Rosuvastatin and Fenofibrate Tablets 10mg/160mg (Rosutaj-F)

1. NAME OF THE MEDICINAL PRODUCT:

Rosuvastatin and Fenofibrate Tablets 5mg/160mg (Rosutaj-F)
Rosuvastatin and Fenofibrate Tablets 10mg/160mg (Rosutaj-F)

• QUALITATIVE AND QUANTITATIVE COMPOSITION:
• Each film-coated tablet contains:

Rosuvastatin Calcium IP

equivalent to Rosuvastatin                   5mg

Fenofibrate IP                                   160mg

Excipients                                               q.s.

Colours: Yellow Oxide of Iron,

Red Oxide of Iron & Titanium Dioxide IP

• Each film-coated tablet contains:

Rosuvastatin Calcium IP

equivalent to Rosuvastatin                   10mg

Fenofibrate IP                                    160mg

Excipients                                                q.s.

Colours: Quinoline Yellow WS,

Titanium Dioxide IP

• PHARMACEUTICAL FORM:

Film-Coated Tablet

Description:

Rosutaj-F is a fixed-dose combination of rosuvastatin and fenofibrate.

• CLINICAL PARTICULARS:
  • Therapeutic indications:

Mixed Dyslipidemia

ROSUTAJ-F is indicated as adjunctive therapy to diet to reduce elevated total-C, LDL-C,           ApoB, and triglycerides and to increase HDL-C in adult patients with mixed dyslipidemia    (Fredrickson Types II a and II b).

Hypercholesterolemia

ROSUTAJ-F is indicated as adjunctive therapy to diet to reduce elevated total-C, LDL-C,           ApoB, and to increase HDL-C in adult patients with primary hypercholesterolemia.

Hypertriglyceridemia

ROSUTAJ-F is indicated as adjunctive therapy to diet for the treatment of adult patients with hypertriglyceridemia (Fredrickson Types IV and V hyperlipidemia).

Lipid-altering agents should be used in addition to a diet restricted in saturated fat and cholesterol when the response to diet and non-pharmacological interventions alone has been inadequate. (see National Cholesterol Education Program Treatment Guidelines, summarized in Table 1 below).

Table 1: NCEP guidelines for lipid management

^*CHD = coronary heart disease

^**Almost all people with 0-1 risk factor have 10-year risk <10%; thus, 10-year risk assessment in people with 0-1 risk factor is not necessary.

After the LDL-C goal has been achieved, if the TG is still ?200 mg/dL, non-HDL-C (total-C minus HDL-C) becomes a secondary target of therapy. Non-HDL-C goals are set 30 mg/dL higher than LDL-C goals for each risk category.

• Dosage and administration:

Patients should be placed on an appropriate lipid-lowering diet before receiving ROSUTAJ-F and should continue this diet during treatment. The recommended dosage is one       tablet once daily

Dosing in Patients with Renal Impairment

Fenofibrate should be initiated at a lower dose in patients having mild to moderately impaired renal function and it should be avoided in patients with severe renal impairment. As ROSUTAJ-F contains 145 mg of fenofibrate, it should be avoided in all renal impairment patients.

Dosage in Asian Patients

In Asian patients, consider initiation of  ROSUTAJ-F therapy with 5mg once daily due to increased rosuvastatin plasma concentrations. The increased systemic exposure should be taken into consideration when treating Asian patients not adequately controlled at doses up to 20 mg/day.

Use with Concomitant Therapy

Patients taking Cyclosporine

The dose of ROSUTAJ-F should not exceed 5    mg once daily

Patients Taking Gemfibrozil

Initiate ROSUTAJ-F therapy with 5 mg once daily. The dose of ROSUTAJ-F should not exceed 10 mg once daily.

Patients Taking Lopinavir and Ritonavir or Atazanavir and Ritonavir

Initiate ROSUTAJ-F therapy with 5 mg once daily. The dose of ROSUTAJ-F should not exceed 10 mg once daily.

