Rosuvas Gold

Rosuvas Gold Uses, Dosage, Side Effects, Food Interaction and all others data.

By decreasing platelet aggregation, Aspirin inhibits thrombus formation on the arterial side of the circulation, where thrombi are formed by platelet aggregation and anticoagulants have little effect. Aspirin is the analgesic of choice for headache, transient musculoskeletal pain and dysmenorrhoea. It has anti-inflammatory and antipyretic properties, which may be useful. Enteric coating reduces the intestinal disturbance and gastrointestinal ulceration due to aspirin.

Effects on pain and fever

Acetylsalicylic acid disrupts the production of prostaglandins throughout the body by targeting cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) . Prostaglandins are potent, irritating substances that have been shown to cause headaches and pain upon injection into humans. Prostaglandins increase the sensitivity of pain receptors and substances such as histamine and bradykinin. Through the disruption of the production and prevention of release of prostaglandins in inflammation, this drug may stop their action at pain receptors, preventing symptoms of pain. Acetylsalicylic acid is considered an antipyretic agent because of its ability to interfere with the production of brain prostaglandin E1. Prostaglandin E1 is known to be an extremely powerful fever-inducing agent .

Effects on platelet aggregation

(Clopidogrel) is an inhibitor of platelet aggregation. Lopirel (Clopidogrel) selectively inhibits the binding of adenosine diphosphate (ADP) to its platelet receptor and the subsequent ADP-mediated activation of the glycoprotein GPIIb/IIIa complex, thereby inhibiting platelet aggregation.

Clopidogrel is a prodrug of a platelet inhibitor used to reduce the risk of myocardial infarction and stroke. It has a long duration of action as it is taken once daily and a large therapeutic window as it is given in doses of 75-300mg daily.

Rosuvastatin is a selective and competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) to mevalonate, a precursor of sterols, including cholesterol.The primary site of action of rosuvastatin is the liver, the target organ for lowering cholesterol. Rosuvastatin increases the number of hepatic LDL receptors on the cell surface, enhancing uptake and catabolism of LDL and it inhibits the hepatic synthesis of VLDL, thereby reducing the total number of VLDL and LDL particles.

Rosuvastatin is a synthetic, enantiomerically pure antilipemic agent. It is used to lower total cholesterol, low density lipoprotein-cholesterol (LDL-C), apolipoprotein B (apoB), non-high density lipoprotein-cholesterol (non-HDL-C), and trigleride (TG) plasma concentrations while increasing HDL-C concentrations. High LDL-C, low HDL-C and high TG concentrations in the plasma are associated with increased risk of atherosclerosis and cardiovascular disease. The total cholesterol to HDL-C ratio is a strong predictor of coronary artery disease and high ratios are associated with higher risk of disease. Increased levels of HDL-C are associated with lower cardiovascular risk. By decreasing LDL-C and TG and increasing HDL-C, rosuvastatin reduces the risk of cardiovascular morbidity and mortality.

Elevated cholesterol levels, and in particular, elevated low-density lipoprotein (LDL) levels, are an important risk factor for the development of CVD. Use of statins to target and reduce LDL levels has been shown in a number of landmark studies to significantly reduce the risk of development of CVD and all-cause mortality. Statins are considered a cost-effective treatment option for CVD due to their evidence of reducing all-cause mortality including fatal and non-fatal CVD as well as the need for surgical revascularization or angioplasty following a heart attack. Evidence has shown that even for low-risk individuals (with 19,20

Skeletal Muscle Effects

Trade Name Rosuvas Gold
Generic Acetylsalicylic Acid + Clopidogrel + Rosuvastatin
Weight 75mg
Type Capsule
Therapeutic Class
Manufacturer Ranbaxy Laboratories (sun Pharma)
Available Country India
Last Updated: September 19, 2023 at 7:00 am
Rosuvas Gold
Rosuvas Gold

Uses

Aspirin is used for its antiplatelet activity in the initial treatment of cardiovascular disorders such as angina pectoris and myocardial infarction and for the prevention of cardiovascular events in a variety of conditions or procedures for patients at risk.

