Each capsule contains:
Rosuvastatin (as calcium)… 10mg
Each capsule contains:
Rosuvastatin (as calcium)… 20mg
Rosuvastatin is a selective and competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts 3-hydroxy-3-methylglutaryl coenzyme A to mevalonate, a precursor of cholesterol. The primary site of action is the liver, the target organ for cholesterol lowering. 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, it inhibits hepatic synthesis of VLDL, which reduces the total number of VLDL and LDL particles.
Rosuvastatin reduces elevated LDL-cholesterol, total cholesterol and triglycerides and increases HDL-cholesterol. It also lowers ApoB, nonHDL-C, VLDL-C, VLDL-TG and increases ApoA-I. Rosuvastatin also lowers the LDL-C/HDL-C, total C/HDL-C and nonHDL-C/HDL-C and the ApoB/ApoA-I ratios.
Aspirin has antiplatelet, analgesic, antipyretic and anti-inflammatory properties.
Experimental data suggest that ibuprofen may inhibit the effect of low dose Aspirin on platelet aggregation when they are dosed concomitantly. In one study, when a single dose of ibuprofen 400mg was taken within 8 hours before or within 30 minutes after immediate release Aspirin (81mg), a decreased effect of Aspirin on the formation of thromboxane or platelet aggregation occurred. However, the limitations of these data and the uncertainties regarding extrapolation of ex vivo data to the clinical situation imply that no firm conclusions can be made for regular ibuprofen use, and no clinically relevant effect is considered to be likely for occasional ibuprofen use.
Rosuvastatin and Fenofibrate combination is indicated for correction of dyslipidemia and antiplatelet therapy.
Rosuvastatin is contraindicated in the following:
Patients with hypersensitivity to Rosuvastatin or to any of the excipients
Patients with active liver disease including unexplained, persistent elevations of serum transaminases and any serum transaminase elevation exceeding three times the upper limit of normal (ULN).
Patients with severe renal impairment (creatinine clearance <30mL/minute)
Patients with myopathy
Patients with receiving concomitant cyclosporine
During pregnancy and lactation and in women of childbearing potential not using appropriate contraceptive measures
Aspirin is contraindicated in patients with active or history of peptic ulceration, hemophilia and other bleeding disorders, hypersensitivity to Aspirin.
The recommended dosage of Rosuvastatin and Fenofibrate combination is one capsule once daily. Or as prescribed by the physician.
WARNINGS AND PRECAUTION
Renal: Proteinuria, detected by dipstick testing and mostly tubular in origin, has been observed in patients treated with higher doses of Rosuvastatin, in particular 40mg, where it was transient or intermittent in most cases. Proteinuria has not been shown to be predictive of acute or progressive renal disease. The reporting rate for serious renal events in post-marketing use is higher at the 40mg dose. An assessment of renal function should be considered during routine follow-up of patients treated with a dose of 40mg.
Skeletal muscle: Effects on skeletal muscle e.g. myalgia, myopathy and rarely, rhabdomyolysis have been reported in Rosuvastatin-treated patients with all doses and in particular with doses >20mg. Very rare cases of rhabdomyolysis have been reported with the use of ezetimibe in combination with HMG-CoA reductase inhibitors. A pharmacodynamic interaction cannot be excluded 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 40mg dose.
Creatinine Kinase Measurement: Creatinine 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 fibrate, alcohol abuse, age >70 years, situations where an increase in plasma levels may occur, and 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.
During treatment: Patients should be asked to report inexplicable muscle pain, weakness or cramps immediately, particularly if associated with malaise or fever. 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.
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 gemfibrozil, 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 niacin should be carefully weighed against the potential risks of such combinations. The 40mg dose is contraindicated with concomitant use of a fibrate.
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: 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 three months following the initiation of treatment. Rosuvastatin should be discontinued or the dose reduced if the level of serum transaminases is greater than three 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 40mg dose.
In patients with secondary hypercholesterolemia 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.
Protease Inhibitors: The concomitant use with protease inhibitors is not recommended.
Lactose Intolerance: Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Interstitial Lung Disease: Exceptional cases of interstitial lung disease have been reported with some statins, especially with long term therapy. Presenting features can include dyspnea, non-productive cough and deterioration in general health (fatigue, weight loss and fever). If it is suspected a patient has developed interstitial lung disease, statin therapy should be discontinued.
Diabetes Mellitus: In patients with fasting glucose 5.6 to 6.9 mmol/L treatment with Rosuvastatin has been associated with an increased risk of diabetes mellitus.
Pediatric Population: The evaluation of linear growth (height), weight, BMI (body mass index), and secondary characteristics of sexual maturation by Tanner staging in pediatric patients 10 to 17 years of age taking Rosuvastatin is limited to a one-year period. After 52 weeks of study treatment, no effect on growth, weight, BMI or sexual maturation was detected. The clinical trial experience in children and adolescent patients is limited and the long-term effects of Rosuvastatin (>1 year) on puberty are unknown.
In a clinical trial 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.
Aspirin may induce gastrointestinal hemorrhage, occasionally major. Patients with hypertension should be carefully monitored.
There is a possible association between Aspirin and Reyes’ syndrome when given to children. Reyes’ syndrome is a very rare disease, which affects the brain and liver, and can be fatal. For this reason Aspirin should not be given to children aged under 16 years unless specifically indicated (e.g. Kawasaki’s disease).