• Contraindications:

ROSUTAJ-F is contraindicated in

• Patients with a known hypersensitivity to any component of this product.      Hypersensitivity reactions, including rash, pruritus, urticaria and angioedema, have been reported with rosuvastatin
• Patients with active liver disease, which may include unexplained persistent elevations of hepatic transaminase levels and primary biliary cirrhosis
• Patients with severe renal dysfunction, including those receiving dialysis
• Patients with pre-existing gallbladder disease.
• Pregnancy
• Nursing mothers
  • Warnings and Precautions:

Skeletal muscle effects

Cases of myopathy and rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with HMG-CoA reductase inhibitors, including rosuvastatin. Fibrates increase the risk for myopathy and have been associated with rhabdomyolysis.

ROSUTAJ-F should be prescribed with caution in patients with predisposing factors for myopathy (e.g., age >65 years, inadequately treated hypothyroidism, renal impairment, diabetes).

The risk of myopathy during treatment with rosuvastatin may be increased with concurrent administration of some other lipid-lowering therapies (fibrates or niacin), gemfibrozil, cyclosporine, lopinavir/ritonavir or atazanavir/ritonavir. Cases of myopathy, including rhabdomyolysis, have been reported with HMG-CoA reductase inhibitors, including rosuvastatin, coadministered with colchicine, and caution should be exercised when prescribing ROSUTAJ-F with colchicine.

ROSUTAJ-F therapy should be discontinued if markedly elevated creatine kinase (CK) levels occur or myopathy is diagnosed or suspected. ROSUTAJ-F therapy should also be temporarily withheld 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, dehydration, major surgery, trauma, severe metabolic, endocrine, and electrolyte disorders, or uncontrolled seizures).

Patients should be advised to report promptly unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever. CK levels should be assessed in patients reporting these symptoms, and fenofibrate therapy should be discontinued if markedly elevated CK levels occur or myopathy/myositis is suspected or diagnosed.

There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use. IMNM is characterized by proximal muscle weakness and elevated serum CK, which persist despite discontinuation of statin treatment;        muscle biopsy showing necrotizing myopathy without significant inflammation; improvement with immunosuppressive agents.

Liver enzyme abnormalities

It is recommended that liver enzyme tests be performed before the initiation of ROSULIP-Therapy and if signs or symptoms of liver injury occur.

Increases in serum transaminases have been reported with HMG-CoA reductase inhibitors, including rosuvastatin as well as fenofibrate at doses equivalent to 96mg to 145 mg per day. In most cases with statins, the elevations were transient and resolved or improved on continued therapy or after a brief interruption in therapy. There were two cases of jaundice, for which a relationship to rosuvastatin therapy could not be determined, which resolved after discontinuation of therapy. There were no cases of liver failure or irreversible liver disease in these trials.

In a pooled analysis of placebo-controlled trials, increases in serum transaminases to >3 times the upper limit of normal occurred in 1.1% of patients taking rosuvastatin versus 0.5% of patients treated with placebo.

There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including rosuvastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with rosuvastatin, promptly interrupt therapy. If an alternate aetiology is not found, do not restart ROSULIP-F.

In a pooled analysis of 10 placebo-controlled trials, increases to >3 times the upper limit of normal occurred in 5.3% of patients taking fenofibrate versus 1.1% of patients treated with placebo.

When transaminase determinations were followed, either after discontinuation of treatment or during continued treatment, a return to normal limits was usually observed. The incidence of an increase in transaminases related to fenofibrate therapy appears to be dose-related. In an 8-week dose-ranging study, the incidence of ALT or AST elevations to at least 3 times the upper limit of normal was 13% in patients receiving dosages equivalent to 96 mg to 145 mg fenofibrate per day and was 0% in those receiving dosages equivalent to 48 mg or less fenofibrate per day, or placebo. 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 function, including serum ALT (SGPT), should be performed for the duration of therapy with fenofibrate, and therapy discontinued if enzyme levels persist above 3 times the normal limit.

ROSUTAJ-F should be used with caution in patients who consume substantial quantities of alcohol and/or have a history of chronic liver disease. Active liver disease, which may include unexplained persistent transaminase elevations, is a contraindication to the use of ROSULIP-F.

Venothromboembolic Disease

In the FIELD trial, pulmonary embolus (PE) and deep vein thrombosis (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).

In the Coronary Drug Project, a higher proportion of the clofibrate group experienced definite or suspected fatal or non-fatal pulmonary embolism or thrombophlebitis than the placebo group (5.2% vs. 3.3% at five years; p<0.01).