  • Aspirin is used as part of the initial treatment of unstable angina.
  • It is given in the early treatment of myocardial infarction.
  • It may also be of some benefit in the initial treatment of acute ischaemic stroke.
  • It is of value for the secondary prevention of cardiovascular events in patients with stable or unstable angina or those with acute or prior myocardial infarction.
  • Aspirin reduces the risk of future serious vascular events, including stroke, in patients who have already suffered an ischaemic stroke or transient ischaemic attack.
  • It is of use in the long-term management of atrial fibrillation, for the prevention of stroke in patients with contraindications to warfarin or if there are no other risk factors for stroke.
  • It is recommended for use in preventing thrombotic complications associated with procedures such as angioplasty and coronary bypass grafting.

(Clopidogrel) is used for the reduction of atherosclerotic events (myocardial infarction, ischaemic stroke, and vascular death) in patients with atherosclerosis documented by recent stroke, recent myocardial infarction, or established peripheral arterial disease.

Primary hypercholesterolemia (type IIa including heterozygous familial hypercholesterolemia), mixed dyslipidemia (type IIb), or homozygous familial hypercholesterolemia in patients who have not responded adequately to diet and other appropriate measures; prevention of cardiovascular events in patients at high risk of a first cardiovascular event.

Rosuvas Gold is also used to associated treatment for these conditions: Acute Coronary Syndrome (ACS), Anxiety, Arthritis, Atherothrombotic cerebral infarction, Cardiovascular Disease (CVD), Cardiovascular Events, Cardiovascular Mortality, Colorectal Adenomas, Colorectal Cancers, Common Cold, Coronary artery reocclusion, Death, Dyspeptic signs and symptoms, Fever, Flu Like Symptom, Flu caused by Influenza, Headache, Heterozygous Familial Hypercholesterolemia, Inflammation, Juvenile Idiopathic Arthritis (JIA), Kawasaki Syndrome, Major Adverse Cardiovascular and Cerebrovascular Events (MACCE), Migraine, Morbidity, Mucocutaneous Lymph Node Syndrome, Muscle Contraction, Myocardial Infarction, Myocardial Infarction (MI), first occurrence, Neuralgia, Pain, Pain caused by Common Cold, Pain, Menstrual, Pericarditis, Polycythemia Vera (PV), Preeclampsia, Rheumatic Pain, Rheumatism, Rheumatoid Arthritis, Rhinosinusitis, Severe Pain, Soreness, Muscle, Spondyloarthropathies, Stroke, Systemic Lupus Erythematosus (SLE), Tension Headache, Thromboembolism, Toothache, Transient Ischemic Attack, Venous Thromboembolism, Acute Inflammation, Atherothrombotic events, Death by myocardial infarction, Moderate Pain, Thrombotic events, Antiplatelet Therapy, Hemodialysis Treatment, Secondary PreventionAcute Coronary Syndrome (ACS), Acute Myocardial Infarction (AMI), Cardiovascular Events, Atherothrombotic eventsAtherosclerosis, Atherosclerotic Cardiovascular Diseases, Cardiovascular Disease (CVD), Cardiovascular Events, Dysbetalipoproteinemia, Heterozygous Familial Hypercholesterolemia, High Blood Pressure (Hypertension), High Cholesterol, Homozygous Familial Hypercholesterolemia, Hypertension,Essential, Hypertriglyceridemias, Major Adverse Cardiovascular Events, Mixed Dyslipidemias, Postoperative Thromboembolism, Primary Hypercholesterolemia, Primary Hyperlipidemia, Cardiovascular Primary Prevention, Lipid-Lowering Therapy

How Rosuvas Gold works

Acetylsalicylic acid (ASA) blocks prostaglandin synthesis. It is non-selective for COX-1 and COX-2 enzymes . Inhibition of COX-1 results in the inhibition of platelet aggregation for about 7-10 days (average platelet lifespan). The acetyl group of acetylsalicylic acid binds with a serine residue of the cyclooxygenase-1 (COX-1) enzyme, leading to irreversible inhibition. This prevents the production of pain-causing prostaglandins. This process also stops the conversion of arachidonic acid to thromboxane A2 (TXA2), which is a potent inducer of platelet aggregation . Platelet aggregation can result in clots and harmful venous and arterial thromboembolism, leading to conditions such as pulmonary embolism and stroke.

