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ROSULIP GOLD Capsules (Rosuvastatin calcium + Clopidogrel + Aspirin)
Undesirable Effects
Incompatibility
Cardiovascular disease (CVD) is the number one cause of death globally, responsible for at least one-third of all deaths in individuals over 35 years. According to a recent study in India, CVD was found to cause more than 2·1 million deaths in a year and the number of CV deaths were found to increase by more than two-folds from 2000. Atherothrombosis is a complex condition which begins with atherosclerosis. Atherosclerosis is thickening or narrowing of blood vessel wall due to formation of plaque because of dyslipidemia.
Atherothrombosis is caused by sudden, unpredictable disruption (rupture or erosion) of atherosclerotic plaque, leading to platelet activation and thrombus (blood clot) formation.
Atherothrombosis leads to partial or complete blockage of the affected blood vessel and subsequently can lead to occurrence of ischemic events in the arteries of the brain, heart, kidneys, legs and arms. Thus, atherothrombosis is the underlying condition causing coronary artery disease (CAD), cerebrovascular disease, peripheral artery disease (PAD), and CV death.
Rosulip, aspirin, clopidogrel has been approved for the treatment of acute coronary syndrome (ACS); angina, myocardial infarction; and for treatment of stroke. Statin, aspirin and clopidogrel has clinical efficacy studies and is all recommended by various international guidelines in management of acute coronary syndrome and stroke. The combination of rosuvastatin, aspirin and clopidogrel is generally well tolerated. The most common clinical adverse effects in patients treated with this combination are headache, myalgia, asthenia, myopathy, abdominal pain, nausea, constipation, increased risk of bleeding. Other adverse events could be rhabdomyolysis, abnormal increase in liver enzymes, paraesthesia, rhinitis, tinnitus, urticaria.
Cipla has launched rosuvastatin, aspirin and clopidogrel under the brand name of ROSULIP GOLD which is available as fixed dose combination composed of rosuvastatin 10 mg, clopidogrel 75 mg and aspirin 75 mg; rosuvastatin 20 mg, clopidogrel 75 mg and aspirin 75 mg in dosage form capsules. Launching ROSULIP GOLD is Cipla's initiative towards specifically addressing the unmet medical need for the treatment of acute coronary syndrome (ACS) and stroke.
DIMINISHED ANTIPLATELET EFFECT IN PATIENTS WITH TWO LOSS-OF-FUNCTION ALLELES OF THE CYP2C19 GENE
The effectiveness of clopidogrel results from its antiplatelet activity, which is dependent on its conversion to an active metabolite by the cytochrome P450 (CYP) system, principally CYP2C19. Clopidogrel at recommended doses forms less of the active metabolite and so has a reduced effect on platelet activity in patients who are homozygous for nonfunctional alleles of the CYP2C19 gene, (termed "CYP2C19 poor metabolizers"). Tests are available to identify patients who are CYP2C19 poor metabolizers. Consider use of another platelet P2Y12 inhibitor in patients identified as CYP2C19 poor metabolizers.
ROSULIP GOLD 10
Each hard gelatin capsule contains:
Rosuvastatin Calcium equivalent to Rosuvastatin (As pellets) …… 10 mg
Clopidogrel Bisulphate IP equivalent to Clopidogrel (As pellets) ….…… 75 mg
Aspirin IP (As enteric coated pellets) ……75 mg
ROSULIP GOLD Capsules are a fixed-dose combination of rosuvastatin, aspirin and clopidogrel.
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.
Rosuvastatin reduces elevated LDL-cholesterol (LDL-C), total cholesterol (total C) and triglycerides (TG) and increases high density lipoprotein cholesterol (HDL-C). It also lowers apolipoprotein (Apo) B, non-HDL-C, VLDL-cholesterol, VLDL-TG and increases ApoA-1. Rosuvastatin also lowers the LDL-C/HDL-C, total C/HDL-C and non-HDL-C/HDL-C and the ApoB/ApoA-1 ratios.
Aspirin is a more potent inhibitor of both prostaglandin synthesis and aggregation than other salicylic acid derivatives. The differences in activity between aspirin and salicylic acid are thought to be due to the acetyl group on the aspirin molecule. This acetyl group is responsible for the inactivation of cyclo-oxygenase via acetylation.
Aspirin affects platelet aggregation by irreversibly inhibiting prostaglandin cyclo-oxygenase. This effect lasts for the life of the platelet and prevents the formation of the platelet-aggregating factor thromboxane A2. Non-acetylated salicylates do not inhibit this enzyme and have no effect on platelet aggregation. At somewhat higher doses, aspirin reversibly inhibits the formation of prostaglandin I2 (prostacyclin), which is an arterial vasodilator and inhibits platelet aggregation.
At higher doses, aspirin is an effective anti-inflammatory agent, partially due to inhibition of inflammatory mediators via cyclo-oxygenase inhibition in peripheral tissues. In vitro studies suggest that other mediators of inflammation may also be suppressed by aspirin administration, although the precise mechanism of action has not been elucidated. It is this non-specific suppression of cyclo-oxygenase activity in peripheral tissues following large doses that leads to its primary side effect of gastric irritation.
Clopidogrel is a thienopyridine class inhibitor of P2Y12 adenosine diphosphate (ADP) platelet receptors. It is an inhibitor of platelet activation and aggregation through the irreversible binding of its active metabolite to the P2Y12 class of ADP receptors on platelets.
Clopidogrel must be metabolized by cytochrome P (CYP) 450 enzymes to produce the active metabolite that inhibits platelet aggregation. The active metabolite of clopidogrel selectively inhibits the binding of ADP to its platelet P2Y12 receptor and the subsequent ADP-mediated activation of the glycoprotein (GP) IIb/IIIa complex, thereby inhibiting platelet aggregation. This action is irreversible. Consequently, platelets exposed to clopidogrel's active metabolite are affected for the remainder of their lifespan (about 7 to 10 days). Platelet aggregation induced by agonists other than ADP is also inhibited by blocking the amplification of platelet activation by released ADP.
Because the active metabolite is formed by CYP450 enzymes, some of which are polymorphic or subject to inhibition by other medicinal products, not all patients will have adequate platelet inhibition.
Dose-dependent inhibition of platelet aggregation can be seen 2 hours after single oral doses of clopidogrel. Repeated doses of 75 mg clopidogrel per day inhibit ADP-induced platelet aggregation on the first day, and inhibition reaches steady state between Day 3 and Day 7. At steady state, the average inhibition level observed with a dose of 75 mg clopidogrel per day was between 40% and 60%. Platelet aggregation and bleeding time gradually return to baseline values after treatment is discontinued, generally in about 5 days.
In clinical pharmacology studies in man, peak plasma concentrations of rosuvastatin were reached 3 to 5 hours following oral dosing. Both peak concentration (Cmax) 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.
Enteric-coated aspirin products are erratically absorbed from the GI tract. Hydrolysis to salicylic acid occurs in the intestine and in the circulation. The rate of absorption from the GI tract is dependent upon the dosage form, the presence or absence of food, gastric pH (the presence or absence of GI antacids or buffering agents) and other physiologic factors.
After single and repeated oral doses of 75 mg per day, clopidogrel is rapidly absorbed. Absorption is at least 50%, based on urinary excretion of clopidogrel metabolites.
In a study in healthy male subjects when clopidogrel 75 mg per day was given with a standard breakfast, mean inhibition of ADP-induced platelet aggregation was reduced by less than 9%. The active metabolite AUC0-24 was unchanged in the presence of food, while there was a 57% decrease in active metabolite Cmax. Similar results were observed when a clopidogrel 300 mg loading dose was administered with a high-fat breakfast. ROSULIP GOLD can be administered with or without food.
Rosuvastatin is taken up extensively by the liver, which is the primary site of cholesterol synthesis and LDL-C clearance. 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.
Salicylic acid is widely distributed to all tissues and fluids in the body, including the central nervous system (CNS), breast milk and fetal tissues. The highest concentrations are found in the plasma, liver, renal cortex, heart and lungs. The protein binding of salicylate is concentration-dependent, i.e., non-linear. At low concentrations (<100 mcg/mL), approximately 90% of plasma salicylate is bound to albumin while at higher concentrations (>400 mcg/mL), only about 75% is bound.
Clopidogrel and the main circulating (inactive) metabolite bind reversibly in vitro to human plasma proteins (98% and 94% respectively). The binding is non-saturable in vitro over a wide concentration range.
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 (CYP450) 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.
Aspirin is rapidly hydrolyzed in the plasma to salicylic acid such that plasma levels of aspirin are essentially undetectable 1 to 2 hours after dosing. Salicylic acid is primarily conjugated in the liver to form salicyluric acid, a phenolic glucuronide, an acyl glucuronide, and a number of minor metabolites. Salicylic acid has a plasma half-life of approximately 6 hours. Salicylate metabolism is saturable and total body clearance decreases at higher serum concentrations due to the limited ability of liver to form both salicyluric acid and phenolic glucuronide. Following toxic doses (10 to 20 g), the plasma half-life may be increased to over 20 hours.
Clopidogrel is extensively metabolized in the liver by two main metabolic pathways: one mediated by esterases and leading to hydrolysis into an inactive carboxylic acid derivative (85% of circulating metabolites) and one mediated by multiple cytochrome P450 enzymes. Cytochromes first oxidize clopidogrel to a 2-oxo-clopidogrel intermediate metabolite. Subsequent metabolism of the 2-oxo-clopidogrel intermediate metabolite results in formation of the active metabolite, a thiol derivative of clopidogrel. This metabolic pathway is mediated by CYP2C19, CYP3A, CYP2B6 and CYP1A2. The active thiol metabolite binds rapidly and irreversibly to platelet receptors, thus inhibiting platelet aggregation for the lifespan of the platelet.
The Cmax of the active metabolite is twice as high following a single 300 mg clopidogrel loading dose as it is after four days of 75 mg maintenance dose. Cmax occurs approximately 30 to 60 minutes after dosing. In the 75 to 300 mg dose range, the pharmacokinetics of the active metabolite deviates from dose proportionality: increasing the dose by a factor of four results in 2.0- and 2.7-fold increases in Cmax and AUC, respectively.
Following oral administration, approximately 90% of rosuvastatin and its metabolites are primarily excreted in the feces (consisting of absorbed and non-absorbed active substance) while the rest is excreted in the urine. Approximately 5% is excreted unchanged in urine. The elimination half-life (t1/2) of rosuvastatin is approximately 19 hours. The elimination half-life does not increase at higher doses. After an intravenous dose, approximately 28% of total body clearance was via the renal route, and 72% by the hepatic route.
The elimination of salicylic acid follows zero-order pharmacokinetics (i.e. the rate of drug elimination is constant in relation to plasma concentration). Renal excretion of unchanged drug depends upon urine pH. As urinary pH rises above 6.5, the renal clearance of free salicylate increases from <5% to >80%. Alkalization of the urine is a key concept in the management of salicylate overdose. Following therapeutic doses, approximately 10% is found excreted in the urine as salicylic acid, 75% as salicyluric acids, and 10% and 5% as the phenolic and acyl glucuronides, respectively.
Following an oral dose of 14C-labeled clopidogrel in humans, approximately 50% of total radioactivity was excreted in urine and approximately 46% in feces over the 5 days post-dosing. After a single, oral dose of 75 mg, clopidogrel has a half-life of approximately 6 hours. The half-life of the active metabolite is about 30 minutes.
Geriatric: There were no differences in plasma concentrations of rosuvastatin and clopidogrel between the non-elderly and elderly populations (age >65 years).
Gender: There were no in plasma concentrations of rosuvastatin between men and women. In a small study differences comparing men and women, less inhibition of ADP-induced platelet aggregation was observed in, with clopidogrel.
Renal Impairment: Mild to moderate renal women 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 (CLcr <30 mL/min/1.73 m2) not receiving hemodialysis compared with healthy subjects (CLcr >80 mL/min/1.73 m2). After repeated doses of 75 mg clopidogrel per day, patients with severe renal impairment (creatinine clearance from 5 to 15 mL/min) and moderate renal impairment (creatinine clearance from 30 to 60 mL/min) showed low (25%) inhibition of ADP-induced platelet aggregation, however, the prolongation of bleeding time was similar to that seen in healthy subjects receiving 75 mg of clopidogrel per day. In addition, clinical tolerance was good in all patients. Thus, dose adjustment of ROSULIP GOLD in patients with renal dysfunction may not be necessary.
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. After repeated doses of 75 mg clopidogrel per day for 10 days in patients with severe hepatic impairment, inhibition of ADP-induced platelet aggregation was similar to that observed in healthy subjects. The mean bleeding time prolongation was also similar in the two groups.
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 Cmax) in Asian subjects when compared with a Caucasian control group. Asian-Indians show an approximate 1.3-fold elevation in median AUC and Cmax. The prevalence of CYP2C19 alleles that result in intermediate and poor CYP2C19 metabolism of clopidogrel differs according to race/ethnicity. From literature, limited data for clopidogrel in Asian populations are available to assess the clinical implication of genotyping of this CYP on clinical outcome events.
Disposition of HMG-CoA reductase inhibitors, including rosuvastatin, involves organic anion-transporting polypeptide (OATP) 1B1 and other transporter proteins. Higher plasma concentrations of rosuvastatin have been reported in very small groups of patients (n=3 to 5) who have 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.
CYP2C19 is involved in the formation of both the active metabolite and the 2-oxo-clopidogrel intermediate metabolite. Clopidogrel active metabolite pharmacokinetics and antiplatelet effects, as measured by ex vivo platelet aggregation assays, differ according to CYP2C19 genotype. Genetic variants of other CYP450 enzymes may also affect the formation of clopidogrel's active metabolite.
Patients who are homozygous for nonfunctional alleles of the CYP2C19 gene are termed "CYP2C19 poor metabolizers." Approximately 2% of White and 4% of Black patients are poor metabolizers; the prevalence of poor metabolism is higher in Asian patients (e.g., 14% of Chinese). Tests are available to identify patients who are CYP2C19 poor metabolizers.
A crossover study in 40 healthy subjects, 10 each in the four CYP2C19 metabolizer groups, evaluated pharmacokinetic and antiplatelet responses using 300 mg followed by 75 mg per day and 600 mg followed by 150 mg per day, each for a total of 5 days. Decreased active metabolite exposure and diminished inhibition of platelet aggregation were observed in the poor metabolizers as compared to the other groups.
ROSULIP GOLD (rosuvastatin, aspirin and clopidogrel) is indicated for the treatment of acute coronary syndrome; myocardial infarction, angina; and stroke.
Hyperlipidemia and Mixed Dyslipidemia
Rosuvastatin is indicated as adjunctive therapy to diet to reduce elevated total cholesterol (total-C), LDL cholesterol (LDL-C), apoprotein B (ApoB), non-high-density lipoprotein cholesterol (nonHDL-C), and triglycerides (TG) and to increase high-density lipoprotein cholesterol (HDL-C) in adult patients with primary hyperlipidemia or mixed dyslipidemia. Lipid-altering agents should be used in addition to a diet restricted in saturated fat and cholesterol when response to diet and non-pharmacological interventions alone has been inadequate.
Pediatric Patients 10 to 17 Years of Age with Heterozygous Familial Hypercholesterolemia (HeFH)
Adjunct to diet to reduce total-C, LDL-C and ApoB levels in adolescent boys and girls, who are at least one year post-menarche, 10-17 years of age with HeFH, if after an adequate trial of diet therapy the following findings are present: LDL-C >190 mg/dL or >160 mg/dL and there is a positive family history of premature cardiovascular disease (CVD) or two or more other CVD risk factors.
Rosuvastatin is indicated as adjunctive therapy to diet for the treatment of adult patients with hypertriglyceridemia.
Primary Dysbetalipoproteinemia (Type III Hyperlipoproteinemia)
Rosuvastatin is indicated as adjunctive therapy to diet for the treatment of patients with primary dysbetalipoproteinemia (Type III hyperlipoproteinemia).
Homozygous Familial Hypercholesterolemia
Rosuvastatin is indicated as adjunctive therapy to other lipid-lowering treatments (e.g., LDL apheresis) or alone if such treatments are unavailable to reduce LDL-C, total-C, and ApoB in adult patients with homozygous familial hypercholesterolemia.
Slowing of the Progression of Atherosclerosis
Rosuvastatin is indicated as adjunctive therapy to diet to slow the progression of atherosclerosis in adult patients as part of a treatment strategy to lower total-C and LDL-C to target levels.
Vascular Indications
Aspirin is indicated to
Reduce the combined risk of death and non-fatal stroke in patients who have had ischemic stroke or transient ischemia of the brain due to fibrin platelet emboli.
Reduce the risk of vascular mortality in patients with a suspected acute MI.
Reduce the combined risk of death and non-fatal MI in patients with a previous MI or unstable angina pectoris.
Reduce the combined risk of MI and sudden death in patients with chronic stable angina pectoris.
Revascularization Procedures
Aspirin is indicated in patients who have undergone revascularization procedures (i.e. CABG, PTCA or carotid endarterectomy) when there is a pre-existing condition for which aspirin is already indicated.
Acute Coronary Syndrome