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 ROSUTAJ-F at risk for renal insufficiency such as the elderly and patients with diabetes. 

Endocrine effects 

Increases in glycated haemoglobin (HbA1c) and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including rosuvastatin. Based on clinical trial data with rosuvastatin, in some instances, these increases may exceed the threshold for the diagnosis of diabetes mellitus. Although clinical studies have shown that rosuvastatin alone does not reduce basal plasma cortisol concentration or impair adrenal reserve, caution should be exercised if ROSUTAJ-F is administered concomitantly with drugs that may decrease the levels or activity of endogenous steroid hormones such as ketoconazole, spironolactone, and cimetidine.

Proteinuria and Hematuria

In the rosuvastatin clinical trial program, dipstick-positive proteinuria and microscopic hematuria were observed among rosuvastatin treated patients. These findings were more frequent in patients taking rosuvastatin 40mg when compared to lower doses of rosuvastatin or comparator HMG-CoA reductase inhibitors, though it was generally transient and was not associated with worsening renal function.     Although the clinical significance of this finding is unknown, a dose reduction should be considered for patients on ROSUTAJ-F therapy with unexplained persistent proteinuria and/or hematuria during routine urinalysis testing.

Cholelithiasis

Fenofibrate, like clofibrate and gemfibrozil, may increase cholesterol excretion into the bile, leading to cholelithiasis. If cholelithiasis is suspected, gallbladder studies are indicated. ROSUTAJ-F therapy should be discontinued if gallstones are found.

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 haemoglobin, 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 blood cell counts is recommended during the first 12 months of ROSUTAJ-F administration.

Coumarin Anticoagulants

Caution should be exercised when coumarin anticoagulants are given in conjunction with ROSUTAJ-F because of the potentiation of coumarin-type anticoagulant effects in prolonging the prothrombin time (PT)/International Normalized Ratio (INR). To prevent bleeding complications frequent monitoring of PT/INR, and dose adjustment of the anticoagulant are recommended until PT/INR has stabilized. In patients taking coumarin anticoagulants and ROSULIP-Fconcomitantly, INR should be determined before starting ROSUTAJ-F and frequently enough during early therapy to ensure that no significant alteration of INR occurs.

Hypersensitivity reactions

Acute hypersensitivity reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis requiring patient hospitalization and treatment with steroids have been reported in individuals treated with fenofibrate. Urticaria was seen in 1.1 vs. 0%, and rash in 1.4 vs. 0.8% of fenofibrate and placebo patients, respectively, in controlled trials.

Paradoxical Decreases in HDL-C levels

There have been postmarketing and clinical trial reports of severe decreases in HDL-C 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 decreases 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 the withdrawal of fibrate therapy is rapid and sustained. The clinical significance of this decrease in HDL-C is unknown. It is recommended that HDL-C        levels be checked within the first few months after initiation of fibrate therapy. If a severely depressed HDL-C level is detected, ROSUTAJ-F therapy should be withdrawn, and the HDL-C level monitored until it has returned to baseline, and ROSUTAJ-F therapy should not be re-initiated.

Mortality and Coronary Heart Disease Morbidity

The effect of fenofibrate on coronary heart disease (CHD) morbidity and mortality and non-cardiovascular mortality has not been established.

The Action to Control Cardiovascular Risk in Diabetes Lipid (ACCORD Lipid) trial was a randomized placebo-controlled study of 5,518 patients with type 2 diabetes mellitus on background statin therapy treated with fenofibrate. The mean duration of follow-up was 4.7 years. Fenofibrate plus statin combination therapy showed a non-significant 8% relative risk reduction in the primary outcome of major adverse cardiovascular events (MACE), a composite of non-fatal myocardial infarction, non-fatal stroke, and cardiovascular disease death (hazard ratio: 0.92, 95% CI: 0.79-1.08) (p=0.32) as compared to statin monotherapy. In a gender subgroup analysis, the HR for MACE in men receiving combination therapy versus statin monotherapy was 0.82 (95% CI: 0.69-0.99), and therefore MACE in women receiving combination therapy versus statin monotherapy was 1.38 (95% CI: 0.98-1.94) (interaction           p=0.01). The clinical significance of this subgroup finding is unclear.

