Rosufit CV

Dosage in Special Population

PREGNANCY There are no adequate and well-controlled studies in pregnant women. Hence the therapy should not be used in women who are pregnant, trying to become pregnant or suspect they are pregnant. LACTATION Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the nursing woman.

Indications

Rosufit CV is indicated for the treatment of atherothrombotic complications

Contraindications

The use of the combination of Clopidogrel and Rosuvastatin tablet is contraindicated in the following conditions: Hypersensitivity to the drug substance or any component of the product. Active pathological bleeding such as peptic ulcer or intracranial hemorrhage. Active liver disease or unexplained persistent elevations of serum transaminases

Adverse Effects

Rosuvastatin The most frequent adverse events thought to be related to rosuvastatin were myalgia, constipation, asthenia, abdominal pain, and nausea. Clopidogrel Bleeding, including life-threatening and fatal bleeding, is the most commonly reported adverse reaction with clopidogrel

Drug Interactions

Clopidogrel: Oral anticoagulants: The concomitant administration of clopidogrel with oral anticoagulants is not recommended since it may increase the intensity of bleedings Glycoprotein IIb/IIIa inhibitors: clopidogrel should be used with caution in patients who may be at risk of increased bleeding from trauma, surgery or other pathological conditions that receive concomitant glycoprotein IIb/IIIa inhibitors . Acetylsalicylic acid (ASA): A pharmacodynamic interaction between clopidogrel and acetylsalicylic acid is possible, leading to increased risk of bleeding. Therefore, concomitant use should be undertaken with caution. However, clopidogrel and ASA have been administered together for up to one year. Heparin: A pharmacodynamic interaction between clopidogrel and heparin is possible, leading to increased risk of bleeding. Therefore, concomitant use should be undertaken Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): NSAIDs including Cox-2 inhibitors and clopidogrel should be co-administered with caution 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

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. Clopidogrel Clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to its platelet receptor, and the subsequent ADP-mediated activation of the GPIIb/IIIa complex, thereby inhibiting platelet aggregation. Biotransformation of clopidogrel is necessary to produce inhibition of platelet aggregation. Clopidogrel also inhibits platelet aggregation induced by other agonists by blocking the amplification of platelet activation by released ADP. Clopidogrel acts by irreversibly modifying the platelet ADP receptor

Pharmacokinetics

The half life of Rosuvastatin in Rosufit CV is 19 hours; half life of Clopidogrel in Rosufit CV is 8 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. Clopidogrel: Pregnancy: As no clinical data on exposure to clopidogrel during pregnancy are available, it is preferable not to use clopidogrel during pregnancy as a precautionary measure. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development. Breast Feeding: It is unknown whether clopidogrel is excreted in human breast milk. Animal studies have shown excretion of clopidogrel in breast milk. As a precautionary measure, breastfeeding should not be continued during treatment with Clopidogrel

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 Clopidogrel:Therapeutic experience is limited in patients with renal impairment. Use with caution

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 Clopidogrel: Therapeutic experience is limited in patients with moderate hepatic disease who may have bleeding diatheses. Use with caution

Drug Use in Pediatric Population

Pediatric Use 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. Clopidogrel: Clopidogrel should not be used in children because of efficacy concerns

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. Clopidogrel: No need to adjust the dose in elderly patients