For patients with non-ST-segment elevation ACS , including patients who are to be managed medically and those who are to be managed with coronary revascularization, clopidogrel has been shown to decrease the rate of a combined endpoint of cardiovascular death, myocardial infarction (MI), or stroke as well as the rate of a combined endpoint of cardiovascular death, MI, stroke, or refractory ischemia.
For patients with ST-elevation myocardial infarction (STEMI), clopidogrel has been shown to reduce the rate of death from any cause and the rate of a combined endpoint of death, re-infarction, or stroke. The benefit for patients who undergo primary percutaneous coronary intervention is unknown.
Recent MI, Recent Stroke, or Established Peripheral Arterial Disease
For patients with a history of recent myocardial infarction (MI), recent stroke, or established peripheral arterial disease, clopidogrel has been shown to reduce the rate of a combined endpoint of new ischemic stroke (fatal or not), new MI (fatal or not), and other vascular death.
Patients should be placed on an appropriate lipid-lowering diet before receiving ROSULIP GOLD, and should continue this diet during treatment. The recommended dosage is one capsule once daily.
Hypersensitivity to rosuvastatin, aspirin, clopidogrel, non-steroidal anti-inflammatory drugs (NSAIDs), salicylic acid compounds, prostaglandin synthetase inhibitors or to any of the excipients
Patients with the syndrome of asthma with rhinitis and/or nasal polyps as aspirin may cause severe urticaria, angioedema or bronchospasm (asthma)
Active liver disease, which may include unexplained persistent elevations of hepatic transaminase levels
Active, or history of recurrent peptic ulcer and/or gastric/intestinal hemorrhage or other kinds of bleeding such as cerebrovascular hemorrhages
Hemorrhagic diathesis, coagulation disorders such as hemophilia and thrombocytopenia
In children or teenagers for viral infections, with or without fever, because of the risk of Reye's syndrome with concomitant use of aspirin in certain viral illnesses.
In patients with myopathy
In patients receiving concomitant cyclosporine
Methotrexate used at doses >15 mg/week
Severe renal impairment
Women who are pregnant or may become pregnant
Transporter Protein Inhibitors: Rosuvastatin is a substrate for certain transporter proteins including hepatic uptake transporter OATP1B1 and efflux transporter BCRP. Concomitant administration of ROSULIP GOLD with medicinal products that are inhibitors of these transporter proteins may result in increased rosuvastatin plasma concentrations and an increased risk of myopathy.
Gemfibrozil: Gemfibrozil significantly increased rosuvastatin exposure. Due to an observed increased risk of myopathy/rhabdomyolysis, combination therapy with ROSULIP GOLD and gemfibrozil should be avoided. If used together, the dose of rosuvastatin in ROSULIP GOLD should not exceed 10 mg once daily.
Cyclosporine: Concomitant administration of NSAIDs and cyclosporine may increase the nephrotoxic effect of cyclosporine. During concomitant administration of rosuvastatin and cyclosporine, rosuvastatin AUC values were on average 7 times higher than those observed in healthy volunteers. Therefore, in patients taking cyclosporine, the dose of rosuvastatin should not exceed 5 mg once daily. Hence ROSULIP GOLD is contraindicated in patients receiving concomitant cyclosporine.
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. In patients taking these combinations, the dose of ROSULIP GOLD 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 ROSULIP GOLD is co-administered with protease inhibitors given in combination with ritonavir.
Proton Pump Inhibitors: Avoid concomitant use of ROSULIP GOLD with omeprazole or esomeprazole. In clinical studies, omeprazole was shown to reduce the antiplatelet activity of clopidogrel when given concomitantly or 12 hours apart. A higher dose regimen of clopidogrel concomitantly administered with omeprazole increases antiplatelet response; an appropriate dose regimen has not been established. A similar reduction in antiplatelet activity was observed with esomeprazole when given concomitantly with clopidogrel. Consider using another acid-reducing agent with minimal or no CYP2C19 inhibitory effect on the formation of clopidogrel active metabolite. Dexlansoprazole, lansoprazole and pantoprazole had less effect on the antiplatelet activity of clopidogrel than did omeprazole or esomeprazole.
Anticoagulant Therapy: Rosuvastatin significantly increased the international normalized ratio (INR) in patients receiving coumarin anticoagulants. Patients on anticoagulation therapy are at increased risk for bleeding because of drug–drug interactions and the effect on platelets. Aspirin can displace warfarin from protein binding sites, leading to prolongation of both the prothrombin time and the bleeding time. Aspirin can increase the anticoagulant activity of heparin, increasing bleeding risk. Concomitant therapy of ROSULIP GOLD and anticoagulants is not recommended, since it may increase the intensity of bleeding. Although the administration of clopidogrel 75 mg per day did not modify the pharmacokinetics of S-warfarin (a CYP2C9 substrate) or International Normalized Ratio (INR) in patients receiving long-term warfarin therapy, at high concentrations in vitro, clopidogrel inhibits CYP2C9. Co-administration of ROSULIP GOLD with warfarin increases the risk of bleeding because of independent effects of clopidogrel on hemostasis.
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 exercised when prescribing with ROSULIP GOLD.
Fenofibrate: When rosuvastatin was co-administered with fenofibrate, no clinically significant increase in the AUC of rosuvastatin or fenofibrate was observed. Because it is known that the risk of myopathy during treatment with HMG-CoA reductase inhibitors is increased with concomitant use of fenofibrate, caution should be exercised when prescribing fenofibrate with ROSULIP GOLD.
Ezetimibe: Concomitant use of rosuvastatin (10 mg) and ezetimibe (10 mg) resulted in a 1.2-fold increase in AUC and a 30% decrease in Cmax of rosuvastatin in hypercholesterolemic subjects. A pharmacodynamic interaction, in terms of adverse effects, between rosuvastatin and ezetimibe cannot be ruled out.
Antacids: 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. The excretion of aspirin may be increased by alkaline urine, which can occur with some antacids.
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.
CYP450 enzymes: Results from in vitro and in vivo studies show that rosuvastatin is neither an inhibitor nor an inducer of CYP450 isoenzymes. In addition, rosuvastatin is a poor substrate for these isoenzymes. Therefore, drug interactions resulting from CYP450-mediated metabolism are not expected. No clinically relevant interaction have been observed between rosuvastatin and either fluconazole (an inhibitor of CYP2C9 and CYP3A4) or ketoconazole (an inhibitor of CYP2A6 and CYP3A4).
CYP2C19 Inhibitors: Clopidogrel is metabolized to its active metabolite in part by CYP2C19. Concomitant use of certain drugs that inhibit the activity of this enzyme results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition. The clinical relevance of this interaction is uncertain. As a precaution concomitant use of strong or moderate CYP2C19 inhibitors should be discouraged. Medicinal products that are strong or moderate CYP2C19 inhibitors include for example, omeprazole and esomeprazole, fluvoxamine, fluoxetine, moclobemide, voriconazole, fluconazole, ticlopidine, carbamazepine, and efavirenz.
Substrates of CYP2C8: The acyl-β-glucuronide metabolite of clopidogrel is a strong inhibitor of CYP2C8. Clopidogrel can increase the systemic exposure to drugs that are primarily cleared by CYP2C8, thereby needing dose adjustment and appropriate monitoring.
Clopidogrel increased repaglinide exposures by 3.9-fold to 5.1-fold. Avoid concomitant use of repaglinide with ROSULIP GOLD. If concomitant use cannot be avoided, initiate repaglinide at 0.5 mg before each meal and do not exceed a total daily dose of 4 mg. Increased frequency of glucose monitoring may be required during concomitant use.
Opiods: As with other oral P2Y12 inhibitors, coadministration of opioid agonists delay and reduce the absorption of clopidogrel, presumably because of slowed gastric emptying, resulting in reduced exposure to its metabolites. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring coadministration of morphine or other opioid agonists.
Oral Contraceptives/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.
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 combined use of ROSULIP GOLD and fusidic acid is not recommended. If possible, temporary suspension of ROSULIP GOLD treatment is recommended. If unavoidable, patients should be closely monitored.
Digoxin: Based on data from specific interaction studies, no clinically relevant interaction of rosuvastatin with digoxin is expected. However, aspirin impairs the renal excretion of digoxin, resulting in increased plasma concentrations. Monitoring of plasma concentrations of digoxin is recommended when initiating and terminating treatment with ROSULIP GOLD. Dose adjustment may be necessary.
Colchicine: Cases of myopathy, including rhabdomyolysis, have been reported with HMG-CoA reductase inhibitors, including rosuvastatin, co-administered with colchicine, and caution should be exercised when prescribing ROSULIP GOLD with colchicine.
Eltrombopag: Concomitant administration of rosuvastatin with this drug has shown to increase the AUC of rosuvastatin by 1.6-fold.
Dronedarone: Co-administration of rosuvastatin with dronedarone has shown to increase the AUC of rosuvastatin by 1.4-fold.
Itraconazole: Concomitant administration of rosuvastatin with itraconazole has shown to increase the AUC of rosuvastatin by 1.4-fold.
Baicalin: Administration of rosuvastatin along with baicalin has shown to decrease the AUC of rosuvastatin by 47%.
Lithium: Aspirin impairs the renal excretion of lithium, resulting in increased plasma concentrations. Monitoring of plasma concentrations of lithium is recommended when initiating and terminating treatment with ROSULIP GOLD. Dose adjustment may be necessary.
Tacrolimus: Concomitant administration of NSAIDs and tacrolimus may increase the nephrotoxic effect of tacrolimus. The renal function should be monitored in case of concomitant use of tacrolimus and ROSULIP GOLD.
Angiotensin-converting Enzyme (ACE) Inhibitors: The hyponatremic and hypotensive effects of ACE inhibitors may be diminished by the concomitant administration of aspirin due to its indirect effect on the renin-angiotensin conversion pathway.
Carbonic Anhydrase Inhibitors (Acetazolamide): Concurrent use of aspirin and acetazolamide can lead to high serum concentrations of acetazolamide (and toxicity) due to competition at the renal tubule for secretion. It may result in severe acidosis and increased central nervous system toxicity.
Anticonvulsants: Salicylate can displace protein-bound phenytoin and valproic acid, leading to decrease in the total concentration of phenytoin and an increase in serum valproic acid levels.
Beta-blockers: The hypotensive effects of beta-blockers may be diminished by the concomitant administration of aspirin due to inhibition of renal prostaglandins, leading to decreased renal blood flow and salt and fluid retention.
Diuretics: There is risk of acute renal failure due to decreased glomerular filtration via decreased renal prostaglandin synthesis. Hydrating the patient and monitoring renal function at the start of the treatment is recommended. The effectiveness of diuretics in patients with underlying renal or cardiovascular disease may be diminished by the concomitant administration of aspirin due to inhibition of renal prostaglandins, leading to decreased renal blood flow, and salt and fluid retention.
Methotrexate: Salicylate can inhibit renal clearance of methotrexate, leading to bone marrow toxicity especially in the elderly or renally impaired.
NSAIDs: Concomitant therapy of ROSULIP GOLD with other NSAIDs is not recommended, unless strictly indicated as it may increase the risk of hemorrhage. If the combination cannot be avoided, close observation for signs of bleeding is recommended.
Heparin: In a clinical study conducted in healthy subjects, clopidogrel did not necessitate modification of the heparin dose or alter the effect of heparin on coagulation. Co-administration of heparin had no effect on the inhibition of platelet aggregation induced by clopidogrel. A pharmacodynamic interaction between clopidogrel and heparin is possible, leading to increased risk of bleeding. Therefore, concomitant use should be undertaken with caution.
Selective Serotonin Re-uptake Inhibitors (SSRIs) and Serotonin Norepinephrine Re-uptake Inhibitors (SNRIs): The concomitant administration of selective serotonin re-uptake inhibitors (SSRIs) and serotonin norepinephrine re-uptake inhibitors (SNRIs) with clopidogrel may affect platelet activation. Hence concomitant administration of SSRIs and SNRIs with ROSULIP GOLD may increase the risk of bleeding.
Oral Hypoglycemics/Insulin: Moderate dose of aspirin may increase the effectiveness of oral hypoglycemic drugs and insulin, leading to hypoglycemia.
Systemic Corticosteroids: Use ROSULIP GOLD with caution in patients on oral corticosteroids as it could increase the risk of gastrointestinal (GI) ulceration and bleeding.
Anti-platelet Agents: Concomitant administration of rosuvastatin with clopidogrel has shown to increase the AUC of rosuvastatin by 2-fold. Co-administration of aspirin with drugs such as clopidogrel or dipyridamole is associated with an increased risk of gastrointestinal bleeding and hence should be co-administered with caution. Although aspirin did not modify the clopidogrel-mediated inhibition of ADP-induced platelet aggregation, clopidogrel potentiated the effect of aspirin on collagen-induced platelet aggregation. A pharmacodynamic interaction between clopidogrel and aspirin is possible, leading to increased risk of bleeding. Therefore, ROSULIP GOLD use should be undertaken with caution. However, clopidogrel and aspirin have been administered together for up to one year.
Thrombolytic Agents: Concomitant therapy of ROSULIP GOLD and thrombolytic agents is not recommended, unless strictly indicated as it may increase the risk of hemorrhage. If the combination cannot be avoided, close observation for signs of bleeding is recommended.
Safety of the concomitant administration of clopidogrel, fibrin or non-fibrin specific thrombolytic agents and heparins was assessed in patients with acute myocardial infarction. The incidence of clinically significant bleeding was similar to that observed when thrombolytic agents and heparin are co-administered with aspirin.
Concomitant Coumarin Anticoagulants: Concomitant therapy of ROSULIP GOLD and anti-coagulants is not recommended, unless strictly indicated as it may increase the risk of hemorrhage. If the combination cannot be avoided, INR should be determined before starting ROSULIP GOLD and frequently enough during early therapy to ensure that no significant alteration of INR occurs. Also close observation for signs of bleeding is recommended.
Protease Inhibitors: Increased systemic exposure to rosuvastatin has been observed in subjects receiving rosuvastatin concomitantly with various protease inhibitors in combination with ritonavir. Consideration should be given both to the benefit of ROSULIP GOLD in HIV patients receiving protease inhibitors and the potential for increased rosuvastatin plasma concentrations when initiating and up-titrating ROSULIP GOLD doses in patients treated with protease inhibitors. The concomitant use with certain protease inhibitors is not recommended unless the dose of rosuvastatin in ROSULIP GOLD is adjusted.
Selective Serotonin-Re-uptake Inhibitors (SSRIs): Concomitant therapy of ROSULIP GOLD and SSRIs may affect platelet activation and may increase the risk of bleeding. Hence, it is not recommended, unless strictly indicated as it may increase the risk of hemorrhage. Concomitant use of ROSULIP GOLD and SSRIs could also increase the risk of ulceration.
Deferasirox: Use ROSULIP GOLD with caution in patients on deferasirox as concomitant use could increase the risk of ulceration.
Uricosuric Agents (Probenecid and Sulfinpyrazone): Salicylates antagonize the uricosuric action of uricosuric agents.
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. These risks can occur at any dose level, but are increased at the highest dose (40 mg).
ROSULIP GOLD should be prescribed with caution in patients with predisposing factors for myopathy (e.g., age >65 years, inadequately treated hypothyroidism, renal impairment).
The risk of myopathy during treatment with ROSULIP GOLD 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, co-administered with colchicine, and caution should be exercised when prescribing ROSULIP GOLD with colchicine.
ROSULIP GOLD therapy should be discontinued if markedly elevated creatine kinase (CK) levels occur or myopathy is diagnosed or suspected. ROSULIP GOLD 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).
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.
All patients should be advised to promptly report to their physicians unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever or if muscle signs and symptoms persist after discontinuing ROSULIP GOLD.
Liver Enzyme Abnormalities
It is recommended that liver enzyme tests be performed before the initiation of ROSULIP GOLD therapy, and if signs or symptoms of liver injury occur.
Increases in serum transaminases have been reported with HMG-CoA reductase inhibitors, including rosuvastatin. In most cases, 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 (ULN) 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 ROSULIP GOLD, promptly interrupt therapy. If an alternate etiology is not found, do not restart ROSULIP GOLD.
Active liver disease, which may include unexplained persistent transaminase elevations, is a contraindication to the use of ROSULIP GOLD.
Thrombotic Thrombocytopenic Purpura (TTP)
Thrombotic thrombocytopenic purpura (TTP), sometimes fatal, has been reported following use of clopidogrel, sometimes after a short exposure (<2 weeks). TTP is a serious condition that requires urgent treatment including plasmapheresis (plasma exchange). It is characterized by thrombocytopenia, microangiopathic hemolytic anemia (schistocytes seen on peripheral smear), neurological findings, renal dysfunction, and fever.
Acquired Hemophilia