The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study was a 5-year randomized, placebo-controlled study of 9,795 patients with type 2 diabetes mellitus treated with fenofibrate. Fenofibrate         demonstrated a non-significant 11% relative reduction in the primary outcome of CHD events (HR: 0.89, 95% CI: 0.75-1.05, p=0.16) and a    significant 11% reduction in the secondary outcome of total cardiovascular disease events (HR: 0.89 , p= 0.04). There was a non-significant 11% (HR 1.11, p=0.18) and 19% (HR 1.19, p=0.22) increase in total and CHD mortality, respectively, with fenofibrate as compared to placebo.

Because of chemical, pharmacological, and clinical similarities between fenofibrate, clofibrate and gemfibrozil, the adverse findings in 4 large randomized, placebo-controlled clinical studies with these other fibrate drugs may also apply to fenofibrate.

In the Coronary Drug Project, a large study of post-myocardial infarction of patients treated for 5 years with clofibrate, there was no difference in mortality seen between the clofibrate group and the placebo group. There was, however, a difference in the rate of cholelithiasis and cholecystitis requiring surgery between the two groups (3.0% vs. 1.8%).

In a study conducted by the World Health          Organization (WHO), 5,000 subjects without known coronary artery disease were treated with placebo or clofibrate for 5 years and followed for an additional one year. There was a    statistically significant, higher age-adjusted all-cause mortality in the clofibrate group compared with the placebo group (5.70% vs 3.96%,         p=<0.01). Excess mortality was due to a 33% increase in non-cardiovascular causes, including malignancy, post-cholecystectomy complications, and pancreatitis. This appeared to confirm the higher risk of gallbladder disease seen in clofibrate-treated patients studied in the Coronary Drug Project.

The Helsinki Heart Study was a large (n=4,081) study of middle-aged men without a history of coronary artery disease. Subjects received either placebo or gemfibrozil for 5 years, with a 3.5-year open extension afterwards. Total mortality was numerically higher in the gemfibrozil randomization group but did not achieve statistical significance (p=0.19, 95% CI for relative risk G:P = 0.91-1.64). Although cancer deaths trended higher in the gemfibrozil group (p=0.11), cancers (excluding basal cell carcinoma) were diagnosed with equal frequency in both study groups. Due to the limited size of the study, the relative risk of death from any cause was not shown to be different than that seen in the 9-year follow-up data from the who study (RR=1.29).

A secondary prevention component of the Helsinki Heart Study enrolled middle-aged men excluded from the primary prevention study because of known or suspected CHD. Subjects received gemfibrozil or placebo for 5 years. Although cardiac deaths trended higher in the gemfibrozil group, this was not statistically significant (HR: 2.2, 95% CI: 0.94-5.05). The rate of gallbladder surgery was not statistically significant between study groups but did trend higher in the gemfibrozil group (1.9% vs 0.3%, p=0.07).

Renal impairment

Fenofibrate should be initiated at a lower dose in patients having mild to moderately impaired renal function and it should be avoided in patients with severe renal impairment.  As ROSUTAJ-F contains 145 mg of fenofibrate, it should be avoided in all renal impairment patients.

Hepatic impairment

Rosuvastatin is contraindicated in patients with active liver disease, which may include unexplained persistent elevations of hepatic transaminase levels. Chronic alcohol liver disease is known to increase rosuvastatin exposure; the use of fenofibrate is not evaluated in subjects with hepatic impairment.  ROSUTAJ-F should be used with caution in these patients.

• Drug Interactions:

Cyclosporine: Cyclosporine increased rosuvastatin exposure (AUC) 7-fold. Therefore, in patients taking cyclosporine, the dose of ROSUTAJ-F should not exceed 5 mg once daily.

Gemfibrozil: Gemfibrozil significantly increased rosuvastatin exposure. Due to an observed increased risk of myopathy/rhabdomyolysis, combination therapy with ROSUTAJ-F and gemfibrozil should be avoided. If used together, the dose of ROSUTAJ-F should not exceed 10 mg once daily

Protease Inhibitors: Co-administration of rosuvastatin with certain protease inhibitors given in combination with ritonavir has differing effects on rosuvastatin exposure. The protease inhibitor combinations lopinavir/ritonavir and atazanavir/ritonavir increase rosuvastatin exposure (AUC) up to threefold. For these combinations, the dose of ROSUTAJ-F should not exceed 10 mg once daily. The combinations of tipranavir/ritonavir or fosamprenavir/ritonavir produce little or no change in rosuvastatin exposure. Caution should be exercised when rosuvastatin is co-administered with protease inhibitors given in combination with ritonavir.