It is important to note that there is 60% homology between the protein structures of COX-1 and COX-2. ASA binds to serine 516 residue on the active site of COX-2 in the same fashion as its binding to the serine 530 residue located on the active site of COX-1. The active site of COX-2 is, however, slightly larger than the active site of COX-1, so that arachidonic acid (which later becomes prostaglandins) manages to bypass the aspirin molecule inactivating COX-2 . ASA, therefore, exerts more action on the COX-1 receptor rather than on the COX-2 receptor . A higher dose of acetylsalicylic acid is required for COX-2 inhibition .

Clopidogrel is metabolized to its active form by carboxylesterase-1. The active form is a platelet inhibitor that irreversibly binds to P2Y12 ADP receptors on platelets. This binding prevents ADP binding to P2Y12 receptors, activation of the glycoprotein GPIIb/IIIa complex, and platelet aggregation.

Rosuvastatin is a statin medication and a competitive inhibitor of the enzyme HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase, which catalyzes the conversion of HMG-CoA to mevalonate, an early rate-limiting step in cholesterol biosynthesis. Rosuvastatin acts primarily in the liver, where decreased hepatic cholesterol concentrations stimulate the upregulation of hepatic low density lipoprotein (LDL) receptors which increases hepatic uptake of LDL. Rosuvastatin also inhibits hepatic synthesis of very low density lipoprotein (VLDL). The overall effect is a decrease in plasma LDL and VLDL.

In vitro and in vivo animal studies also demonstrate that rosuvastatin exerts vasculoprotective effects independent of its lipid-lowering properties, also known as the pleiotropic effects of statins. This includes improvement in endothelial function, enhanced stability of atherosclerotic plaques, reduced oxidative stress and inflammation, and inhibition of the thrombogenic response.

Statins have also been found to bind allosterically to β2 integrin function-associated antigen-1 (LFA-1), which plays an important role in leukocyte trafficking and in T cell activation.

Rosuvastatin exerts an anti-inflammatory effect on rat mesenteric microvascular endothelium by attenuating leukocyte rolling, adherence and transmigration. The drug also modulates nitric oxide synthase (NOS) expression and reduces ischemic-reperfusion injuries in rat hearts. Rosuvastatin increases the bioavailability of nitric oxide by upregulating NOS and by increasing the stability of NOS through post-transcriptional polyadenylation. It is unclear as to how rosuvastatin brings about these effects though they may be due to decreased concentrations of mevalonic acid.

Dosage

Rosuvas Gold dosage

Pain, Inflammatory diseases and as Antipyretic: Aspirin 300 mg 1-3 tablets 6 hourly with a maximum daily dose of 4 g.

Thrombotic cerebrovascular or Cardiovascular disease: Aspirin 300 mg 1 tablet or Aspirin 75 mg 4 tablets daily.

After Myocardial infarction: Aspirin 75 mg 2 tablets daily for 1 month.

Following By-pass surgery: Aspirin 75 mg 1 tablet daily.

The recommended dose of Lopirel (Clopidogrel) is 75 mg once daily with or without food.

Before treatment initiation the patient should be placed on a standard cholesterol-lowering diet that should continue during treatment. The dose should be individualized according to the goal of therapy and patient response, using current consensus guidelines.

Treatment of hypercholesterolemia: Patient of Asian origin or with risk factors for myopathy or rhabdomyolysis: initially 5 mg once daily increased if necessary to max. 20 mg daily.

Prevention of cardiovascular events: Patient of Asian origin or with risk factors for myopathy or rhabdomyolysis: initially 5 mg once daily increased if necessary to max. 20 mg daily.

Pediatric Use (Hyperlipidemia including familial hypercholesterolemia):

  • Child younger than 6 years: not recommended.
  • Child 6–9 years: initially 5 mg daily, increased if necessary at intervals of at least 4 weeks to usual max. 10 mg once daily.
  • Child 10–18 years: initially 5 mg daily, increased if necessary at intervals of at least 4 weeks to usual max. 20 mg once daily.

[Reduced dose required with concomitant atazanavir, darunavir, ezetimibe, fibrate, itraconazole, lopinavir, or tipranavir]

Use in the elderly (>70 years): A start dose of 5 mg is recommended. No dose adjustment necessary.