Acquired hemophilia has been reported following the use of clopidogrel. In cases of confirmed isolated activated Partial Thromboplastin Time (aPTT) prolongation with or without bleeding, acquired hemophilia should be considered. Patients with a confirmed diagnosis of acquired hemophilia should be managed and treated by specialists, and ROSULIP GOLD should be discontinued.
Cross-Reactivity among Thienopyridines
Patients should be evaluated for history of hypersensitivity to thienopyridines (such as clopidogrel, ticlopidine, prasugrel) as hypersensitivity including rash, angioedema or hematologic reaction have been reported in patients receiving clopidogrel, including patients with a history of hypersensitivity or hematologic reaction to other thienopyridines. Monitoring for signs of hypersensitivity in patients with a known allergy to thienopyridines is advised.
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 40 mg, 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 ROSULIP GOLD therapy with unexplained persistent proteinuria and/or hematuria during routine urinalysis testing.
Endocrine Effects/Diabetes Mellitus
Increases in 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. Patients at risk (fasting glucose 5.6 to 6.9 mmol/l, body mass index (BMI) >30 kg/m2, raised triglycerides, 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. This risk, however, is outweighed by the reduction in vascular risk with statins and therefore should not be a reason for stopping ROSULIP GOLD treatment.
Although clinical studies have shown that rosuvastatin alone does not reduce basal plasma cortisol concentration or impair adrenal reserve, caution should be exercised if ROSULIP GOLD is administered concomitantly with drugs that may decrease the levels or activity of endogenous steroid hormones such as ketoconazole, spironolactone, and cimetidine.
Asian Patients
Pharmacokinetic studies have demonstrated an approximate 2-fold increase in median exposure to rosuvastatin in Asian subjects when compared with Caucasian controls. ROSULIP GOLD dosage should be adjusted in Asian patients.
Patients who consume three or more alcoholic drinks every day should be counselled about the bleeding risks involved with chronic, heavy alcohol use while taking ROSULIP GOLD. ROSULIP GOLD should be used with caution in patients who consume substantial quantities of alcohol and/or have a history of chronic liver disease, lactose Intolerance
ROSULIP GOLD should be avoided in patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.
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, ROSULIP GOLD therapy should be discontinued.
Coagulation Abnormalities
Even low doses of aspirin can inhibit platelet function leading to an increase in bleeding time. This can adversely affect patients with inherited (hemophilia) or acquired (liver disease or vitamin K deficiency) bleeding disorders.
GI Side Effects
GI side effects include stomach pain, heartburn, nausea, vomiting and gross GI bleeding. Although minor upper GI symptoms, such as dyspepsia are common and can occur anytime during therapy, physicians should remain alert for signs of ulceration and bleeding, even in the absence of previous GI symptoms. Physicians should inform patients about the signs and symptoms of GI side effects and what steps to take if they occur.
History of Peptic Ulcer Disease/Hemorrhagic Episodes
Patients with a history of active peptic ulcer disease or hemorrhagic episodes should avoid using ROSULIP GOLD, since aspirin can cause gastric mucosal irritation and bleeding.
Sodium-retaining Disease States
Patients with sodium-retaining states, such as congestive heart failure or renal failure, should avoid sodium-containing buffered aspirin preparations because of their high sodium content.
Surgery/Minor Procedures
Aspirin is associated with an increased risk of hemorrhage particularly during or after operative procedures (even in cases of minor procedures, e.g., tooth extraction). Use ROSULIP GOLD with caution before surgery, including tooth extraction. Temporary discontinuation of treatment may be necessary.
ROSULIP GOLD is not recommended during menorrhagia where it may increase menstrual bleeding.
Hypersensitivity
Aspirin may promote bronchospasm and asthma attacks or other hypersensitivity reactions. Risk factors are existing asthma, hay fever, nasal polyps or chronic respiratory diseases. The same applies for patients who also show allergic reaction to other substances (e.g., with skin reactions, itching or urticaria).
Serious skin reactions, including Steven-Johnsons syndrome, have rarely been reported in association with the use of aspirin. ROSULIP GOLD should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.
Aspirin especially in low doses may reduce uric acid excretion. Due to this fact, patients who tend to have reduced uric acid excretion may experience gout attacks. Hence, use ROSULIP GOLD with caution in these patients.
Glucose 6-phosphate Dehydrogenase Deficiency
High doses of aspirin may precipitate acute hemolytic anemia in patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency. Hence, use ROSULIP GOLD with caution in these patients.
Rosuvastatin exposure is not influenced by mild- to moderate renal impairment (CLcr>30 mL/min/1.73 m2); however, exposure to rosuvastatin is increased to a clinically significant extent in patients with severe renal impairment who are not receiving hemodialysis. Aspirin needs to be avoided in patients with severe renal failure (glomerular filtration rate <10 mL/min). Hence, ROSULIP GOLD should be used with caution in patients with moderately impaired renal function while it should be avoided in those with severe renal failure.
Aspirin should be avoided in patients with severe hepatic insufficiency. Liver function tests should be performed regularly in patients presenting slight or moderate hepatic insufficiency. Rosuvastatin is contraindicated in patients with active liver disease which may include unexplained persistent elevations in hepatic transaminase levels. Thus, ROSULIP GOLD is contraindicated in patients with active liver disease, including unexplained persistent elevations in hepatic transaminase levels.
Pregnancy Category X
Rosuvastatin is contraindicated in women who are or may become pregnant. Rosuvastatin may cause fetal harm when administered to a pregnant woman. It is recommended that pregnant women should take aspirin only if clearly needed. Aspirin has the ability to alter platelet function and, therefore, there may be a risk of hemorrhage in infants whose mothers have consumed aspirin during pregnancy. The onset of labor may be delayed and the duration increased, with an increase in maternal blood loss. High doses of aspirin may result in closure of fetal arteriosus in utero and possibly persistent pulmonary hypertension in the new born. Kenicterus may be a consequence of jaundice in neonates.
ROSULIP GOLD should be administered to women of childbearing potential only when such patients are highly unlikely to conceive and have been informed of the potential hazards. If the patient becomes pregnant while taking ROSULIP GOLD, it should be discontinued immediately and the patient should be apprised of the potential risks to the fetus.
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. Salicylate is excreted in breast milk. Use of salicylates at high doses may lead to rashes, platelet abnormalities and bleeding in nursing infants. Nursing mothers should avoid using ROSULIP GOLD. Women who require ROSULIP GOLD treatment should be advised not to nurse their infants.
The safety and effectiveness of rosuvastatin in patients 10 to 17 years of age with HeFH were evaluated in a controlled clinical trial of 12 weeks duration followed by 40 weeks of open-label exposure. Patients treated with 5 mg, 10 mg and 20 mg daily rosuvastatin had an adverse experience profile generally similar to that of patients treated with placebo. Although not all adverse reactions identified in the adult population have been observed in clinical trials of children and adolescent patients, the same warnings and precautions for adults should be considered for children and adolescents. There was no detectable effect of rosuvastatin on growth, weight, BMI, or sexual maturation in pediatric patients (10 to 17 years of age). Rosuvastatin has not been studied in controlled clinical trials involving pre-pubertal patients or patients younger than 10 years of age. Doses of rosuvastatin greater than 20 mg have not been studied in the pediatric population.
In children and adolescents with homozygous familial hypercholesterolemia experience is limited to eight patients (aged ≥8 years).
In a pharmacokinetic study, 18 patients (9 boys and 9 girls), 10 to 17 years of age with HeFH, received single and multiple oral doses of rosuvastatin. Both Cmax and AUC of rosuvastatin were similar to values observed in adult subjects administered the same doses.
Aspirin is not recommended for use in adolescents/children aged under 16 years unless the expected benefits outweigh the risks. It may be a contributory factor in the causation of Reye's syndrome in some children. ROSULIP GOLD should be avoided in children below 16 years unless expected benefits outweigh the risks.
Of the 10,275 patients in clinical studies with rosuvastatin, 3,159 (31%) were ≥65 years, and 698 (6.8%) were ≥75 years. 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.
Elderly patients are particularly susceptible to the adverse effects of NSAIDs (including aspirin), especially GI bleeding and perforation, which may be fatal.
Elderly patients are at higher risk of myopathy and GI bleeding and, hence, ROSULIP GOLD should be prescribed with caution in the elderly.
The following serious adverse reactions are discussed in greater detail in other sections:
· 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:
The most commonly reported adverse reactions (incidence >2%) in the rosuvastatin controlled clinical trial database of 5,394 patients were:
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 treatment duration of up to 12 weeks.
Table 1: Adverse reactions* reported by >2% of patients treated with rosuvastatin and greater than placebo in placebo-controlled trials (% of patients)
Total Rosuvastatin
5 mg - 40 mg
*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 creatine kinase (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 greater than placebo in the METEOR trial (% of Patients)
Rosuvastatin 40 mg
Increased CK
ǂAlanine transaminase (ALT) >3x ULN
* Adverse reactions by MedDRA (Medical Dictionary for regulatory Affairs) preferred term.
ǂFrequency recorded as abnormal laboratory value.
In the JUPITER study, 17,802 participants were 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 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 a HbA1c >6.5% at the end of the trial was significantly higher in rosuvastatin-treated versus placebo-treated patients.
Table 3: Adverse reactions* reported by >2% of patients treated with rosuvastatin and greater than placebo in the JUPITER trial (% of Patients)
N=8,901
*Treatment-emergent adverse reactions by MedDRA preferred term
In a 12-week controlled study in boys and post-menarchal girls, the safety and tolerability profile of rosuvastatin 5 to 20 mg daily was generally similar to that of placebo.
However, elevations in serum CK >10 × 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 × ULN, compared to 0 of 46 children on placebo.
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 non-serious and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks).
Many adverse reactions are due to aspirin ingestion are dose-related. The following is a list of adverse reactions that have been reported in the literature:
Body as a Whole: Fever, hypothermia, thirst
Cardiovascular: Dysrhythmias, hypotension, tachycardia
Central Nervous System: Agitation, cerebral edema, coma, confusion, dizziness, headache, subdural or intracranial hemorrhage, lethargy, seizures
Fluid and Electrolyte: Dehydration, hyperkalemia, metabolic acidosis, respiratory alkalosis
GI: Dyspepsia, GI bleeding, ulceration and perforation, nausea, vomiting, transient elevations of hepatic enzymes, hepatitis, Reye's syndrome, pancreatitis
Hematologic: Increased bleeding tendencies, prolongation of prothrombin time, disseminated intravascular coagulation, coagulopathy, thrombocytopenia, granulocytosis, aplastic anemia
Hypersensitivity: Acute anaphylaxis including shock, angioedema, allergic edema, asthma, bronchospasm, laryngeal edema, urticaria
Metabolism: Hypoglycemia (in children), hyperglycemia
Musculoskeletal: Rhabdomyolysis
Reproductive: Menorrhagia, prolonged pregnancy and labor, stillbirths, low birth weight infants, antepartum and postpartum bleeding
Respiratory: Rhinitis, dyspnea, hyperpena, pulmonary edema, tachypnea
Skin: Steven-Johnsons syndrome, Lyells syndrome, purpura, erythema nodosum, erythema multiforme
Special Senses: Hearing loss, tinnitus. Patients with higher frequency hearing loss may have difficulty perceiving tinnitus. In these patients, tinnitus cannot be used as a clinical indicator of salicylism.
Urogenital: Interstitial nephritis, papillary necrosis, proteinuria, renal insufficiency and failure
Vascular: Hemorrhagic vasculitis
Blood and lymphatic system disorders: Increased bleeding tendencies, agranulocytosis, thrombocytopenia, leucopenia, eosinophilia, neutropenia, aplastic anemia/pancytopenia, thrombotic thrombocytopenic purpura (TTP), acquired hemophilia A, granulocytopenia, anemia
Eye disorders: Eye (conjunctival, ocular, retinal) bleeding
Ear and labyrinth disorders: Vertigo
Gastrointestinal disorders: Gastrointestinal and retroperitoneal hemorrhage with fatal outcome, colitis (including ulcerative or lymphocytic colitis), pancreatitis, stomatitis, gastric/duodenal ulcer, diarrhea, abdominal pain, dyspepsia, gastritis, vomiting, nausea, constipation, flatulence
General disorders and administration site condition: Fever, hemorrhage of operative wound, bleeding at puncture site
Hepato-biliary disorders: Acute liver failure, hepatitis (non-infectious), abnormal liver function test
Immune system disorders: Hypersensitivity reactions (including cross reactive drug hypersensitivity among thienopyridines), anaphylactoid reactions, serum sickness
Musculoskeletal, connective tissue and bone disorders: Musculoskeletal bleeding (hemarthrosis), myalgia, arthralgia, arthritis
Nervous system disorders: Taste disorders, fatal intracranial bleeding, headache, ageusia, paraesthesia, dizziness
Psychiatric disorders: Confusion, hallucinations
Respiratory, thoracic and mediastinal disorders: Bronchospasm, interstitial pneumonitis, respiratory tract bleeding, eosinophilic pneumonia, epistaxis, hemoptysis, pulmonary hemorrhage
Renal and urinary disorders: Increased creatinine levels, hematuria, glomerulonephritis
Skin and subcutaneous tissue disorders: Maculopapular, erythematous or exfoliative rash, urticaria, bullous dermatitis, eczema, toxic epidermal necrolysis, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis (AGEP), angioedema, drug-induced hypersensitivity syndrome, drug rash with eosinophilia and systemic symptoms (DRESS), erythema multiforme, skin bleeding (purpura), lichen planus, generalized pruritus, bruising
Reproductive systems and breast disorders: Gynecomastia
Vascular disorders: Vasculitis, hypotension, hematoma
Investigations: Bleeding time prolonged, neutrophil count decreased, platelet count decreased
Cardiac disorders: Kounis syndrome (vasospastic allergic angina/allergic myocardial infarction) in the context of a hypersensitivity reaction due to clopidogrel
If you experience any side-effects, talk to your doctor or pharmacist or write to drugsafety@cipla.com. You can also report side effects directly via the national pharmacovigilance program of India by calling on 18002677779 (Cipla Number) or you can report to PvPI on 1800 180 3024.
By reporting side-effects, you can help provide more information on the safety of this product.
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. Hemodialysis does not significantly enhance clearance of rosuvastatin.
Salicylate toxicity may result from acute ingestion (overdose) or chronic intoxication. The early signs of salicylic overdose (salicylism), including tinnitus, occur at plasma concentrations approaching 200 mcg/mL. Plasma concentrations of aspirin above 300 mcg/mL are clearly toxic. Severe toxic effects are associated with levels above 400 mcg/mL. A single lethal dose of aspirin in adults is not known with certainty but death may be expected at 30 g.
Platelet inhibition by clopidogrel is irreversible and will last for the life of the platelet. Overdose following clopidogrel administration may result in bleeding complications. Appropriate therapy should be considered if bleeding is observed. No antidote to the pharmacological activity of clopidogrel has been found. If prompt correction of prolonged bleeding time is required, platelet transfusion may reverse the effects of clopidogrel.
Symptoms and Signs
In acute overdose, severe acid-base and electrolyte disturbances may occur and are complicated by hyperthermia and dehydration. Respiratory alkalosis occurs early while hyperventilation is present, but is quickly followed by metabolic acidosis.
Treatment consists primarily of supporting vital functions, increasing salicylates elimination, and correcting the acid-base disturbance. Gastric emptying and/or lavage is recommended as soon as possible after ingestion, even if the patient has vomited spontaneously. After lavage and/or emesis, administration of activated charcoal, as slurry, is beneficial, if less than 3 hours have passed since ingestion. Charcoal adsorption should not be employed prior to emesis and lavage.
Severity of aspirin intoxication is determined by measuring the blood salicylates level. Acid-base status should be closely followed with serial blood gas and serum pH measurements. Fluid and electrolyte balance should also be maintained. In severe cases, hyperthermia and hypovolemia are major immediate threats to life. Children should be sponged with tepid water. Replacement fluid should be administered intravenously and augmented with correction of acidosis. Plasma electrolytes and pH should be monitored to promote alkaline diuresis of salicylates if renal function is normal. Infusion of glucose may be required to control hypoglycemia.
Hemodialysis and peritoneal dialysis can be performed to reduce the body drug content. In patients with renal impairment or in cases of life-threatening intoxication, dialysis is usually required. Exchange transfusion may be indicated in infants and young children
Store in a cool, dry and dark place.
ROSULIP GOLD 10: Strip pack of 10 capsules