Coumarin Anticoagulants: Rosuvastatin and fenofibrate significantly increased INR in patients receiving coumarin anticoagulants. Therefore, caution should be exercised when coumarin anticoagulants are given in conjunction with ROSUTAJ-F. In patients taking coumarin anticoagulants and ROSUTAJ-F concomitantly, INR should be determined before starting ROSUTAJ-F and frequently enough during early therapy to ensure that no significant alteration of INR occurs. The dosage of the anticoagulants should be reduced to maintain the PT/INR at the desired level to prevent bleeding complications.

Niacin: The risk of skeletal muscle effects may be enhanced when rosuvastatin is used in combination with lipid-modifying doses (?1 g/day) of niacin; thus caution should be used when prescribing with ROSUTAJ-F.

Colchicine: Cases of myopathy, including rhabdomyolysis, have been reported with HMG-CoA reductase inhibitors, including rosuvastatin and fenofibrate, co-administered with colchicine, and caution should be exercised when prescribing ROSUTAJ-F with colchicine.

Immunosuppressants: Immunosuppressants such as cyclosporine and tacrolimus can produce nephrotoxicity with decreases in CL cr 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         ROSUTAJ-F 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 ROSUTAJ-F at least 1 hour before or 4 to 6 hours after a bile acid-binding resin to avoid impeding its absorption.

• Pregnancy, lactation and others:

Pregnancy

Teratogenic Effects: Category X

Rosuvastatin is contraindicated in women who are or may become pregnant. Serum cholesterol and triglycerides increase during normal pregnancy, and cholesterol products are essential for fetal development. Atherosclerosis is a           chronic process and discontinuation of lipid-lowering drugs during pregnancy should have little impact on long-term outcomes of primary hyperlipidemia therapy.

There are no adequate and well-controlled studies of rosuvastatin as well as fenofibrate in pregnant women. There have been rare reports of congenital anomalies following intrauterine exposure to HMG-CoA reductase inhibitors.

Safety of fenofibrate in pregnant women has not been established. Fenofibrate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

ROSUTAJ-F may cause fetal harm when administered to a pregnant woman. If the patient becomes pregnant while taking ROSUTAJ-F, the patient should be apprised of the potential risks to the fetus and the lack of known clinical benefit with continued use during pregnancy.

Lactation

It is not known whether rosuvastatin is excreted in human milk, but a small amount of another drug in this class does pass into breast milk. In rats, breast milk concentrations of rosuvastatin are three times higher than plasma levels; however, animal breast milk drug levels may not accurately reflect human breast milk levels. Because another drug in this class passes into human milk and because HMG-CoA reductase inhibitors have a potential to cause serious adverse reactions in nursing infants, women who require rosuvastatin treatment should be advised not to nurse their infants. Fenofibrate should not be used in nursing mothers.

ROSUTAJ-F should not be used in nursing mothers.

Paediatric Use

Safety and efficacy of ROSUTAJ-F in pediatric patients have not been established.

Geriatric Use

Of the 10,275 patients in clinical studies with rosuvastatin, 3,159 (31%) were 65 years and older, and 698 (6.8%) were 75 years and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Fenofibric acid is known to be substantially excreted by the kidneys, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Fenofibric acid exposure is not influenced by age. Since elderly patients have a higher incidence of renal impairment, dose selection for the elderly should be made on the basis of renal function. Elderly patients with normal renal function should require no dose modifications.

Elderly patients are at a greater risk of myopathy and ROSUTAJ-F should be prescribed with caution in the elderly.

• Undesirable effects:

Rosuvastatin

The following serious adverse reactions are discussed in greater detail in other sections of the label:

• Rhabdomyolysis with myoglobinuria and      acute renal failure and myopathy (including myositis)
• Liver enzymes abnormalities

In the rosuvastatin controlled clinical trials database (placebo or active-controlled) of 5,394 patients with a mean treatment duration of 15 weeks, 1.4% of patients discontinued due to adverse reactions. The most common adverse reactions that led to treatment discontinuation were:

• Myalgia
• Abdominal pain
• Nausea

The most commonly reported adverse reactions (incidence >2%) in the rosuvastatin controlled clinical trial database of 5,394 patients were:

• Headache
• Myalgia
• Abdominal pain
• Asthenia
• Nausea

Clinical Studies Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice.

