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For the Use Only of a Registered Medical Practitioners Or a Hospital Or a Laboratory

For the Use Only of a Registered Medical Practitioners Or a Hospital Or a Laboratory

For the use only of a Registered Medical Practitioners or a Hospital or a Laboratory

Rosuvastatin & Tablets Rosukem-FL

1. NAME OF THE MEDICINAL PRODUCT Rosukem-FL 5 (Rosuvastatin & Fenofibrate Tablets) Rosukem-FL 10 (Rosuvastatin & Fenofibrate Tablets)

2. QUALITATIVE AND QUANTITATIVE COMPOSITION: Rosukem-FL 5 Each film-coated contains: Rosuvastatin IP Equivalent to Rosuvastatin………………5 mg Fenofibrate IP (Micronised)………………67 mg Excipients………………………………………..q.s.

Rosukem-FL 10 Each film-coated tablet contains: Rosuvastatin Calcium IP Equivalent to Rosuvastatin………………10 mg Fenofibrate IP (Micronised)………………67 mg Excipients………………………………………..q.s.

3. PHARMACEUTICAL FORM Film-coated Tablets

4. CLINICAL PARTICULARS 4.1 Therapeutic Indications: For the treatment of in patients with normal hepatic and renal function.

4.2 Posology and Method of Administration Rosukem-FL is given orally once daily with or without food.

4.3 Contraindications: Rosuvastatin Rosuvastatin is contraindicated in the following conditions: - In patients with hypersensitivity to rosuvastatin or to any of the excipients. - in patients with active disease including unexplained, persistent elevations of serum transaminases and any serum transaminase elevation exceeding 3 x the upper limit of normal (ULN). - In patients with severe renal impairment (creatinine clearance <30 ml/min). - In patients with myopathy.

- In patients receiving concomitant . - During and lactation and in women of childbearing potential not using appropriate contraceptive measures. - Cyclosporine increased rosuvastatin exposure (AUC) 7 fold. Therefore, exceed than Rosuvastatin 5 mg once daily is contraindicated with Cyclosporine.

Fenofibrate Fenofibrate is contraindicated in patients with severe liver or renal dysfunction, gallbladder disease, biliary cirrhosis and in patients hypersensitive to fenofibrate or any component of this medication, known photoallergy or phototoxic reaction during treatment with or ketoprofen. Chronic or acute pancreatitis with the exception of acute pancreatitis due to severe . Use during pregnancy and lactation. This medicine contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.4 Special Warnings and Special Precautions for Use Rosuvastatin Renal Effects Proteinuria, detected by dipstick testing and mostly tubular in origin, has been observed in patients treated with higher doses of rosuvastatin, in particular 40 mg, where it was transient or intermittent in most cases. Proteinuria has not been shown to be predictive of acute or progressive renal disease (see Section 4.8). The reporting rate for serious renal events in post-marketing use is higher at the 40 mg dose. An assessment of renal function should be considered during routine follow-up of patients treated with a dose of 40 mg. Skeletal Muscle Effects Effects on skeletal muscle e.g. , myopathy and, rarely, have been reported in rosuvastatin- treated patients with all doses and in particular with doses > 20 mg. Very rare cases of rhabdomyolysis have been reported with the use of in combination with HMG-CoA reductase inhibitors. A pharmacodynamic interaction cannot be excluded (see Section 4.5) and caution should be exercised with their combined use. As with other HMG-CoA reductase inhibitors, the reporting rate for rhabdomyolysis associated with rosuvastatin in post-marketing use is higher at the 40 mg dose. 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. Before Treatment Rosuvastatin, as with other HMG-CoA reductase inhibitors, should be prescribed with caution in patients with pre- disposing factors for myopathy/rhabdomyolysis. Such factors include: • renal impairment • hypothyroidism • personal or family history of hereditary muscular disorders • previous history of muscular toxicity with another HMG-CoA reductase inhibitor or • alcohol abuse