Renal insufficiency:Initially 5mg once daily (do not exceed 20 mg daily) if eGFR is 30-60 mL/minute/1.73 m2. Avoid if eGFR is less than 30 mL/minute/1.73 m2

Hepatic impairment:

  • Child-Pugh scores of <7: no increase in systemic exposure to rosuvastatin.
  • Child-Pugh scores of 8 and 9: increased systemic exposure has been observed. In these patients an assessment of renalfunction should be considered.
  • Child-Pugh scores >9: no study.

Rosuvastatin is contraindicated in patients withactive liver disease.

Race: Increased systemic exposure has been seen in Asian subjects. The recommended starting dose is 5 mg for patients of Asian ancestry. The 40 mg dose is contraindicated in these patients.

Genetic polymorphisms: Specific types of genetic polymorphisms are known that can lead to increased rosuvastatin exposure. For patients who are known to have such specific types of polymorphisms, a lower daily dose of Rosuvastatin is recommended.

Dosage in patients with pre-disposing factors to myopathy: The recommended starting dose is 5 mg in patients with predisposing factors to myopathy. The 40 mg dose is contraindicated in some of these patients.

Rosuvastatin may be given at any time of day, with or without food

Side Effects

Side effects for usual dosage of Aspirin are mild including nausea, dyspepsia, gastrointestinal ulceration and bronchospasm etc.

Generally Clopidogrel is well tolerated. However, a few common side effects i.e. Influenza-like symptoms, headache, upper respiratory tract infection, dizziness, muscle and back pain, and rash may occur.

Common or very common: Proteinuria.

Rare: Hepatitis, jaundice.

Very rare: Gynecomastia, hematuria, hepati failure, interstitial lung disease, lupus erythematosus-like reactions, pancreatitis.

Frequency not known: Alopecia, altered liver function tests, amnesia, arthralgia, asthenia, depression, dizziness, edema, fatigue, gastrointestinal disturbances, headache, hypersensitivity reactions, hyperglycemia -may be associated with the development of diabetes mellitus (particularly in those already at risk of the condition), myalgia, myopathy, myositis, paresthesia, peripheral neuropathy, pruritus, rash, rhabdomyolysis, sexual dysfunction, sleep disturbance, Stevens-Johnson syndrome, thrombocytopenia, urticaria, visual disturbance.

Muscle effects: The risk of myopathy, myositis, and rhabdomyolysis associated with statin use is rare. Although myalgia has been reported commonly in patients receiving statins, muscle toxicity truly attributable to statin use is rare. Muscle toxicity can occur with all statins, however the likelihood increases with higher doses If muscular symptoms or raised creatine kinase occur during treatment, other possible causes (e.g. rigorous physical activity, hypothyroidism, infection, recent trauma, and drug or alcohol addiction) should be excluded before statin therapy is implicated, particularly if statin treatment has previously been tolerated for more than 3 months. When a statin is suspected to be the cause of myopathy, and creatine kinase concentration is markedly elevated (more than 5 times upper limit of normal), or if muscular symptoms are severe, treatment should be discontinued. If symptoms resolve and creatine kinase concentrations return to normal, the statin should be reintroduced at a lower dose and the patient monitored closely; an alternative statin should be prescribed if unacceptable side-effects are experienced with a particular statin. Statins should not be discontinued in the event of small, asymptomatic elevations of creatine kinase. Routine monitoring of creatine kinase is unnecessary in asymptomatic patients.Statins should not be discontinued if there is an increase in the blood-glucose concentration or HbA1C as the benefits continue to outweigh the risks.

Interstitial lung disease: If patients develop symptoms such as dyspnoea, cough, and weight loss, they should seek medical attention.

Toxicity

Lethal doses

Acute oral LD50 values have been reported as over 1.0 g/kg in humans, cats, and dogs, 0.92 g/kg - 1.48 g/kg in albino rats, 1.19 g/kg in guinea pigs, 1.1 g/kg in mice, and 1.8 g/kg in rabbit models .

Acute toxicity

Salicylate toxicity is a problem that may develop with both acute and chronic salicylate exposure . Multiple organ systems may be affected by salicylate toxicity, including the central nervous system, the pulmonary system, and the gastrointestinal system. Severe bleeding may occur. In the majority of cases, patients suffering from salicylate toxicity are volume-depleted at the time of presentation for medical attention. Fluid resuscitation should occur immediately and volume status should be monitored closely. Disruptions in acid-base balance are frequent in ASA toxicity .