Adverse reactions reported in >2% of patients in placebo-controlled clinical studies and at a rate greater than placebo are shown in Table 1. These studies had a treatment duration of up to 12 weeks.

Table 1: Adverse reactions* reported by >2% of patients treated with rosuvastatin and >placebo in placebo-controlled trials (% of patients)

* Adverse reactions by COSTART (Coding Symbols for a Thesaurus of Adverse Reaction Terms) preferred term

Other adverse reactions reported in clinical studies were abdominal pain, dizziness, hypersensitivity (including rash, pruritus, urticaria, and angioedema) and pancreatitis. The following laboratory abnormalities have also been reported: dipstick-positive proteinuria and microscopic hematuria; elevated CK,    transaminases, glucose, glutamyl transpeptidase, alkaline phosphatase, and bilirubin; and thyroid function abnormalities.

In the METEOR study, involving 981    participants treated with rosuvastatin 40 mg (n=700) or placebo (n=281) with a mean treatment duration of 1.7 years, 5.6% of subjects treated with rosuvastatin versus 2.8% of placebo-treated subjects discontinued due to adverse reactions. The most common adverse reactions that led to treatment discontinuation were: myalgia, hepatic enzyme increased,          headache, and nausea.

Adverse reactions reported in >2% of patients and at a rate greater than placebo are shown in Table 2.

Table 2: Adverse reactions * reported by >2% of patients treated with rosuvastatin and >placebo in the METEOR trial (% of patients)

* Adverse reactions by MedDRA (Medical Dictionary for regulatory Affairs) preferred term.

^?Frequency recorded as abnormal laboratory value.

In the JUPITER study, 17,802 participants have treated with rosuvastatin 20 mg (n=8,901) or placebo (n=8,901) for a mean duration of 2 years. A higher percentage of rosuvastatin-treated patients versus placebo-treated patients, 6.6% and 6.2%, respectively, discontinued study medication due to an adverse event, irrespective of treatment causality. Myalgia was the most common adverse reaction that led to treatment discontinuation.

In JUPITER, there was a significantly higher frequency of diabetes mellitus reported in patients taking rosuvastatin (2.8%) versus patients taking a placebo (2.3%). Mean HbA1c was significantly increased by 0.1% in rosuvastatin-treated patients compared to placebo-treated patients. The number of patients with an HbA1c >6.5% at the end of the trial was significantly higher in rosuvastatin-treated versus placebo-treated patients.

Adverse reactions reported in >2% of patients and at a rate greater than placebo are shown in Table 3.

Table 3: Adverse reactions * reported by >2% of patients treated with rosuvastatin and >placebo in the JUPITER trial (% of patients)

*Treatment-emergent adverse reactions by MedDRA preferred term

Pediatric Patients 10 to 17 Years of Age

In a 12-week controlled study in boys and postmenarchal girls, the safety and tolerability profile of rosuvastatin 5 to 20mg daily was generally similar to that of placebo.

However, elevations in serum CK>10 x ULN were observed more frequently in rosuvastatin compared with placebo-treated children. Four of 130 (3%) children treated with rosuvastatin (2 treated with 10 mg and 2 treated with 20 mg) had increased CK >10 x ULN, compared to 0 of 46 children on placebo.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of rosuvastatin: arthralgia, fatal and non-fatal hepatic failure, hepatitis, jaundice,        thrombocytopenia, depression, sleep disorders (including insomnia and nightmares), peripheral neuropathy and gynecomastia. Because these reactions are reported voluntarily from a          population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

There have been rare reports of immune-mediated necrotizing myopathy associated with statin use.

There have been rare postmarketing reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use. These cognitive issues have been reported for all statins. The reports are generally nonserious and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks).

Fenofibrate

Clinical Trials Experience

Because clinical studies are conducted under widely varying conditions, adverse reactions rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

Adverse events reported by 2% or more of patients treated with fenofibrate (and greater than placebo) during the double-blind, placebo-controlled trials, regardless of causality, are listed in Table 4 below. Adverse events led to discontinuation of treatment in 5.0% of patients treated with fenofibrate and in 3.0% treated with placebo. Increases in liver function tests were the most frequent events, causing discontinuation of fenofibrate treatment in 1.6% of patients in double-blind trials.