• age >70 years • situations where an increase in plasma levels may occur (see Sections 4.2, 4.5 and 5.2) • concomitant use of fibrates. In such patients the risk of treatment should be considered in relation to possible benefit and clinical monitoring is recommended. If CK levels are significantly elevated at baseline (>5xULN) treatment should not be started. Whilst on Treatment Patients should be asked to report inexplicable muscle pain, weakness or cramps immediately, particularly if associated with malaise or . CK levels should be measured in these patients. Therapy should be discontinued if CK levels are markedly elevated (>5xULN) or if muscular symptoms are severe and cause daily discomfort (even if CK levels are ≤ 5x ULN). If symptoms resolve and CK levels return to normal, then consideration should be given to re-introducing rosuvastatin or an alternative HMG-CoA reductase inhibitor at the lowest dose with close monitoring. Routine monitoring of CK levels in asymptomatic patients is not warranted. There have been very rare reports of an immune-mediated necrotising myopathy (IMNM) during or after treatment with , including rosuvastatin. IMNM is clinically characterised by proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of treatment. In clinical trials there was no evidence of increased skeletal muscle effects in the small number of patients dosed with rosuvastatin and concomitant therapy. However, an increase in the incidence of myositis and myopathy has been seen in patients receiving other HMG-CoA reductase inhibitors together with fibric acid derivatives including , ciclosporin, nicotinic acid, azole antifungals, protease inhibitors and macrolide antibiotics. Gemfibrozil increases the risk of myopathy when given concomitantly with some HMG-CoA reductase inhibitors. Therefore, the combination of rosuvastatin and gemfibrozil is not recommended. The benefit of further alterations in lipid levels by the combined use of rosuvastatin with fibrates or should be carefully weighed against the potential risks of such combinations. The 40 mg dose is contraindicated with concomitant use of a fibrate (see Section 4.5 and Section 4.8). Combination with rosuvastatin and fusidic acid is not recommended. There have been reports of rhabdomyolysis (including some fatalities) in patients receiving this combination (see Section 4.5). Rosuvastatin should not be used in any patient with an acute, serious condition suggestive of myopathy or predisposing to the development of renal failure secondary to rhabdomyolysis (e.g. sepsis, hypotension, major surgery, trauma, severe metabolic, endocrine and electrolyte disorders; or uncontrolled seizures). Liver Effects As with other HMG-CoA reductase inhibitors, rosuvastatin should be used with caution in patients who consume excessive quantities of alcohol and/or have a history of liver disease. It is recommended that liver function tests be carried out prior to, and 3 months following, the initiation of treatment. Rosuvastatin should be discontinued or the dose reduced if the level of serum transaminases is greater than 3 times the upper limit of normal. The reporting rate for serious hepatic events (consisting mainly of increased hepatic transaminases) in post-marketing use is higher at the 40 mg dose. In patients with secondary hypercholesterolaemia caused by hypothyroidism or nephrotic syndrome, the underlying disease should be treated prior to initiating therapy with rosuvastatin. Race Pharmacokinetic studies show an increase in exposure in Asian subjects compared with Caucasians (see Section 4.2, Section 4.3 and Section 5.2). Protease inhibitors

Increased systemic exposure to rosuvastatin has been observed in subjects receiving rosuvastatin concomitantly with various protease inhibitors in combination with . 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 (see Sections 4.2 and 4.5). Interstitial lung disease Exceptional cases of interstitial lung disease have been reported with some statins, especially with long term therapy (see Section 4.8). Presenting features can include dyspnoea, non-productive and deterioration in general health (, weight loss and fever). If it is suspected a patient has developed interstitial lung disease, statin therapy should be discontinued. 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 , hypertension) should be monitored both clinically and biochemically according to national guidelines. In the JUPITER study, the reported overall frequency of diabetes mellitus was 2.8% in rosuvastatin and 2.3% in placebo, mostly in patients with fasting glucose 5.6 to 6.9 mmol/l. Paediatric population The evaluation of linear growth (height), weight, BMI (body mass index), and secondary characteristics of sexual maturation by Tanner staging in paediatric patients 6 to 17 years of age taking rosuvastatin is limited to a two- year period. After two years of study treatment, no effect on growth, weight, BMI or sexual maturation was detected (see Section 5.1). In a of children and adolescents receiving rosuvastatin for 52 weeks, CK elevations >10xULN and muscle symptoms following exercise or increased physical activity were observed more frequently compared to observations in clinical trials in adults.

Fenofibrate Mortality and Coronary Heart Disease Morbidity The effect of Fenofibrate on coronary heart disease morbidity and mortality and noncardiovascular mortality has not been established. Skeletal Muscle Fenofibrates increase the risk of myopathy and have been associated with rhabdomyolysis. The risk for serious muscle toxicity appears to be increased in elderly patients and in patients with diabetes, renal insufficiency, or hypothyroidism. Data from observational studies indicate that the risk for rhabdomyolysis is increased when fibrates, in particular gemfibrozil, are co-administered with an HMG-CoA reductase inhibitor (statin). The combination should be avoided unless the benefit of further alterations in lipid levels is likely to outweigh the increased risk of this drug combination. Myopathy should be considered in any patient with diffuse , muscle tenderness or weakness, and/or marked elevations of creatine phosphokinase (CPK) levels. Patients should be advised to report promptly unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever. CPK levels should be assessed in patients reporting these symptoms, and