The newly-designed front seats with integrated headrest guarantee greater comfort and better support when cornering. A new bezel underneath the headrest adds an extra sporty touch. In combination with the leather, the central part of the seat and back can be upholstered in perforated Alcantara® (standard on the version with MC Shift electro-actuated gearbox).
When they place their hands on the new steering wheel, drivers will notice its flattened rim, the longer Trofeo Design gear shift paddles and the new, more distinctively profiled grip. All these features make it more comfortable but are also tailored to the needs of a sporty driving style. It comes with three different finishes: all-leather, leather/Alcantara or leather/carbon fibre.
Another very important feature for those who appreciate a more sporty interior is the lightweight pedal board in perforated aluminium, which provides a direct link between the driver's instinct and skill and the car's response. The instrument panel is highly legible in all lighting conditions and, with its digital rpm counter, clearly displays exactly the right time for gear shifts.


The updating to 3.4.5 is giving me the warning of "JFolder::create: Infinite loop detected".
Warning of "JFolder::create: Infinite loop detected".
This comment was created with the J!Tracker Application at issues.joomla.org/joomla-cms/8355.
Update on this issue as i just had this error message after a website transport.
error on any website update: Warning of "JFolder::create: Infinite loop detected".
Issue: on the transfer the log and tmp folder where left to the uld urls.
Solution: Make sure the urls are valid and in the System Information ->Folder Permissions are both Writeable.


