Rosutor A Capsule

Indications

Rosutor A Capsule is indicated for the treatment of atherothrombotic complications

Adverse Effects

Rosuvastatin The most frequent adverse events thought to be related to rosuvastatin were myalgia, constipation, asthenia, abdominal pain, and nausea.

Drug Interactions

Rosuvastatin:Cytochrome P450 3A4: In vitro and in vivo data indicate that rosuvastatin clearance is not dependent on metabolism by cytochrome P450 3A4 to a clinically significant extent. This has been confirmed in studies with known cytochrome P450 3A4 inhibitors (ketoconazole, erythromycin, itraconazole); Ketoconazole: Coadministration of ketoconazole (200 mg twice daily for 7 days) with rosuvastatin (80 mg) resulted in no change in plasma concentrations of rosuvastatin Antacid: Coadministration of an antacid (aluminum and magnesium hydroxide combination) with rosuvastatin (40 mg) resulted in a decrease in plasma concentrations of rosuvastatin by 54%. However, when the antacid was given 2 hours after rosuvastatin, there were no clinically significant changes in plasma concentrations of rosuvastatin Warfarin: Coadministration of warfarin (20 mg) with rosuvastatin (40 mg) did not change warfarin plasma concentrations but increased the International Normalized Ratio (INR) Itraconazole: Itraconazole (200 mg once daily for 5 days) resulted in a 39% and 28% increase in AUC of rosuvastatin after 10 mg and 80 mg dosing, respectively. These increases are not considered clinically significant. Fluconazole: Coadministration of fluconazole (200 mg once daily for 11 days) with rosuvastatin (80 mg) resulted in a 14% increase in AUC of rosuvastatin. This increase is not considered clinically significant. Cyclosporine: Coadministration of cyclosporine with rosuvastatin resulted in no significant changes in cyclosporine plasma concentrations. However, Cmax and AUC of rosuvastatin increased 11- and 7-fold, respectively, compared with historical data in healthy subjects. These increases are considered to be clinically significant Aspirin: The combined drugs, methotrexate and acetylsalicylic acid, enhance haematological toxicity of methotrexate due to the decreased renal clearance of methotrexate by acetylsalicylic acid. Therefore, the concomitant use of methotrexate (at doses >15 mg/week) with Aspirin Tablets is contraindicated; Not recommended with Uricosuric agents, e.g. probenecid, sulfinpyrazone; Combinations requiring precautions for use or to be taken into account like: Anticoagulants and thrombolytics e.g. coumarin, heparin, warfarin, alteplase; Increased risk of bleeding due to inhibited thrombocyte function, injury of the duodenal mucosa and displacement of oral anticoagulants from their plasma protein binding sites. The bleeding time should be monitored. Particularly, treatment with acetylsalicylic acid should not be initiated within the first 24 hours after treatment with alteplase in acute stroke patients. Concomitant use is therefore not recommended. Anti-platelet agents (e.g. clopidogrel, ticlopidine, cilostazol and and dipyridamole) and selective serotonin reuptake inhibitors (SSRIs; such as sertraline or paroxetine). Antidiabetics, e.g. sulfonylureas and insulin: Salicylics may increase the hypoglycaemic effect of antidiabetics. Thus, some downward readjustment of the dosage of the antidiabetic may be appropriate if large doses of salicylates are used. Increased blood glucose controls are recommended. Diuretics and antihypertensives: NSAIDs may decrease the antihypertensive effects of diuretics and other antihypertensive agents. Blood pressure should be well monitored. Concomitant administration with ACE-inhibitors, angiotensin II receptor antagonists and calciumchannel blocker increases the risk of acute renal insufficiency in combination with high-dose ASA. Diuretics: Risk of acute renal failure due to the decreased glomerual filtration via decreased renal prostaglandin synthesis. Hydrating the patient and monitoring renal function at the start of the treatment is recommended. In case of association with verapamil the bleeding time should be monitored. The combined drugs, methotrexate and acetylsalicylic acid, may increase haematological toxicity of methotrexate due to decreased renal clearance of methotrexate by acetylsalicylic acid. Weekly blood count checks should be done during the first weeks of the combination. Enhanced monitoring should take place in the presence of even mildly impaired renal function, as well, as in elderly.