The acute toxicity of acetylsalicylic in animals has been widely studied. The signs of poisoning in rats from lethal doses are mild to severe gastroenteritis, hepatitis, nephritis, pulmonary edema, encephalopathy, shock and some toxic effects on other organs and tissues. Mortality has been observed following convulsions or cardiovascular shock. An important differentiating property between various animal species is the ability to vomit toxic doses. Humans, cats and dogs have this ability, but rodents or rabbits do not .

Chronic toxicity and carcinogenesis

Chronic ASA toxicity is frequently accompanied by atypical clinical presentations that may be similar to diabetic ketoacidosis, delirium, cerebrovascular accident (CVA), myocardial infarction (MI) or cardiac failure. Plasma salicylate concentrations should be measured if salicylate intoxication is suspected, even if there no documentation available to suggest ASA was ingested. In older age, nephrotoxicity from salicylates increases, and the risk of upper gastrointestinal hemorrhage is increased, with higher rates of mortality . It is also important to note that ASA toxicity may occur even with close to normal serum concentrations. Prevention of chronic ASA includes the administration of smallest possible doses, avoidance of concurrent use of salicylate drugs, and therapeutic drug monitoring. Renal function should be regularly monitored and screening for gastrointestinal bleeding should be done at regular intervals .

Chronic toxicity studies were performed in rodents. ASA was administered at doses measured to be 2 to 20 times the maximum tolerated clinical dose to mice for up to one year. Negative dose-related effects were seen. These include decreased mean survival time, decreased number of births and progeny reaching an appropriate age for weaning. No evidence of carcinogenesis was found in 1-year studies . At daily doses of 0.24 g/kg/day given for 100 days to albino rats, ASA led to signs to excessive thirst, aciduria, diuresis, drowsiness, hyperreflexia, piloerection, changes in respiration, tachycardia, followed by soft stools, epistaxis, sialorrhea, dacryorrhea and mortality during hypothermic coma in the second study month .

Use in pregnancy and lactation

While teratogenic effects were observed in animals nearly lethal doses, no evidence suggests that this drug is teratogenic in humans . It is advisable, however, to avoid ASA use the first and second trimester of pregnancy, unless it is clearly required. If acetylsalicylic acid containing drugs are ingested by a patient attempting to conceive, or during the first and second trimester of pregnancy, the lowest possible dose at the shortest possible duration should be taken . This drug is contraindicated in the 3rd trimester of pregnancy .

A single dose of clopidogrel at 1500-2000mg/kg was lethal to mice and rats while 3000mg/kg was lethal to baboons. Symptoms of overdose include vomiting, breathing difficulty, gastrointestinal hemorrhage, and prostration. Clopidogrel is irreversibly bound to platelets for their lifetime, which is approximately 11 days. Overdoses of clopidogrel can be treated with platelet transfusions to restore clotting ability.

Generally well-tolerated. Side effects may include myalgia, constipation, asthenia, abdominal pain, and nausea. Other possible side effects include myotoxicity (myopathy, myositis, rhabdomyolysis) and hepatotoxicity. To avoid toxicity in Asian patients, lower doses should be considered. Pharmacokinetic studies show an approximately two-fold increase in peak plasma concentration and AUC in Asian patients (Philippino, Chinese, Japanese, Korean, Vietnamese, or Asian-Indian descent) compared to Caucasian patients.

Precaution

It should be administered cautiously in asthma, uncontrolled blood pressure and pregnant women.It is specially important not to use aspirin during the last 3 months of pregnancy unless specifically directed to do so by a doctor because it may cause problems in unborn child or complication during delivery. It should be administered with caution to patients in nasal polyp and nasal allergy. Aspirin penetrates into breast milk. So, it should be administered with caution to lactating mothers.

As with other anti-platelet agents, Clopidogrel should be used with caution in patients who may be at risk of increased bleeding from trauma, surgery, or other pathological conditions. Clopidogrel should be discontinued 7 days prior to surgery. Clopidogrel should be used with caution in hepatically impaired patients who may have bleeding diatheses.