Okay, story time! I got glasses when I was in the 3rd grade and I hated it!! I remember my first day wearing glasses to school (right in the middle of the school year), I had my mom walk me to the classroom and tell my teacher that I got glasses. Like that wasn't obvious! At that age, kids can be pretty rough to changes and I was such a baby about what people would think. Growing up, I was always annoyed with my glasses and I wanted nothing more than to have contacts. I did eventually get contacts in 10th grade - right after I got my braces off, conveniently enough. But now I don't mind glasses as much and wear whatever I feel like each day. It's memories like those that make me thankful for how much self love comes with maturity.
I'm sure we all know how expensive glasses can be and although insurance is a beautiful thing, I'm still a little stuck because I'm high maintenance and want contacts too. So after searching for the best priced glasses I could find, I ended up on the GlassesUSA website. I thought I had heard of them before, but it was their prices that sucked me in. Just as an example before we get into all of this, I bought a pair of glasses and sunglasses on my first order for $200 after all their discounts! Do I have your attention yet??
To fix it from sitting on my nose was an easy fix, but when I left the store and got home I realized they had damaged my glasses. I obviously don't know what they did since I wasn't wearing my glasses and couldn't see, but my local shop sprayed it with something that ended up melting the blue screen coating. You can see in the picture below what they look like now. Unfortunately, the local shop refuses that they did anything and won't fix it. And since I was so excited purchasing these, I didn't even see the option to purchase insurance on the GlassesUSA website. GlassesUSA does offer 100% money back within 14 days. Unfortunately for me, it had been 21 days and there was nothing I could do.
The sunglasses I ordered are the Dickenson Brown style and I just paired it with brown lenses. These are like my backup sunglasses since I do usually wear my contacts and other sunglasses more often, so I didn't do a bunch of add-ons with these. They're very comfortable to wear and I'm really happy with the frame shape on my face. It is a little disorientating switching between these and my other glasses during the day, but it's manageable.
Since my other glasses were ruined, it was cheaper to buy an entire new pair from the GlassesUSA website than it would've been to just change the lenses in town for the Corvallis frame. This is the RayGL10 Brown style and they are the glasses I wear now when I don't have contacts on. I kept the Corvallis as an emergency backup. Although I think these and the Corvallis are equally as cute, the RayGL10 style is much more comfortable. The Corvallis has a bigger nose piece that hugs the sides of my nose, whereas these just rest on top comfortably. The sides are definitely my favorite part!
Overall, I would definitely recommend checking out GlassesUSA if you are in the market. I mentioned them back in my October Favorites when I first got them and in that post, I mentioned that I had seen some negative things said about this company online. I'm not sure where all those claims came from or what the deal is, but based on both of my orders I can say I'm very happy. I wouldn't recommend the blue shield coating just in case something happens and because it had quite the blue glare when light hit it, which wasn't the cutest in pictures. But other than that, I don't have any complaints. My orders showed up on time and I found their customer service to always be respectful.
Have you had any experience with ordering glasses online? Let me know in the comments!


