders (abdominal pain, nausea, vomiting, diarrhoea, and flatulence) moderate in severity.
Uncommon: Pancreatitis.
Hepato-biliary disorders: Common: Moderately elevated levels of serum transaminases (see Precautions).
Uncommon: Development of gallstones.
Very rare: Episodes of hepatitis. When symptoms (e.g. jaundice, pruritus) indicative of hepatitis occur, laboratory tests are to be conducted for verification and fenofibrate discontinued, if applicable (see Precautions).
Cardiovascular system: Uncommon: Thromboembolism (pulmonary embolism, deep vein thrombosis).
Skin and subcutaneous tissue disorder: Uncommon: rashes, pruritus, urticaria or photosensitivity reactions.
Rare: alopecia.
Very rare: cutaneous photosensitivity with erythema, vesiculation or nodulation on parts of the skin expose to sunlight or artificial light (e.g. sunlamp) in individual cases (even after many months of uncomplicated use).
Musculoskeletal, connective tissue and bone disorders: Rare: diffuse myalgia, myositis, muscular cramps and weakness.
Not known: rhabdomyolysis.
Blood and lymphatic system disorders: Rare: decrease in haemoglobin and leukocytes.
Nervous system disorder: Rare: sexual asthenia.
Respiratory, thoracic and mediastinal disorders: Not known: interstitial pneumopathies.
Investigation: Uncommon: increases in serum creatinine and urea.

Oral Anticoagulants: If coumarin anticoagulants and Rosuvastatin / Fenofibrate are co-administered, the dosage of the anticoagulant should be reduced to maintain the prothrombin time/INR at the desired level to prevent bleeding complications. Frequent prothrombin time/INR determinations are advisable until it has been definitely determined that the prothrombin time/INR has stabilized.
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.
The benefits and risks of using Rosuvastatin / Fenofibrate with immunosuppressants and other potentially nephrotoxic agents should be carefully considered. Also, the risk of myopathy during treatment with statins is increased with concurrent administration of cyclosporine. Hence, caution should be exercised when co-administering Rosuvastatin / Fenofibrate with cyclosporine.
Cytochrome P450 enzymes: In vitro studies using human liver microsomes indicate that fenofibrate and fenofibric acid are not inhibitors of cytochrome (CYP) P450 isoforms CYP3A4, CYP2D6, CYP2E1, or CYP1A2. They are weak inhibitors of CYP2C19 and CYP2A6, and mild-to-moderate inhibitors of CYP2C9 at therapeutic concentrations.
Patients co-administered fenofibrate and CYP2C19, CYP2A6, and especially CYP2C9 metabolised drugs with a narrow therapeutic index should be carefully monitored and, if necessary, dose adjustment of these drugs is recommended.
Transporter protein inhibitors: Rosuvastatin is a substrate for certain transporter proteins including the hepatic uptake transporter OATP1B1 and efflux transporter BCRP. Concomitant administration of Rosuvastatin with medicinal products that are inhibitors of these transporter proteins may result in increased rosuvastatin plasma concentrations and an increased risk of myopathy.
Protease inhibitors: The concomitant use of Rosuvastatin and some protease inhibitor combinations may be considered after careful consideration of Rosuvastatin dose adjustments based on the expected increase in rosuvastatin exposure.
Vitamin K antagonists: As with other HMG-CoA reductase inhibitors, the initiation of treatment or dosage up-titration of Rosuvastatin in patients treated concomitantly with vitamin K antagonists (e.g. warfarin or another coumarin anticoagulant) may result in an increase in International Normalised Ratio (INR). Discontinuation or down-titration of Rosuvastatin may result in a decrease in INR. In such situations, appropriate monitoring of INR is desirable.
Oral contraceptive/hormone replacement therapy (HRT): Concomitant use of Rosuvastatin and an oral contraceptive resulted in an increase in ethinyl estradiol and norgestrel AUC of 26% and 34%, respectively. These increased plasma levels should be considered when selecting oral contraceptive doses. There is no pharmacokinetic data available in subjects taking concomitant Rosuvastatin and HRT and therefore a similar effect cannot be excluded. However, the combination has been extensively used in women in clinical trials and was well tolerated.
Other medicinal products: Digoxin: Based on data from specific interaction studies no clinically relevant interaction with digoxin is expected.
Fusidic Acid: Interaction studies with rosuvastatin and fusidic acid have not been conducted. The risk of myopathy including rhabdomyolysis may be increased by the concomitant administration of systemic fusidic acid with statins. The mechanism of this interaction (whether it is pharmacodynamic or pharmacokinetic, or both) is yet unknown. There have been reports of rhabdomyolysis (including some fatalities) in patients receiving this combination.
If treatment with systemic fusidic acid is necessary, Rosuvastatin treatment should be discontinued throughout the duration of the fusidic acid treatment.

Store at temperatures not exceeding 30°C.

Dyslipidaemic Agents

C10BA09 - rosuvastatin and fenofibrate ; Belongs to the class of HMG CoA reductase inhibitors in combination with other lipid modifying agents. Used in the treatment of hyperlipidemia.

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