Hypothyroidism should be managed adequately before starting treatment with a statin. Statins should be used with caution in those with a history of liver disease or with a high alcohol intake. There is little information available on a rational approach to liver-function monitoring; however, a NICE guideline1 suggests that liver enzymes should be measured before treatment, and repeated within 3 months and at 12 months of starting treatment, unless indicated at other times by signs or symptoms suggestive of hepatotoxicity. Those with serum transaminases that are raised, but less than 3 times the upper limit of the reference range, should not be routinely excluded from statin therapy. Those with serum transaminases of more than 3 times the upper limit of the reference range should discontinue statin therapy.

Statins should be used with caution in those with risk factors for myopathy or rhabdomyolysis; patients should be advised to report unexplained muscle pain. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose galactose malabsorption should not take this medicine.

Interaction

Salicylates may enhance the effect of anticoagulants, oral hypoglycaemic agents, phenytoin and sodium valporate. They inhibit the uricosuric effect of probenecid and may increase the toxicity of sulphonamides. They may also precipitate bronchospasm or induce attacks of asthma in susceptible subjects.

Concomitant use of Heparin, Warfarin and NSAIDs with Clopidogrel should be undertaken with caution. Clopidogrel potentiate the effect of Aspirin on collagen-induced platelet aggregation. The safety of chronic concomitant administration of Aspirin and Clopidogrel has not been established.

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

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

Protease Inhibitors: Coadministration of rosuvastatin with certain protease inhibitors has differing effects on rosuvastatin exposure. Simeprevir, which is a hepatitis C virus (HCV) protease inhibitor, or combinations of atazanavir/ritonavir or lopinavir/ritonavir, which are HIV-1 protease inhibitors, increase rosuvastatin exposure (AUC) up to threefold. For these protease inhibitors, the dose of Rosuvastatin should not exceed 10 mg once daily. The combinations of fosamprenavir / ritonavir or tipranavir / ritonavir, which are HIV 1 protease inhibitors, produce little or no change in rosuvastatin exposure. Caution should be exercised when rosuvastatin is coadministered with protease inhibitors.

Coumarin Anticoagulants: Rosuvastatin significantly increased INR in patients receiving coumarin anticoagulants. Therefore, caution should be exercised when coumarin anticoagulants are given in conjunction with Rosuvastatin. In patients taking coumarin anticoagulants and Rosuvastatin concomitantly, INR should be determined before starting Rosuvastatin and frequently enough during early therapy to ensure that no significant alteration of INR occurs.

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; caution should be used when prescribing with Rosuvastatin.

Fenofibrate: When Rosuvastatin was coadministered 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 statins is increased with concomitant use of fenofibrates, caution should be used when prescribing fenofibrates with Rosuvastatin.

Colchicine: Cases of myopathy, including rhabdomyolysis, have been reported with statins, including rosuvastatin, coadministered with colchicine, and caution should be exercised when prescribing Rosuvastatin with colchicine

Volume of Distribution

This drug is distributed to body tissues shortly after administration. It is known to cross the placenta. The plasma contains high levels of salicylate, as well as tissues such as spinal, peritoneal and synovial fluids, saliva and milk. The kidney, liver, heart, and lungs are also found to be rich in salicylate concentration after dosing. Low concentrations of salicylate are usually low, and minimal concentrations are found in feces, bile, and sweat .

The apparent volume of distribution of clopidogrel is 39,240±33,520L.

Rosuvastatin undergoes first-pass extraction in the liver, which is the primary site of cholesterol synthesis and LDL-C clearance. The mean volume of distribution at steady-state of rosuvastatin is approximately 134 litres.

Elimination Route

Absorption is generally rapid and complete following oral administration but absorption may be variable depending on the route, dosage form, and other factors including but not limited to the rate of tablet dissolution, gastric contents, gastric emptying time, and gastric pH .

Detailed absorption information

When ingested orally, acetylsalicylic acid is rapidly absorbed in both the stomach and proximal small intestine. The non-ionized acetylsalicylic acid passes through the stomach lining by passive diffusion. Ideal absorption of salicylate in the stomach occurs in the pH range of 2.15 - 4.10. Intestinal absorption of acetylsalicylic acid occurs at a much faster rate. At least half of the ingested dose is hydrolyzed to salicylic acid in the first-hour post-ingestion by esterases found in the gastrointestinal tract. Peak plasma salicylate concentrations occur between 1-2 hours post-administration .