Fenofibrate therapy should be discontinued if markedly elevated CPK levels occur or myopathy/myositis is suspected. Cases of myopathy, including rhabdomyolysis, have been reported with fenofibrates coadministered with , and caution should be exercised when prescribing fenofibrate with . Liver Function Fenofibrate can increase serum transaminases [AST (SGOT) or ALT (SGPT)]. Hepatocellular, chronic active and cholestatic hepatitis associated with fenofibrate therapy have been reported after exposures of weeks to several years. In extremely rare cases, cirrhosis has been reported in association with chronic active hepatitis. Baseline and regular periodic monitoring of liver tests, including serum ALT (SGPT) should be performed for the duration of Fenofibrate therapy and therapy should be discontinued if levels persist above three times the normal limit. Serum Creatinine Elevations in serum creatinine have been reported in patients on fenofibrate. These elevations tend to return to baseline following discontinuation of fenofibrate. The clinical significance of these observations is unknown. Monitor renal function in patients with renal impairment taking Fenofibrate. Renal monitoring should also be considered for patients taking Fenofibrate at risk for renal insufficiency such as the elderly and patients with diabetes. Cholelithiasis Fenofibrate, like and gemfibrozil, may increase into the bile, leading to cholelithiasis. If cholelithiasis is suspected, gallbladder studies are indicated. Fenofibrate therapy should be discontinued if gallstones are found. Coumarin Caution should be exercised when anticoagulants are given in conjunction with Fenofibrate because of the potentiation of coumarin-type anti-coagulant effects in prolonging the prothrombin time/International Normalized Ration (PT/INR). The dosage of the should be reduced to maintain the PT/INR at the desired level to prevent bleeding complications. Frequent PT/INR determinations are advisable until it has been definitely determined that the PT/INR has stabilized. Pancreatitis Pancreatitis has been reported in patients taking fenofibrate, gemfibrozil, and clofibrate. 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 with obstruction of the common bile duct. Hematologic Changes Mild to moderate hemoglobin, hematocrit, and white blood cell decreases have been observed in patients following initiation of fenofibrate therapy. However, these levels stabilize during long-term administration. Thrombocytopenia and agranulocytosis have been reported in individuals treated with fenofibrate. Periodic monitoring of red and white cell counts is recommended during the first 12 months of Fenofibrate administration. Hypersensitivity Reactions Acute hypersensitivity reactions such as Stevens - Johnson syndrome and toxic epidermal necrolysis requiring patient hospitalization and treatment with have been reported in individuals treated with fenofibrates. Urticaria was seen in 1.1 vs. 0%, and in 1.4 vs. 0.8% of fenofibrate and placebo patients respectively in controlled trials. Venothromboembolic Disease In the FIELD trial, pulmonary embolus (PE) and (DVT) were observed at higher rates in the fenofibrate- than the placebo-treated group. Of 9,795 patients enrolled in FIELD, there were 4,900 in the placebo group and 4,895 in the fenofibrate group. For DVT, there were 48 events (1%) in the placebo group and 67 (1%) in the fenofibrate group (p = 0.074); and for PE, there were 32 (0.7%) events in the placebo group and 53 (1%) in the fenofibrate group (p = 0.022). Paradoxical Decrease in HDL Cholesterol Levels There have been postmarketing and clinical trial reports of severe decreases in HDL cholesterol levels (as low as 2 mg/dL) occurring in diabetic and non-diabetic patients initiated on fibrate therapy. The decrease in HDL-C is mirrored by a decrease in apolipoprotein A1. This decrease has been reported to occur within 2 weeks to years after initiation of fibrate therapy. The HDL-C levels remain depressed until fibrate therapy has been withdrawn; the response to withdrawal of fibrate therapy is rapid and sustained. The clinical significance of this decrease in HDLC is unknown. It is recommended that the HDL-C levels be checked within the first few months after initiation of fibrate therapy. If a severely depressed HDL-C level is detected, fibrate therapy should be withdrawn, and the HDLC level monitored until it has returned to baseline, and fibrate therapy should not be re-initiated.

4.5 Interaction with Other Medicinal Products and Other Forms of Interaction Rosuvastatin Effect of co-administered medicinal products on rosuvastatin 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 (see Sections 4.2, 4.4 and 4.5 Table 1). Ciclosporin: During concomitant treatment with rosuvastatin and ciclosporin, rosuvastatin AUC values were on average 7 times higher than those observed in healthy volunteers (see Table 1). Rosuvastatin is contraindicated in patients receiving concomitant ciclosporin (see Section 4.3). Concomitant administration did not affect plasma concentrations of ciclosporin. Protease inhibitors: Although the exact mechanism of interaction is unknown, concomitant protease inhibitor use may strongly increase rosuvastatin exposure (see Table 1). For instance, in a pharmacokinetic study, co- administration of 10 mg rosuvastatin and a combination product of two protease inhibitors (300 mg / 100 mg ritonavir) in healthy volunteers was associated with an approximately three-fold and seven-fold increase in rosuvastatin AUC and Cmax respectively. 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 (see Sections 4.2, 4.4 and 4.5 Table 1). Gemfibrozil and other lipid-lowering products: Concomitant use of rosuvastatin and gemfibrozil resulted in a 2- fold increase in rosuvastatin C max and AUC (see Section 4.4). Based on data from specific interaction studies no pharmacokinetic relevant interaction with fenofibrate is expected, however a pharmacodynamic interaction may occur. Gemfibrozil, fenofibrate, other fibrates and lipid lowering doses (> or equal to 1g/day) of niacin (nicotinic acid) increase the risk of myopathy when given concomitantly with HMG-CoA reductase inhibitors, probably because they can produce myopathy when given alone. The 40 mg dose is contraindicated with concomitant use of a fibrate (see Sections 4.3 and 4.4). These patients should also start with the 5 mg dose. Ezetimibe: Concomitant use of 10 mg rosuvastatin and 10 mg ezetimibe resulted in a 1.2 fold increase in AUC of rosuvastatin in hypercholesterolaemic subjects (Table 1). A pharmacodynamic interaction, in terms of adverse effects, between rosuvastatin and ezetimibe cannot be ruled out (see Section 4.4).