I've noticed for some time what looks like the occasional "scratch" on the stuff I'm engraving/cutting - put it down to using a bucket load of off-cuts until now when I'm making up a celebration plaque for a friend. I've done 2 now on brand new acrylic sheet which I inspected before hand and both have come out with what I think is a mis-fire of the laser and want to know if anyone else has seen this.
Right now, I don't know if it's a software glitch, some sort of noise on the wires or something wrong with the internals of the laser cutter itself.
So what now? Any clues?
Are you only getting these 'glitches' when engraving ?
I think those are related to engraving. I also had some of them: http://redmine.laoslaser.org/issues/47. Are you using the latest firmware?
However I've just run another cut using the same SD card image - and got the glitches in exactly the same place. However the place is different in the very first version of that plaque I made - I've only shown a small part of it - but I'd made a mistake in some of the text above that photo - and the glitches were elsewhere.
As for the firmware - not using the new one released a few days ago, but the version I am using is dated 14th May 2014.
Last try before bed... Went back into Inkscape, trying to follow the issue 58.. nothing was grouped, but I selected all & ungroup anyway, then convert to path, but I don't know how to "split paths". I'm very new to Inkscape. There is "Cut Path", and "Break Apart" options, but I can't find a "Split Path" option or anything close.
I think we want to switch to github for issues, so I started a issue there and tried to assemble the relevant links.
Again help with the previewer would be appreciated.
Has anyone tried exporting from Inkscape as a different format - ie. not SVG? Would it make a difference?
Are you sure, you are using the latest firmware version? I did not observe those glitches for a long time now, so I assumed they were fixed.
Anyway, if you need to engrave something urgently: The glitches seem to be always at the end of engraved stuff, so adding a thin frame in your engraving, which is outside your workpiece should save you, eventhough it makes the job duration much longer of cause.
If you are using VisiCut, the input file format can not matter, because visicut rasters the images internally and only gives the result to the underlying LAOS driver.
Masking isn't going to be possible here, but the glitches seem to move every time I change the file in Inkscape and re-run it through VisiCut, so maybe I can find a combination that puts them in a less obtrusive place. Not a long-term solution though.
I might look at the visicut viewer though - I think it would be good to isolate the issue - VisiCut or the firmware - I think it's hard to tell right now.
On a whim, I decided to take my original in Inkscape and take the bottom 3 lines - the ones in the photo above which is about 1/4 of the whole plaque and moved them to another layer (I use the layers method of specifying cut/engrave, etc. type in VisiCut). I intended to only laser cut the outline and engrave the top 3/4, then send the bottom 1/4 as a separate file, but decided to do the lot. So I selected one layer to be cut, and 2 layers to be engraved - sent it to the LAOS board and bingo. The output - on cardboard at least is perfect.
That still doesn't tell me if the issue here is with Inkscape, VisiCut or the LAOS firmware, but at least I have a workaround for now, and maybe this might help someone else with a similar issue.
Did anyone experiment with the Additional space per raster line option in Visicut? This allows you to tweak the distance the laserhead sweeps outwards beyond the width of the raster line.
By looking at those line-bitmap-data you can clearly see that everything looks pretty correct so far. Visicut generates the bitmap data with a lead-in and lead-out area of at least 64 bits which are those double zeros in every line starting with a 9 (for bitmap transfer). Now it is clear that the issue is not on the Visicut side and also the transfer of the file is not the issue!
By using pos_l the next pixel to be put on the laser is retrieved, but here is no check against bitmap boundaries. So our understanding to the error is the following: If something goes wrong with the mapping between pos_l and the area over that the laser is moving - for example moving one point too far - the laser will pick bitmap data from outside the bitmap area filled prior with the last "9" command! That explains why this error only appears if in the past this bitmap data was filled with more data - here by the triangle that is getting bigger and bigger from top to bottom.
By turning off bi-directional engraving (which didn't work correctly due speed issues, but let's dig that down later...) we got the prove of our assumption: The miss-firing only occured at the END of the bitmapped line - so the error is that pos_l is counting too far (very likely just by one pixel).
With this patch the issue disappeared proving the erratic behaviour of the firmware.
I'll try to compile with your patch, could you test it?
yes I can test it, if not today than within next 2 days. By uploading the drei.lgc file it should be reproduceable on any Laos laser (but you have to laser this file at least twice).
Thank you for your effort. Anyhow, can you explain me how this bitmap-thing should work? Does it use a specific length-per-pixel or does it automatically map the pixelcount over the whole length of the next line?
Build it. Please try it.
I will be able to try it on Tuesday.
Great work for tracking this down!
As the index is calculated there might well be a +/- 1 calculation error. Zeroing the original data is indeed required.
Luz/Peter: As for the definition of the raster line: the bitmap data is mapped at equal pixel spacing between the startpoint and endpoint of the next "line" command.
So if the raster data is 1000 pixels, and we move 100mm during the next move: 1 bit equals 100mm/1000pixels = 0.1mm.
"9 1 160 0 0 134217728 0 0"
Note that the line can be in any direction (you can raster diagonally).
I've written a "offline" simulator before in c# that interpreted a LGC file (code is no longer online). Can dig locally if I can find the code.
Trying to fix this in Visicut is not the right direction (it will become a mess).
The firmware fix is trivial, and we will implement and test it.
I just tested. Without patch, the triangle makes misfires when engraved twice. With patch, the misfires are gone.
I tested it now myself and it works with the new Firmware. Cancel button now also, but I start a new thread for that now.