A 75mg oral dose of clopidogrel is 50% absorbed from the intestine. Clopidogrel can be taken with or without food. A meal decreases the AUC of the active metabolite by 57%. The active metabolite of clopidogrel reaches a maximum concentration after 30-60 minutes. Clopidogrel reached a Cmax of 2.04±2.0ng/mL in 1.40±1.07h.

The AUC for a 300mg oral dose of clopidogrel was 45.1±16.2ng*h/mL for poor metabolizers, 65.6±19.1ng*h/mL for intermediate metabolizers, and 104.3±57.3ng*h/mL for extensive metabolizers. The Cmax was 31.3±13ng/mL for poor metabolizers, 43.9±14ng/mL for intermediate metabolizers, and 60.8±34.3ng/mL for extensive metabolizers.

In a study of healthy white male volunteers, the absolute oral bioavailability of rosuvastatin was found to be approximately 20% while absorption was estimated to be 50%, which is consistent with a substantial first-pass effect after oral dosing. Another study in healthy volunteers found that the peak plasma concentration (Cmax) of rosuvastatin was 6.06ng/mL and was reached at a median of 5 hours following oral dosing. Both Cmax and AUC increased in approximate proportion to dose. Neither food nor evening versus morning administration was shown to have an effect on the AUC of rosuvastatin. Many statins are known to interact with hepatic uptake transporters and thus reach high concentrations at their site of action in the liver.

Breast Cancer Resistance Protein (BCRP) is a membrane-bound protein that plays an important role in the absorption of rosuvastatin, particularly as CYP3A4 has minimal involvement in its metabolism. Evidence from pharmacogenetic studies of c.421C>A single nucleotide polymorphisms (SNPs) in the gene for BCRP has demonstrated that individuals with the 421AA genotype have reduced functional activity and 2.4-fold higher AUC and Cmax values for rosuvastatin compared to study individuals with the control 421CC genotype. This has important implications for the variation in response to the drug in terms of efficacy and toxicity, particularly as the BCRP c.421C>A polymorphism occurs more frequently in Asian populations than in Caucasians. Other statin drugs impacted by this polymorphism include fluvastatin and atorvastatin.

Genetic differences in the OATP1B1 (organic-anion-transporting polypeptide 1B1) hepatic transporter have also been shown to impact rosuvastatin pharmacokinetics. Evidence from pharmacogenetic studies of the c.521T>C SNP showed that rosuvastatin AUC was increased 1.62-fold for individuals homozygous for 521CC compared to homozygous 521TT individuals. Other statin drugs impacted by this polymorphism include simvastatin, pitavastatin, atorvastatin, and pravastatin.

For patients known to have the above-mentioned c.421AA BCRP or c.521CC OATP1B1 genotypes, a maximum daily dose of 20mg of rosuvastatin is recommended to avoid adverse effects from the increased exposure to the drug, such as muscle pain and risk of rhabdomyolysis.

Half Life

The half-life of ASA in the circulation ranges from 13 - 19 minutes. Blood concentrations drop rapidly after complete absorption. The half-life of the salicylate ranges between 3.5 and 4.5 hours .

That half life of clopidogrel is approximately 6 hours following a 75mg oral dose while the half life of the active metabolite is approximately 30 minutes.

The elimination half-life (t½) of rosuvastatin is approximately 19 hours and does not increase with increasing doses.

Clearance

The clearance rate of acetylsalicylic acid is extremely variable, depending on several factors . Dosage adjustments may be required in patients with renal impairment . The extended-release tablet should not be administered to patients with eGFR of less than 10 mL/min .

The clearance of a 75mg oral dose was 18,960±15,890L/h and for a 300mg oral dose was 16,980±10,410L/h.

Elimination Route

Excretion of salicylates occurs mainly through the kidney, by the processes of glomerular filtration and tubular excretion, in the form of free salicylic acid, salicyluric acid, and, additionally, phenolic and acyl glucuronides .

Salicylate can be found in the urine soon after administration, however, the entire dose takes about 48 hours to be completely eliminated. The rate of salicylate is often variable, ranging from 10% to 85% in the urine, and heavily depends on urinary pH. Acidic urine generally aids in reabsorption of salicylate by the renal tubules, while alkaline urine increases excretion .