Antacid: The simultaneous dosing of rosuvastatin with an antacid suspension containing aluminium and magnesium hydroxide resulted in a decrease in rosuvastatin plasma concentration of approximately 50%. This effect was mitigated when the antacid was dosed 2 hours after rosuvastatin. The clinical relevance of this interaction has not been studied. Erythromycin: Concomitant use of rosuvastatin and erythromycin resulted in a 20% decrease in AUC and a 30% decrease in Cmax of rosuvastatin. This interaction may be caused by the increase in gut motility caused by erythromycin. Cytochrome P450 : Results from in vitro and in vivo studies show that rosuvastatin is neither an inhibitor nor an inducer of cytochrome P450 isoenzymes. In addition, rosuvastatin is a poor substrate for these isoenzymes. Therefore, drug interactions resulting from cytochrome P450-mediated metabolism are not expected. No clinically relevant interactions have been observed between rosuvastatin and either fluconazole (an inhibitor of CYP2C9 and CYP3A4) or (an inhibitor of CYP2A6 and CYP3A4). Interactions requiring rosuvastatin dose adjustments (see also Table 1): When it is necessary to co-administer rosuvastatin with other medicinal products known to increase exposure to rosuvastatin, doses of rosuvastatin should be adjusted. Start with a 5 mg once daily dose of rosuvastatin if the expected increase in exposure (AUC) is approximately 2-fold or higher. The maximum daily dose of rosuvastatin should be adjusted so that the expected rosuvastatin exposure would not likely exceed that of a 40 mg daily dose of rosuvastatin taken without interacting medicinal products, for example a 20 mg dose of rosuvastatin with gemfibrozil (1.9-fold increase), and a 10 mg dose of rosuvastatin with combination ritonavir/atazanavir (3.1-fold increase). Table 1 Effect of co-administered medicinal products on rosuvastatin exposure (AUC; in order of decreasing magnitude) from published clinical trials Interacting drug dose regimen Rosuvastatin dose regimen Change in rosuvastatin AUC* Ciclosporin 75 mg BID to 200 mg BID, 6 months 10 mg OD, 10 days 7.1-fold ↑ Atazanavir 300 mg/ritonavir 100 mg OD, 8 days 10 mg, single dose 3.1-fold ↑ 150 mg OD, 7 days 10 mg, single dose 2.8-fold ↑ Lopinavir 400 mg/ritonavir 100 mg BID, 17 days 20 mg OD, 7 days 2.1-fold ↑ Clopidogrel 300 mg loading, followed by 75 mg at 24 20 mg, single dose 2-fold ↑ hours Gemfibrozil 600 mg BID, 7 days 80 mg, single dose 1.9-fold ↑ Eltrombopag 75 mg OD, 5 days 10 mg, single dose 1.6-fold ↑ Darunavir 600 mg/ritonavir 100 mg BID, 7 days 10 mg OD, 7 days 1.5-fold ↑ Tipranavir 500 mg/ritonavir 200 mg BID, 11 days 10 mg, single dose 1.4-fold ↑ Dronedarone 400 mg BID Not available 1.4-fold ↑ Itraconazole 200 mg OD, 5 days 10 mg, single dose **1.4-fold ↑ Ezetimibe 10 mg OD, 14 days 10 mg, OD, 14 days **1.2-fold ↑ Fosamprenavir 700 mg/ritonavir 100 mg BID, 8 days 10 mg, single dose ↔ Aleglitazar 0.3 mg, 7 days 40 mg, 7 days ↔ Silymarin 140 mg TID, 5 days 10 mg, single dose ↔