text:
Q: I'm trying to find the percentage of calories in fat but my output is never correct Here's my code
import java.util.Scanner;
import java.text.DecimalFormat;

public class Calories
{
    public static void main (String[] args)
    {

    int fat;    //Grams of fat
    int fcal;   //Calories from fat
    int total;  //Number of Calories
    long result;    //Percent of calories from fat

    System.out.println("This program finds the percent of calories from fat");

    //Here the user inputs the numbers
    Scanner keyboard = new Scanner (System.in);
    System.out.print("Enter the total grams of fat " );

    fat = keyboard.nextInt();
    fcal = fat * 9;
    System.out.print("Enter the total number of calories " );

    total = keyboard.nextInt();
    result = fcal / total * 100;

    if(result <= 30)
    {
      System.out.println("Food is low in fat!");
    }
    DecimalFormat formatter = new DecimalFormat("#0");
    System.out.println("Calories from fat : " + formatter.format(result) + "%");
    }
}

No matter what I input my output always comes out as zero. Can anyone tell me what I'm doing wrong here? I'm not sure whether DecimalFormat, the datatype, or keyboard.nextInt(); is part of my problem, I've gone over it multiple times and asked another person who said the code was running fine for them.

A: Your fcal and total variables are both integers, so you're performing integer division. Any time fcal < total, you'll always get 0 as your answer.
You need to cast as a double when doing your division.
That won't quite work either since result is declared as long so there'll be a loss of precision. Either change the datatype of result or else cast the result back to a long.

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The interesting picture below, is part of 2018 Toyota Celica Release Date Specs write-up which is labeled within Review, 2018 toyota celica release date, and posted at January 15th, 2019 04:03:39 AM by admin.
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text:
Q: ¿Cómo podría hacer para no mostrar filas a los usuarios que están en una tabla específica? Estoy creando un sitio web donde los usuarios pueden publicar enlaces e interactuar con ellos.
A todos los usuarios se les muestra una tabla con todos los enlaces de los usuarios para poder interactuar con ellos.
Pero necesito hacer una consulta, para que cuando un usuario interactúa con un enlace, ese enlace no se le muestre mas. Es decir, cuando un usuario hace clic en un enlace, el enlace desaparece solo para el usuario que hizo clic.
He hecho lo siguiente.
Tengo la tabla (users) donde se almacenan todos los usuarios.
Table1 (users):
----------------
| id | username |
----------------
|  1 |  user1   |
----------------
|  2 |  user2   |
----------------
|  3 |  user3   |
----------------

Esta es la segunda tabla donde se almacenan todos los enlaces.
Table2 (links):
----------------
| id | urls |
----------------
|  1 |  url1   |
----------------
|  2 |  url2   |
----------------
|  3 |  url3   |
----------------

Ahora supongamos que (User2 de la tabla 1 (users)) hizo clic en los siguientes enlaces (URL1 y URL2 de tabla2 (links)).
Cuando el usuario hace clic en una URL, los siguientes valores se almacenan en una tercera tabla de la siguiente manera:
Table3 (blockuser):
-----------------------
| id | idLinks | users |
-----------------------
|  1 |    1    | user2 |
------------------------
|  2 |    2    | user2 |
-----------------------

Ahora me gustaría que la tabla que contiene todos los enlaces se muestre a cada usuario de la siguiente manera.
Esto es lo que quiero lograr:
        User1:                    User2:                   User3:
--------------------      --------------------     --------------------
| TABLE: ALL LINKS |      | TABLE: ALL LINKS |     | TABLE: ALL LINKS |
--------------------      --------------------     --------------------
|  ID   |  URLS    |      |  ID   |  URLS    |     |  ID   |  URLS    |
--------------------      --------------------     --------------------
|  1    |  url1    |      |  3    |  url3    |     |  1    |  url1    |
--------------------      --------------------     --------------------
|  2    |  url2    |                               |  1    |  url2    |
--------------------                               --------------------
|  3    |  url3    |                               |  1    |  url3    |
--------------------                               --------------------

Pero esto es lo que he podido lograr.
        User1:                    User2:                   User3:
--------------------      --------------------     --------------------
| TABLE: ALL LINKS |      | TABLE: ALL LINKS |     | TABLE: ALL LINKS |
--------------------      --------------------     --------------------
|  ID   |  URLS    |      |  ID   |  URLS    |     |  ID   |  URLS    |
--------------------      --------------------     --------------------
|  3    |  url3    |      |  3    |  url3    |     |  3    |  url3    |
--------------------      --------------------     --------------------

Es decir, cuando un usuario hace clic en un enlace, el enlace ya no se muestra para todos los usuarios.
Pero lo que quiero lograr es que cuando un usuario haga clic en un enlace, el enlace dejará de mostrarse, solo para el usuario que hizo clic en dicho enlace.
Este es el código que tengo para mostrar la tabla:
SELECT
    *
FROM
    links
LEFT JOIN
    blockuser ON blockuser.idLinks = links.id
WHERE
    blockuser.idLinks IS NULL

Gracias a todos por su tiempo!