Table 4: Adverse Reactions Reported by 2% or More of Patients Treated with Fenofibrate ad Greater than Placebo During the Double-Blind, Placebo-Controlled Trials

* Dosage equivalent to 145 mg fenofibrate

** Significantly different from placebo

Postmarketing Experience

The following adverse reactions have been         identified during post-approval use of   fenofibrate: myalgia, rhabdomyolysis,           pancreatitis, acute renal failure, muscle spasm, hepatitis, cirrhosis, anemia, arthralgia, decreases in hemoglobin, decreases in hematocrit, white blood cell decrease, asthenia and severely  depressed HDL-C levels. Because these   reactions are reported voluntarily from a           population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• Overdosage:

There is no specific treatment in the event of overdose for ROSUTAJ-F.

General supportive care of the patient is indicated, including monitoring of vital signs and observation of clinical status, should an overdose occur. If indicated, elimination of unabsorbed drug should be achieved by emesis or gastric lavage; usual precautions should be observed to maintain the airway. Due to extensive drug binding to plasma proteins, hemodialysis should not be considered.

• PHARMACOLOGICAL PROPERTIES:
  • Pharmacodynamic properties:

Rosuvastatin

Rosuvastatin is a selective and competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme that converts HMG-CoA 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 low-density lipoprotein (LDL) receptors on the cell-surface to enhance uptake and catabolism of LDL. Second,          rosuvastatin inhibits hepatic synthesis of very-low-density lipoprotein (VLDL), which reduces the total number of VLDL and LDL particles.

Fenofibrate

The active moiety 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 peroxisome proliferator-activated receptor-alpha (PPAR-alpha). Through this mechanism, fenofibrate increases lipolysis and elimination of triglyceride (TG)-rich particles from plasma by activating lipoprotein lipase and reducing the 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 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 PPAR-alpha also induces an increase in the synthesis of apolipoproteins A-I, A-II and high-density lipoprotein cholesterol (HDL-C).

Fenofibrate also reduces serum uric acid levels in hyperuricemic and normal individuals by increasing the urinary excretion of uric acid.

A variety of clinical studies have demonstrated that elevated levels of total cholesterol (total-C), LDL cholesterol (LDL-C), and apolipoprotein B (apo B), an LDL membrane complex, are associated with human atherosclerosis. Similarly, decreased levels of HDL-C and its transport complex, apolipoprotein A (apo AI and apo AII) are associated with the development of atherosclerosis. Epidemiologic investigations have established that cardiovascular morbidity and mortality vary directly with the level of total-C, LDL-C, and TG, and inversely with the level of HDL-C. The independent effect of raising HDL-C or lowering TG on the risk of cardiovascular morbidity and mortality has not been determined.

Fenofibric acid, the active metabolite of fenofibrate, produces reductions in total-C,       LDL-C, apo B, total TG and TG rich lipoprotein (VLDL) in treated patients. In addition,        treatment with fenofibrate results in increases in HDL-C and apolipoproteins apoAI and apo A-II.

• Pharmacokinetic properties:

Absorption

In clinical pharmacology studies in man, peak plasma concentrations of rosuvastatin were reached 3 to 5 hours following oral dosing. Both peak concentration (C max) and area under the plasma concentration-time curve (AUC) increased in approximate proportion to rosuvastatin dose. The absolute bioavailability 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.

Plasma concentrations of fenofibric acid after administration of one 145 mg tablet are equivalent under fed conditions to one 200 mg micronized fenofibrate capsule. Fenofibrate is a pro-drug of the active chemical moiety fenofibric acid. Fenofibrate is converted by ester hydrolysis in the body of fenofibric acid, which is the active constituent measurable in the circulation. The absolute bioavailability of fenofibrate cannot be determined as the compound is virtually insoluble in aqueous media suitable for injection. However,           fenofibrate is well absorbed from the gastrointestinal tract. Following oral administration in healthy volunteers,     approximately 60% of a single dose of radiolabeled fenofibrate appeared in urine, primarily as fenofibric acid and its glucuronate conjugate, and 25% was excreted in the faeces. Peak plasma levels of fenofibric acid occur within 6 to 8    hours after administration. Exposure to fenofibric acid in plasma, as measured by C max and AUC, is not significantly different when a single 145 mg dose of fenofibrate is administered under fasting or nonfasting conditions.