Fenofibrate 67 mg TID, 7 days 10 mg, 7 days ↔ Rifampin 450 mg OD, 7 days 20 mg, single dose ↔ Ketoconazole 200 mg BID, 7 days 80 mg, single dose ↔ Fluconazole 200 mg OD, 11 days 80 mg, single dose ↔ Erythromycin 500 mg QID, 7 days 80 mg, single dose 20% ↓ Baicalin 50 mg TID, 14 days 20 mg, single dose 47% ↓ *Data given as x-fold change represent a simple ratio between co-administration and rosuvastatin alone. Data given as % change represent % difference relative to rosuvastatin alone. Increase is indicated as “↑“, no change as “↔”, decrease as “↓”. **Several interaction studies have been performed at different rosuvastatin dosages, the table shows the most significant ratio OD = once daily; BID = twice daily; TID = three times daily; QID = four times daily Effect of rosuvastatin on co-administered medicinal products 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. 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 are 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. As with other statins, muscle related events, including rhabdomyolysis, have been reported in post-marketing experience with rosuvastatin and fusidic acid given concurrently. Therefore, the combination rosuvastatin and fusidic acid is not recommended. If possible, temporary suspension of rosuvastatin treatment is recommended. If unavoidable, patients should be closely monitored. Paediatric population: Interaction studies have only been performed in adults. The extent of interactions in the paediatric population is not known.

Fenofibrate Drug-Drug Interactions: 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 CYP2C8, CYP2C19 and CYP2A6, and mild-to-moderate inhibitors of CYP2C9 at therapeutic concentrations. Coumarin Anticoagulants

Potentiation of coumarin-type anticoagulant effects has been observed with prolongation of the PT/INR. Caution should be exercised when coumarin anticoagulants are given in conjunction with Fenofibrate. The dosage of the anticoagulants should be reduced to maintain the PT/INR at the desired level to prevent bleeding complications. Frequent PT/INR determinations are advisable until it has been definitely determined that the PT/INR has stabilized. Immunosuppressants Immunosuppressants such as cyclosporine and tacrolimus 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 of renal function. The benefits and risks of using Fenofibrate with immunosuppressants and other potentially nephrotoxic agents should be carefully considered, and the lowest effective dose employed and renal function monitored. Bile-Acid Binding Resins Since bile acid binding resins may bind other drugs given concurrently, patients should take Fenofibrate at least 1 hour before or 4 to 6 hours after a bile acid binding resin to avoid impeding its absorption. Colchicine Cases of myopathy, including rhabdomyolysis, have been reported with fenofibrates coadministered with colchicine, and caution should be exercised when prescribing fenofibrate with colchicine.

4.6 Fertility, Pregnancy and Lactation: Rosuvastatin 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. Rosuvastatin is excreted in the milk of rats. There are no data with respect to excretion in milk in humans.

Fenofibrate 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 (see section 5.3). The potential risk for humans is unknown. There are no data on the excretion of fenofibrate and/or its metabolites into breast milk. It is therefore recommended that Fenofibrate should not be administered to women who are pregnant or are breast feeding.

4.7 Effects on Ability to Drive and Use Machines Rosuvastatin Studies to determine the effect of rosuvastatin on the ability to drive and use machines have not been conducted. However, based on its pharmacodynamic properties, rosuvastatin is unlikely to affect this ability. When driving vehicles or operating machines, it should be taken into account that may occur during treatment. Fenofibrate No effect noted to date.

4.8 Undesirable Effects 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 below are classified according to frequency and system organ class (SOC). The frequencies of adverse reactions are ranked according to the following convention: Common (≥1/100 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). Table 2. Adverse reactions based on data from clinical studies and post-marketing experience System organ class Common Uncommon Rare Very rare Not known Blood and lymphatic Thrombocytopenia system disorders Immune system Hypersensitivity disorders reactions including angioedema Endocrine disorders Diabetes mellitus1 Psychiatric disorders Depression Nervous system Headache Polyneuropathy Peripheral disorders Dizziness Memory loss neuropathy Sleep disturbances (including and nightmares) Respiratory, thoracic Cough and mediastinal Dyspnoea disorders Gastro-intestinal Pancreatitis Diarrhoea disorders Abdominal pain Hepatobiliary Increased hepatic disorders transaminases Hepatitis Skin and subcutaneous Pruritis Stevens- tissue disorders Rash Johnson Urticaria syndrome