Cyclosporine: During concomitant treatment with Rosuvastatin and cyclosporine, Rosuvastatin AUC values were on average 7 times higher than those observed in healthy volunteers. Concomitant administration did not affect plasma concentration of ciclosporin.
Vitamin K antagonists: As with other HMG-CoA reductase inhibitors, the initiation of treatment or dosage up-titration of Rosuvastatin in patients treated concomitantly with vitamin K antagonists (e.g. warfarin or another coumarin anticoagulant) may result in an increase in International Normalized Ratio (INR). Discontinuation or drown-titration of Rosuvastatin may result in a decrease in INR. In such situations, appropriate monitoring of INR is desirable.
Ezetimibe: Concomitant use of Rosuvastatin and ezetimibe resulted in no change to AUC or Cmax for either drug. However, a pharmacodynamic interaction, in terms of adverse effects, between Rosuvastatin and ezetimibe cannot be ruled out.
Gemfibrozil and other lipid-lowering products: Concomitant use of Rosuvastatin and gemfibrozil resulted in a 2-fold increase in Rosuvastatin Cmax and AUC.
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 40mg dose is contraindicated with concomitant use of a fibrate. These patients should also start with the 5mg dose.
Protease Inhibitors: Although the exact mechanism of interaction is unknown, concomitant protease inhibitor use may strongly increase Rosuvastatin exposure. In a pharmacokinetic study, co-administration of 20mg Rosuvastatin and a combination product of two protease inhibitors (400mg lopinavir/ 100mg ritonavir) in healthy volunteers was associated with an approximately two-fold and five-fold increase in Rosuvastatin steady-state AUC (0-24) and Cmax respectively. Therefore, concomitant use of Rosuvastatin in HIV patients receiving protease inhibitors is not recommended.
Antacid: The simultaneous dosing of Rosuvastatin with an antacid suspension containing aluminum 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 (0-t) and a 30% decrease in Cmax of Rosuvastatin. This interaction may be caused by the increase in gut motility caused by erythromycin.
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: Based on data from specific interaction studies no clinically relevant interaction with digoxin is expected.
Cytochrome P450 enzymes: 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. No clinically relevant interactions has been observed between Rosuvastatin and either fluconazole (an inhibitor of CYP2C9 and CYP3A4) or ketoconazole (an inhibitor of CYP2A6 and CYP3A4). Concomitant administration of itraconazole (an inhibitor of CYP3A4) and Rosuvastatin resulted in a 28% increase in AUC of Rosuvastatin. This small increase is not considered clinically significant. Therefore, drug interactions resulting from cytochrome P450-mediated metabolism are not expected.
Aspirin may enhance the effects of anticoagulants and may inhibit the action of uricosurics. Experimental data suggest that ibuprofen may inhibit the effect of low dose Aspirin on platelet aggregation when they are dosed concomitantly. However, the limitations of these data and the uncertainties regarding extrapolation of ex-vivo data to the clinical situation imply that no firm conclusions can be made for regular ibuprofen use and no clinically relevant effect is considered to be likely for occasional ibuprofen use.
PREGNANCY AND LACTATION
Rosuvastatin and Aspirin combination is contraindicated in pregnant women and nursing mothers.
EFFECTS ON ABILITY TO DRIVE AND USE MACHINE
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 not be taken into account that dizziness may occur during treatment.
No known effect of Aspirin on the ability to drive and use machines.
The adverse events seen with Rosuvastatin are generally mild and transient. In controlled clinical trials, less than 4% of Rosuvastatin-treated patients were drawn due to adverse events.
The frequencies of adverse events are ranked according to the following: Common (>1/100, <1/10); Uncommon (>1/1,000, <1/100); Rare (>1/10,000, <1/1000); Very rare (<1/10,000); Not known (cannot be estimated from the available data).
Immune system disorders
Rare: hypersensitivity reactions including angioedema
Common: diabetes mellitus
Nervous system disorders
Common: headache, dizziness
Common: constipation, nausea, abdominal pain
Skin and subcutaneous tissue disorders
Uncommon: pruritus, rash and urticaria
Musculoskeletal, connective tissue and bone disorders
Rare: myopathy (including myositis) and rhabdomyolysis
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 urine protein from none or trace to ++ or more were seen in <1% of patients at some time during treatment with 10 and 20mg, and in approximately 3% of patients treated with 40mg. A minor increase in shift from none or trace to + was observed with the 20mg 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.
Hematuria 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 >20mg.
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.
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.
Aspirin may enhance the effects of anticoagulants and may inhibit the action of uricosurics. Aspirin may precipitate bronchospasm and may induce attacks of asthma in susceptible subjects. Hypersensitivity reactions have been reported in susceptible individuals.
There is no specific treatment in the event of overdose. In the event of overdose, the patient should be treated symptomatically and supportive measures instituted as required. Liver function and CK levels should be monitored. Hemodialysis is unlikely to be of benefit.
Overdosage is unlikely due to the low level of Aspirin in Angettes. If necessary gastric lavage, forced alkaline dieresis and supportive therapy may be employed. Restoration of acid/base balance may be required.
Foods, Drugs, Devices and Cosmetics Act prohibits dispensing without prescription.
STORE AT TEMPERATURES NOT EXCEEDING 300C.
Aspirin / Rosuvastatin (as calcium) 80mg/10mg Capsule (Rosuprin): alu-alu blister pack x 10’s (box of 30’s)
Aspirin / Rosuvastatin (as calcium) 80mg/20mg Capsule (Rosuprin): alu-alu blister pack x 10’s (box of 30’s)