A: Lo que estas buscando, es mas simple.
La clausula not in, del where, te va a ayudar.
Con ella, podes traer todos los id que estan en una tabla y NO estan en otra
Sabiendo el usuario que entro (IdUsuario), podemos hacer lo siguiente:
Select * from links
where id not in (select idlinks from blockuser where users = 'IdUsuario')


Let's face it; moving day is no picnic! Packing and moving is never easy, whether you're moving to the other side of town or across the country. Use this essential checklist to help make your move to Raleigh-Triangle as seamless and stress-free as possible!
Don't wait until the last minute! Start packing and planning as soon as possible to alleviate some of the stress.
Start one room at a time and begin to organize and declutter. Set aside anything that can be donated, sold, or thrown away. The less stuff you have, the less you'll have to pack!
Host a yard sale to get rid of any unwanted clothing, furniture, or decor. You can also consider donating any shoes or clothing that are in good condition.
It usually takes a few weeks for the post office to process your change of address and start forwarding your mail, so request it at least two weeks before the move.
Reinforce: Use sturdy, reinforced boxes. And don't be afraid to get friendly with bubble wrap and other packing material for fragile items.
Innovate: Pack dishes, bowls, plates, and other glass objects vertically, rather than flat and stacked. For extra padding, pack glasses and stemware inside socks.
Pack small: Pack heavier items in smaller boxes so they're easier to carry.
Prevent leaks: Remove the tops and cover the openings of soaps, shampoos, and lotions with cling wrap, then twist the caps back on. You can also use cling wrap around dresser drawers or jewelry displays to keep them intact, or around furniture to prevent scratches.
Prepare: Create an "Open Me First" box containing personal items that you will need immediately, such as toilet paper, soap, instant coffee, tools and box cutters, and paper dishes. Make sure it's one of the first things off the moving truck.
It's not just the packing that's overwhelming - moving day itself can be very stressful if you're not prepared. Here are some tips for a low-stress moving day.
Don't pack your most important essentials and emergency prep items - like first aid supplies, medication, financial records, medical records, IDs, and other important documentation or high-value items. Always keep them with you.
If you make it home before the moving truck, make sure you're prepared with things like a change of clothes, your toiletries, and a phone charger.
Keep your moving foreman's content information with you in case you need to contact your movers for any reason. It's also handy to have your Bill of Loading and shipment registration number with you.
It's much easier to deep-clean your bathrooms and kitchen before they're loaded down with all your stuff (or before you're too tired to clean!). Clean first, unpack second.
Make the seemingly endless process smaller by breaking it down into several smaller projects, and do them in order of importance.
Don't forget to smile... Your new life in your new place just began. Welcome home.
Still Have Questions or Ready to Buy a Home in Raleigh-Triangle?
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Made at Yamaha Music Craft in Japan, the CG32S is crafted with a solid solid Spruce top and solid Rosewood back and sides. It features an African mahogany neck, ebony fingerboard, and rosewood bridge with bone saddle.
Developed with the know-how gained from decades of experience making hand-made instruments, the GC series is Yamaha's handcrafted line of classical guitars. Carefully crafted from hand-select woods, these all-solid guitars are equipped with many excellent features. These redesigned Grand Concert guitars provide enhanced sound characteristics with a thinner soundboard, modern bracing pattern, and a thinner finish. Yamaha's craftsmen's close attention to detail makes sure that each instrument is of the best quality possible. The rich and resonant spruce top provides discerning players with outstanding tone and clarity. Includes a semi-hard case to protect it at home or on the road.


Richardson & Wrench National Richardson & Wrench is a network of real estate professionals who know and understand that their business is about more than just property.
Richardson & Wrench is a network of real estate professionals who know and understand that their business is about more than just property. It's about people. People whose homes are the central plank upon which they will nurture families, build wealth, and find sanctuary. Founded in 1858, Richardson & Wrench has been part of the fabric of Australian life for more than 150 years. We've helped many thousands of people realise their dreams and we intend to be doing so well into the future. Over the years Richardson & Wrench has established an untarnished reputation for honesty, integrity and professionalism. It's a reputation we aim to keep. We believe that a good result and integrity are not mutually exclusive. Indeed our sales results show that honesty and profits do mix. The Richardson & Wrench network consists of 98 independently owned offices in metropolitan and regional locations throughout NSW and Queensland – and growing. We are small enough to feel like family with local knowledge and experience but large enough to see the big picture.


text:
Der International Financial Reporting Standard for small and medium-sized entities (IFRS for SMEs) ist ein Rechnungslegungstandard des IASB, der die Rechnungslegung für kleine und mittlere Unternehmen (KMU) regelt. Der Standard wurde am  9. Juli 2009 veröffentlicht und ist am Tag der Veröffentlichung in Kraft getreten.

Es handelt sich um einen eigenständigen Standard (englisch ), der auf den vollen International Financial Reporting Standards (IFRS) basiert. Rechnungslegungsvorschriften zur Bilanzierung und Bewertung von Vermögenswerten, Verbindlichkeiten, Erträgen und Aufwendungen wurden vereinfacht, nichtrelevante Themengebiete weggelassen und die Anzahl der vorgeschriebenen Anhangangaben reduziert.

Anwendungsbereich

Unter den Anwendungsbereich fallen Unternehmen, die nicht zur öffentlichen Rechnungslegung verpflichtet sind. Ein kapitalmarktorientiertes Unternehmen fällt damit nicht in den Anwendungsbereich. Unternehmen, die Vermögen von Kunden verwalten, wie z. B. Banken und Versicherungen können die IFRS for SMEs ebenfalls nicht anwenden.

Eine abschließende Definition, welche Unternehmen als klein oder mittelgroß einzustufen sind, trifft der IASB nicht. Diese Qualifizierung wird jeweils auf nationaler Ebene von den Gesetzgebern der jeweiligen Staaten getroffen.

Der IASB geht davon aus, dass weltweit für etwa 95 % aller Unternehmen nicht die vollen IAS/IFRS, sondern die IFRS for SMEs maßgeblich sein werden. Im Gegensatz zu den vollen IFRS ist eine Anerkennung des Standards (englisch ) durch die Europäische Kommission nicht erforderlich. Die nationalen Gesetzgeber entscheiden unmittelbar, ob sie den Standard anwenden werden.

Deutschland
Für Deutschland ist keine Übernahme des Standards geplant. Durch das am 29. Mai 2009 in Kraft getretene Gesetz zur Modernisierung des Bilanzrechts (Bilanzrechtsmodernisierungsgesetz, BilMoG) hat der Gesetzgeber eine eigenständige Vorgehensweise zur Rechnungslegung von kleinen und mittleren Unternehmen geschaffen. Der Standard kann auf freiwilliger Basis zusätzlich zum handelsrechtlichen Einzelabschluss angewendet werden.

Ziel
Der Standard soll den Bedürfnissen und Anforderungen der KMU und deren Nutzern Rechnung tragen. Es soll eine bessere Vergleichbarkeit von internationalen Jahresabschlüssen erreicht werden. Das Vertrauen der Nutzer in die Rechnungslegung der KMUs soll dadurch gestärkt werden. Darüber hinaus soll eine Kostenreduzierung erreicht werden, da ein einheitlicher internationaler Standard zahlreiche nationale Vorschriften ersetzt.

Historie
Die Entwicklung des Standards erstreckte sich auf einen Zeitraum von fünf Jahren. Der Beginn der IASB-Beratungen begann im Juli 2003. Der englischsprachige Entwurf wurde im Februar 2007 verabschiedet. Die deutsche Übersetzung wurde im Juni 2007 veröffentlicht. Ab Juni 2007 wurde der Standard versuchsweise von 116 Gesellschaften aus 20 Ländern angewendet. Nachfolgend wurden die Erkenntnisse aus der versuchsweisen Anwendung und aus den eingereichten Stellungnahmen der Fachverbände in den Standard eingearbeitet. Die endgültige Verabschiedung erfolgte im Juli 2009.

Aufbau des Standards
Der Standard ist in 35 Kapitel unterteilt und umfasst 231 Seiten. Im Folgenden werden die jeweiligen Kapitel des Standards den jeweiligen IAS/IFRS gegenübergestellt, aus deren Grundprinzipien sie abgeleitet worden sind.

Unterschiede im Vergleich zu den vollen IFRS

Die wichtigsten Unterschiede im Vergleich zu den vollen IFRS lassen sich in fünf Bereiche unterteilen:

 Einige Themengebiete der vollen IFRS entfallen, da sie in der Regel für KMUs nicht relevant sind. Dies betrifft das Ergebnis je Aktie, die Zwischenberichterstattung, die Segmentberichterstattung, und die besondere Bilanzierung für zum Verkauf gehaltene Vermögenswerte.
 Einige Wahlrechte der vollen IFRS sind für die IFRS for SMEs nicht zulässig. (Beispiele: kein Wahlrecht zur Klassifizierung von Finanzinstrumenten, kein Wahlrecht zur Anwendung der Neubewertungsmethode für Sachanlagen und immaterielle Vermögenswerte, kein Wahlrecht zur Quotenkonsolidierung für Joint Ventures, weniger Wahlrechte bei der Bilanzierung und Darstellung von Zuwendungen der öffentlichen Hand)
 Vereinfachung von zahlreichen Ansatz- und Bewertungsvorschriften. (Beispiele: Bei Vorliegen bestimmter Bedingungen werden Finanzinstrumente mit den fortgeführten Anschaffungskosten bewertet. Liegen diese Bedingungen nicht vor, erfolgt die Bewertung erfolgswirksam zum Zeitwert. Ein Verweis auf IAS 39 bietet Unternehmen allerdings die Möglichkeit, anstelle der vereinfachten Vorschriften IAS 39 anzuwenden. Goodwill und andere Vermögenswerte mit nicht befristeter Lebensdauer sind über einen maximalen Zeitraum von zehn Jahren abzuschreiben. Anteile an assoziierten Unternehmen und Joint Ventures können grundsätzlich zu Anschaffungskosten bewertet werden)
 Es sind deutlich weniger Anhangsangaben erforderlich.
 Änderungen des Standards sollen nur alle drei Jahre erfolgen.

Online-Zugang zum Standard

Der IFRS for SMEs steht auf der Seite des IASB kostenlos zum Download bereit (in vielen, jedoch nicht in der deutschen Sprache). Dafür ist eine Registrierung sowie die Zustimmung zu den Nutzungsbedingungen erforderlich. Der deutsche Text ist als Buch verfügbar.

Siehe auch
 International Financial Reporting Standards
 International Accounting Standards Committee
 International Accounting Standards Board

Einzelnachweise

Weblinks
 Die Projektseite des IASB zu den IFRS for SMEs
 Eine Zusammenfassung des IFRS for SMEs

IFRS

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