Musculo-skeletal and Myalgia Myopathy (including Arthralgia Tendon connective tissue myositis) disorders, disorders Rhabdomyolysis sometimes complicated by rupture Immune- mediated necrotising myopathy Renal and urinary Haematuria disorders Reproductive system Gynaecomastia and breast disorders General disorders and Asthenia Oedema administration site conditions 1 Frequency will depend on the presence or absence of risk factors (fasting blood glucose ≥ 5.6 mmol/L, BMI >30 kg/m2, raised triglycerides, history of hypertension). As with other HMG-CoA reductase inhibitors, the incidence of adverse drug reactions tends to be dose dependent. Renal effects: Proteinuria, detected by dipstick testing and mostly tubular in origin, has been observed in patients treated with rosuvastatin. Shifts in protein from none or trace to ++ or more were seen in <1% of patients at some time during treatment with 10 and 20 mg, and in approximately 3% of patients treated with 40 mg. A minor increase in shift from none or trace to + was observed with the 20 mg dose. In most cases, proteinuria decreases or disappears spontaneously on continued therapy. Review of data from clinical trials and post- marketing experience to date has not identified a causal association between proteinuria and acute or progressive renal disease. Haematuria has been observed in patients treated with rosuvastatin and clinical trial data show that the occurrence is low. Skeletal muscle effects: Effects on skeletal muscle e.g. myalgia, myopathy (including myositis) and, rarely, rhabdomyolysis with and without acute renal failure have been reported in rosuvastatin-treated patients with all doses and in particular with doses > 20 mg. A dose-related increase in CK levels has been observed in patients taking rosuvastatin; the majority of cases were mild, asymptomatic and transient. If CK levels are elevated (>5xULN), treatment should be discontinued (see Section 4.4). Liver effects: As with other HMG-CoA reductase inhibitors, a dose-related increase in transaminases has been observed in a small number of patients taking rosuvastatin; the majority of cases were mild, asymptomatic and transient. The following adverse events have been reported with some statins: Sexual dysfunction. Exceptional cases of interstitial lung disease, especially with long term therapy (see Section 4.4). The reporting rates for rhabdomyolysis, serious renal events and serious hepatic events (consisting mainly of increased hepatic transaminases) is higher at the 40 mg dose.

Paediatric population: Creatine kinase elevations >10xULN and muscle symptoms following exercise or increased physical activity were observed more frequently in a 52-week clinical trial of children and adolescents compared to adults (see Section 4.4). In other respects, the safety profile of rosuvastatin was similar in children and adolescents compared to adults.

Fenofibrate The adverse drug reactions are stated in the table below using the following convention: 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. Blood and lymphatic system Rare: disorders Decrease in haemoglobin and leukocytes Nervous system disorders Common: Headache Rare: Peripheral neuropathy Ear and labyrinth disorders Common: Vertigo Vascular disorders Uncommon: Thromboembolism (pulmonary embolism, deep vein thrombosis)* Respiratory, thoracic and Very rare: mediastinal disorders Interstitial pneumopathies Gastrointestinal disorders Common: Digestive, gastric or intestinal disorders (abdominal pain, nausea, vomiting, diarrhoea, and flatulence) Uncommon: Pancreatitis* Hepato-biliary disorders Uncommon: Elevated levels of serum transaminases (see section 4.4) Very rare: hepatitis (see section 4.4), gallstones Skin and subcutaneous Common: tissue disorders Reactions such as , pruritus, urticaria or photosensitivity reactions; cutaneous photosensitivity may occur with erythema, vesiculation or nodulation on parts of the skin exposed to sunlight or artificial UV light (e.g. sun lamp) Rare: Alopecia Musculoskeletal, connective Uncommon: tissue and bone disorders muscle toxicity (diffuse myalgia, myositis, muscular cramps and weakness) (see section 4.4) Very rare: Rhabdomyolysis. (see section 4.4)

Renal and urinal disorders Rare: Increases in serum creatinine and urea General disorders and Common: administration site Fatigue conditions Rare: Sexual asthenia * In the FIELD-study, a randomized 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 same 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 thromboses (placebo: 1.0 % [48/4900 patients] versus fenofibrate 1.4% [67/4895 patients]; p = 0.074).

4.9 Overdose 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. Haemodialysis is unlikely to be of benefit.

Fenofibrate No case of overdosage has been reported. No specific antidote is known. If overdose is suspected, treat symptomatically and institute appropriate supportive measures as required. Fenofibrate cannot be eliminated by haemodialysis.

5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic Properties: Mechanism of Action Rosuvastatin Rosuvastatin is a selective and competitive inhibitor of HMG-CoA reductase, the ratelimiting enzyme that converts 3-hydroxy-3-methylglutaryl coenzyme A to mevalonate, a precursor of cholesterol. In vivo studies in animals, and in vitro studies in cultured animal and human cells have shown rosuvastatin to have a high uptake into, and selectivity for, action in the liver, the target organ for cholesterol lowering. In in vivo and in vitro studies, rosuvastatin produces its lipid-modifying effects in two ways. First, it increases the number of hepatic LDL receptors on the cell-surface to enhance uptake and catabolism of LDL. Second, rosuvastatin inhibits hepatic synthesis of VLDL, which reduces the total number of VLDL and LDL particles.