Mechanism of Action

Rosuvastatin: Rosuvastatin is a selective and competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts 3-hydroxy-3-methylglutaryl coenzyme A to mevalonate, a precursor for cholesterol. The primary site of action of rosuvastatin is the liver, the target organ for cholesterol lowering. Rosuvastatin increases the number of hepatic LDL receptors on the cell-surface, enhancing uptake and catabolism of LDL and it inhibits the hepatic synthesis of VLDL, thereby reducing the total number of VLDL and LDL particles. Aspirin inhibits platelet aggregation 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: Acetylsalicylic acid inhibits the platelet activation: blocking the platelet cyclooxygenase by acetylation, it inhibits thromboxane A2 synthesis, a physiological activating substance released by the platelets and which would play a role in the complications of the atheromatosic lesions. Inhibition of TXA2-synthesis is irreversible, because thrombocytes, which have no nucleus, are not capable (due to lack of protein synthesis capability) to synthesise new cyclooxygenase, which had been acetylated by acetylsalicylic acid. The repeated doses from 20 to 325 mg involve an inhibition of the enzymatic activity from 30 to 95%. Due to the irreversible nature of the binding, the effect persists for the lifespan of a thrombocyte (7-10 days). The inhibiting effect does not exhaust during prolonged treatments and the enzymatic activity gradually begins again upon renewal of the platelets 24 to 48 hours after treatment interruption.

Pharmacokinetics

The half life of Rosuvastatin in Rosutor A is 19 hours; half life of Aspirin in Rosutor A is 2-3 hours

Drug Use in Pregnancy

Rosuvastatin: Pregnancy Category X. 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. Breast Feeding: Rosuvastatin is excreted in the milk of rats. There are no data with respect to excretion in milk in humans. Aspirin: Pregnancy Low doses (up to 100 mg/day): Clinical studies indicate that doses up to 100 mg/day for restricted obstetrical use, which require specialised monitoring, appear safe. Doses of 100 mg/day and higher is contraindicated during the third trimester of pregnancy. Breast feeding:Low quantities of salicylates and of their metabolites are excreted into the breast milk. Since adverse effects for the infant have not been reported up to now, short-term use of the recommended dose does not require suspending lactation. In cases of long-term use and/or administration of higher doses, breastfeeding should be discontinued

Drug Use in Renal Impairment

Rosuvastatin: No modification of dosage is necessary for patients with mild to moderate renal insufficiency. For patients with severe renal impairment (CLcr <30 mL/min/1.73 m2) not on hemodialysis, dosing of Rosuvastatin should be started at 5 mg once daily and not to exceed 10 mg once daily Aspirin :Contraindicated

Drug Use in Hepatic Impairment

Hepatic Impairment: Rosuvastatin is contraindicated in patients with active liver disease or with unexplained persistent elevations of serum transaminases 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 Aspirin :Contraindicated

Drug Use in Pediatric Population

Rosuvastatin: The safety and effectiveness in pediatric patients have not been established. Treatment experience with rosuvastatin in a pediatric population is limited to 8 patients with homozygous FH. None of these patients was below 8 years of age. Aspirin: Paediatric population Acetylsalicylic acid should not be administered to children and adolescents younger than 16 years, except on medical advice where the benefit outweighs the risk.

Drug Use in Geriatric Population

Rosuvastatin: 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. The overall frequency of adverse events and types of adverse events were similar in patients above and below 65 years of age. Aspirin : Elderly In general, acetylsalicylic acids should be used with caution in elderly patients who are more prone to adverse events. The usual adult dose is recommended in the absence of severe renal or hepatic insufficiency.Treatment should be reviewed at regular intervals.