Distribution

The mean volume of distribution at steady-state of rosuvastatin is approximately 134 litres. Rosuvastatin is 88% bound to plasma proteins, mostly albumin. This binding is reversible and independent of plasma concentrations.

Upon multiple dosing of fenofibrate, fenofibric acid steady state is achieved within 9 days. Plasma concentrations of fenofibric acid at steady state are approximately double of those following a single dose. Serum protein binding was approximately 99% in normal and hyperlipidemic subjects.

Metabolism

Rosuvastatin is not extensively metabolized; approximately 10% of a radiolabeled dose is recovered as a metabolite. The major metabolite is N-desmethyl rosuvastatin, which is formed principally by cytochrome (CY) 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.

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 the urine. A small amount of fenofibric acid is reduced at the carbonyl moiety to a benzhydryl metabolite which is, in turn, conjugated with glucuronic acid and excreted in the urine. In vivo metabolism data indicate that neither fenofibrate nor fenofibric acid undergoes oxidative metabolism (e.g., CYP450) to a  significant extent.

Excretion

Following oral administration, rosuvastatin and its metabolites are primarily excreted in the faeces (90%). The elimination half-life (t 1/2) 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.

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 faeces. Fenofibric acid is eliminated with a half-life of 20 hours, allowing once-daily dosing.

Special Population

Geriatric: There were no differences in plasma concentrations of rosuvastatin between the non-elderly and elderly populations (age >65 years).

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 with normal renal function,        without increasing accumulation of the drug or metabolites.

Pediatric: The pharmacokinetics of fenofibrate has not been studied in pediatric populations.

Gender: No pharmacokinetic difference between males and females has been observed for rosuvastatin or fenofibrate.

Renal Impairment: Mild to moderate renal impairment 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 (CL cr<30 mL/min/1.73 m 2) not receiving hemodialysis compared with healthy subjects (CL cr>80 mL/min/1.73 m 2).

The pharmacokinetics of fenofibric acid was examined in patients with mild, moderate, and severe renal impairment. Patients with severe renal impairment (estimated glomerular filtration rate <30 mL/min/1.73 m 2) showed a 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 (eGFR 30-59 mL/min/1.73 m 2) had similar exposure but an increase in the half-life for fenofibric acid compared to that of healthy subjects. Based on these findings, the use of ROSULIP-F should be avoided in patients who have severe renal impairment and dose reduction is required in patients having a mild-to-moderate renal impairment.

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 alcoholic liver disease, plasma concentrations of rosuvastatin were modestly increased. In patients with Child-Pugh A disease, C max and AUC were increased by 60% and 5%,      respectively, as compared with patients with normal liver function. In patients with Child-Pugh B disease, C max and AUC were increased 100% and 21%, respectively, compared with patients with normal liver function.

No pharmacokinetic studies have been conducted with fenofibrate in patients having hepatic insufficiency.

Race: A population pharmacokinetic analysis revealed no clinically relevant differences in pharmacokinetics among Caucasian, Hispanic and Black or Afro-Caribbean groups, However, pharmacokinetic studies have demonstrated an approximate 2-fold elevation in median exposure (AUC and C max) in Asian subjects when compared with a Caucasian control group.

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.

• PHARMACEUTICAL PARTICULARS:

• Incompatibilities:

None stated.

• Shelf life:

2 years

• Storage and handling instructions:

Store in a cool dry place. Protect from light.

• Packaging information:

ROSUTAJ-F5 Tablets: Strip of 10 tablets

ROSUTAJ-F10 Tablets: Strip of 10 tablets

• Special precautions for disposal and another handling:

N/A

7. Manufactured in India By:
TAJ LIFE SCIENCES PVT. LTD.
Unit No. 214, Old Bake House,
Bake House Lane, Fort,
Mumbai-400001
at: Ahmedabad- Gujarat, INDIA.
Ho.NO. +91 8448 444 095
Toll Free Phone: (1800-222-434 / 1800-222-825)