Fenofibrate The active moiety of Fenofibrate is fenofibric acid. The pharmacological effects of fenofibric acid in both animals and humans have been extensively studied through oral administration of fenofibrate. The lipid-modifying 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 perxisome proliferators activated receptor α (PPARα). Through this mechanism, fenofibrate increases lipolysis and elimination of -rich particles from plasma by activating lipoprotein lipase and reducing production of apoprotein C-III (an inhibitor of lipoprotein lipase activity). The resulting decrease in TG produces an alteration in the size and composition of LDL from small, dense particles (which are thought to be artherogenic 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 PPARα also induces an increase in the synthesis of apoproteins A-I, A-II and HDL-cholesterol. Fenofibrate also reduces serum uric acid levels in hyperuricemic and normal individuals by increasing the urinary excretion of uric acid. Fenofibric acid, the active metabolite of fenofibrate, produces reductions in total cholesterol, LDL cholesterol, apolipoprotein B, total triglycerides and triglyceride rich lipoprotein (VLDL) in treated patients. In addition, treatment with fenofibrate results in increases in high density lipoprotein (HDL) and apoproteins apo AI and apo AII.

5.2 Pharmacokinetic Properties Rosuvastatin Absorption: In clinical pharmacology studies in man, peak plasma concentrations of rosuvastatin were reached 3 to 5 hours following oral dosing. Both Cmax and AUC increased in approximate proportion to Rosuvastatin dose. The absolute of rosuvastatin is approximately 20%. Administration of Rosuvastatin with food did not affect the AUC of rosuvastatin. The AUC of rosuvastatin does not differ following evening or morning drug administration. Distribution: Mean volume of distribution at steady-state of rosuvastatin is approximately 134 liters. Rosuvastatin is 88% bound to plasma proteins, mostly albumin. This binding is reversible and independent of plasma concentrations. Metabolism: Rosuvastatin is not extensively metabolized; approximately 10% of a radiolabeled dose is recovered as metabolite. The major metabolite is N-desmethyl rosuvastatin, which is formed principally by cytochrome P450 2C9, and in vitro studies have demonstrated that N-desmethyl rosuvastatin has approximately one-sixth to one- half the HMG-CoA reductase inhibitory activity of the parent compound. Overall, greater than 90% of active plasma HMG-CoA reductase inhibitory activity is accounted for by the parent compound. Excretion: Following oral administration, rosuvastatin and its metabolites are primarily excreted in the (90%). The elimination half-life (t1/2) of rosuvastatin is approximately 19 hours. After an intravenous dose, approximately 28% of total body clearance was via the renal route, and 72% by the hepatic route. Race: A population pharmacokinetic analysis revealed no clinically relevant differences in among Caucasian, Hispanic, and Black or Afro-Caribbean groups However, pharmacokinetic studies, including one reported in the US, have demonstrated an approximate 2-fold elevation in median exposure (AUC and Cmax) in Asian subjects when compared with a Caucasian control group. Gender: There were no differences in plasma concentrations of rosuvastatin between men and women. Geriatric: There were no differences in plasma concentrations of rosuvastatin between the nonelderly and elderly populations (age ≥ 65 years). Renal Impairment: Mild to moderate renal impairment (CLcr ≥ 30 mL/min/1.73 m 2 ) had no influence on plasma concentrations of rosuvastatin. However, plasma concentrations of rosuvastatin increased to a clinically significant extent (about 3-fold) in patients with severe renal impairment (CLcr < 30 mL/min/1.73 m 2 ) not receiving hemodialysis compared with healthy subjects (CLcr > 80 mL/min/1.73 m 2 ). Hemodialysis: Steady-state plasma concentrations of rosuvastatin in patients on chronic hemodialysis were approximately 50% greater compared with healthy volunteer subjects with normal renal function.

Hepatic Impairment: In patients with chronic alcohol liver disease, plasma concentrations of rosuvastatin were modestly increased. In patients with Child-Pugh A disease, Cmax and AUC were increased by 60% and 5%, respectively, as compared with patients with normal liver function. In patients with Child-Pugh B disease, Cmax and AUC were increased 100% and 21%, respectively, compared with patients with normal liver function.

Fenofibrate Fenofibrate is a pro-drug of the active chemical moiety fenofibric acid. Fenofibrate is converted by ester hydrolysis in the body to fenofibric acid which is the active constituent measurable in the circulation. Absorption: The absolute bioavailability of fenofibrate cannot be determined as the compound is virtually insoluble in aqueous media suitable for injection. Fenofibrate is insoluble in water and its bioavailability is optimized when taken with meals. However, after fenofibrate is dissolved, fenofibrate is well absorbed from the . Following oral administration in healthy volunteers, approximately 60% of a single dose of radiolabelled fenofibrate appeared in urine, primarily as fenofibric acid and its glucuronate conjugate, and 25% was excreted in the feces. Peak plasma levels of fenofibric acid occur an average of 3 hours after administration. The extent of absorption of Fenofibrate (AUC) is comparable between fed and fasted conditions. Food increases the rate of absorption of Fenofibrate approximately 55%. Distribution: In healthy volunteers, steady-state plasma levels of fenofibric acid were shown to be achieved within a week of dosing and did not demonstrate accumulation across time following multiple dose administration. Serum protein binding was approximately 99% in normal and hyperlipidemic subjects. Metabolism: Following oral administration, fenofibrate is rapidly hydrolyzed by esterases to the active metabolite, fenofibric acid; no unchanged fenofibrate is detected in plasma. Fenofibric acid is primarily conjugated with glucuronic acid and then excreted in urine. A small amount of fenofibric acid is reduced at the carbonyl moiety to a benzhydrol metabolite which is, in turn, conjugated with glucuronic acid and excreted in urine. In vivo metabolism data indicate that neither fenofibrate nor fenofibric acid undergo oxidative metabolism (e.g., cytochrome P450) to a significant extent. Elimination: After absorption, fenofibrate is mainly excreted in the urine in the form of metabolites, primarily fenofibric acid and fenofibric acid glucuronide. After administration of radiolabelled fenofibrate, approximately 60% of the dose appeared in the urine and 25% was excreted in the feces. Fenofibric acid is eliminated with a half- life of approximately 16 hours, allowing once daily dosing. Geriatrics: In elderly volunteers 77 to 87 years of age, the oral clearance of fenofibric acid following a single oral dose of fenofibrate was 1.2 L/h, which compares to 1.1 L/h in young adults. This indicates that a similar dosage regimen can be used in the elderly, without increasing accumulation of the drug or metabolites. Gender: No pharmacokinetic difference between males and females has been observed for fenofibrate. Race: The influence of race on the pharmacokinetics of fenofibrate has not been studied; however, fenofibrate is not metabolized by enzymes known for exhibiting inter-ethnic variability. Renal Impairment: The pharmacokinetics of fenofibric acid was examined in patients with mild, moderate, and severe renal impairment. Patients with severe renal impairment (creatinine clearance [CrCl ≤ 30 mL/min] < 30 mL/min or estimated glomerular filtration rate [eGFR] less than 30 mL/min/1.73m2) showed 2.7-fold increase in exposure for fenofibric acid and increased accumulation of fenofibric acid during chronic dosing compared to that of healthy subjects. Patients with mild to moderate renal impairment (CrCl 30-80 mL/min or eGFR 30-59 mL/min/1.73m2 ) had similar exposure but an increase in the halflife for fenofibric acid compared to that of healthy subjects. Based on these findings, the use of Fenofibrate should be avoided in patients who have severe renal impairment and dose reduction is required in patients having mild to moderate renal impairment

Hepatic Impairment: No pharmacokinetic studies have been conducted in patients having hepatic impairment.

Pharmacogenomics Rosuvastatin Disposition of HMG-CoA reductase inhibitors, including rosuvastatin, involves OATP1B1 and other transporter proteins. Higher plasma concentrations of rosuvastatin have been reported in very small groups of patients (n=3 to 5) who have two reduced function alleles of the gene that encodes OATP1B1 (SLCO1B1 521T>C). The frequency of this genotype (i.e., SLCO1B1 521 C/C) is generally lower than 5% in most racial/ethnic groups. The impact of this polymorphism on efficacy and/or safety of rosuvastatin has not been clearly established. Doses should be titrated according to patient response and tolerability.

5.3 Preclinical safety data Rosuvastatin Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, genotoxicity and carcinogenicity potential. Specific tests for effects on hERG have not been evaluated. Adverse reactions not observed in clinical studies, but seen in animals at exposure levels similar to clinical exposure levels were as follows: In repeated-dose toxicity studies histopathologic liver changes likely due to the pharmacologic action of rosuvastatin were observed in mouse, rat, and to a lesser extent with effects in the gall bladder in dogs, but not in monkeys. In addition, testicular toxicity was observed in monkeys and dogs at higher dosages. Reproductive toxicity was evident in rats, with reduced litter sizes, litter weight and pup survival observed at maternally toxic doses, where systemic exposures were several times above the therapeutic exposure level. Fenofibrate Chronic toxicity studies have yielded no relevant information about specific toxicity of fenofibrate. Studies on mutagenicity of fenofibrate have been negative. In rats and mice, liver tumours have been found at high dosages, which are attributable to peroxisome proliferation. These changes are specific to small rodents and have not been observed in other animal species. This is of no relevance to therapeutic use in man. Studies in mice, rats and rabbits did not reveal any teratogenic effect. Embryotoxic effects were observed at doses in the range of maternal toxicity. Prolongation of the gestation period and difficulties during delivery were observed at high doses. No sign of any effect on fertility has been detected.

6. PHARMACEUTICAL PARTICULARS 6.1 Shelf-life 24 months 6.2 Special Precautions for Storage Store in a cool and dry place. Protect from light. Keep out of reach of children. 6.3 Nature and Contents of Container 3 X 10 tablets

7. MARKETED BY Alkem Laboratories Ltd. Alkem House,

Senapati Bapat Marg, Lower Parel, Mumbai- 400 013.

8. DATE OF PREPARATION/REVISION OF THE TEXT 28/02/2016

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