After the administration of a typical 325mg dose, the elimination of ASA is found to follow first order kinetics in a linear fashion. At high concentrations, the elimination half-life increases .

An oral dose of radiolabelled clopidogrel is excreted 50% in the urine and 46% in the feces over 5 days. The remainder of clopidogrel is irreversibly bound to platelets for their lifetime, or approximately 8-11 days.

Rosuvastatin is not extensively metabolized; approximately 10% of a radiolabeled dose is recovered as metabolite. Following oral administration, rosuvastatin and its metabolites are primarily excreted in the feces (90%). After an intravenous dose, approximately 28% of total body clearance was via the renal route, and 72% by the hepatic route.

A study in healthy adult male volunteers found that approximately 90% of the rosuvastatin dose was recovered in feces within 72 hours after dose, while the remaining 10% was recovered in urine. The drug was completely excreted from the body after 10 days of dosing. They also found that approximately 76.8% of the excreted dose was unchanged from the parent compound, with the remaining dose recovered as the metabolites n-desmethyl rosuvastatin and rosuvastatin-5S-lactone.

Renal tubular secretion is responsible for >90% of total renal clearance, and is believed to be mediated primarily by the uptake transporter OAT3 (Organic anion transporter 1), while OAT1 had minimal involvement.

Pregnancy & Breastfeeding use

Aspirin should be avoided during the last 3 months of pregnancy. As aspirin is excreted in breast milk, aspirin should not be taken by patients who are breast-feeding.

Pregnancy: There are no adequate and well-controlled studies of Clopidogrel in pregnant women. However, Clopidogrel should be used during pregnancy only if clearly needed.

Lactation: Clopidogrel is not recommended for use while breast-feeding. It is not known for sure whether Clopidogrel is excreted in breast milk, although it is suspected that it is.

Pregnancy Category X. Teratogenic effects. Rosuvastatin is contraindicated in pregnancy and lactation. Women of child bearing potential should use appropriate contraceptive measures. If a patient becomes pregnant during use of this product, treatment should be discontinued immediately.

Rosuvastatin is excreted in the milk of rats. There are no data with respect to excretion in milk in humans

Contraindication

Aspirin is contraindicated to the children (Reye's syndrome) under 12 years, in breast-feeding and active peptic ulcer. It is also contraindicated in bleeding due to haemophilia and other ulceration. Hypersensitivity to aspirin, hypoprothrombinaemia is also contraindicated

Clopidogrel is contraindicated in patients with a hypersensitivity to the drug substance or any component of the product, and those with active pathological bleeding such as peptic ulcer or intracranial hemorrhage.

Rosuvastatin is contraindicated:

  • In patients with hypersensitivity to rosuvastatin or to any of the excipients.
  • In patients with active liver disease including unexplained, persistent elevations of serum transaminases and any serum transaminase elevation exceeding 3 x the upper limit of normal (ULN).
  • In patients with severe renal impairment (creatinine clearance < mL/minute/1.73m2).
  • In patients with myopathy.
  • In patients receiving concomitant cyclosporine.
  • During pregnancy and lactation and in women of childbearing potential not using appropriate contraceptive measures.

Special Warning

Use in children: Safety and effectiveness of Clopidogrel in pediatric population have not been established.

Age and sex: There was no clinically relevant effect of age or sex on the pharmacokinetics of Rosuvastatin in adults.

Race: Pharmacokinetic studies show an increase in exposure in Asian subjects compared with Caucasians.

Severe renal impairment (not on hemodialysis): Starting dose is 5 mg, not to exceed 10 mg

Use in the elderly: Patients > 70 years: A start dose of 5 mg is recommended. No dose adjustment necessary.

Renal insufficiency: Initially 5mg once daily (do not exceed 20mg daily) if eGFR is 30–60 mL/ minute/ 1.73 m2. Avoid if eGFR is less than 30 mL /minute/ 1.73 m2.

Genetic polymorphisms: Specific types of genetic polymorphisms are known that can lead to increased rosuvastatin exposure. For patients who are known to have such specific types of polymorphisms, a lower daily dose of Rosuvastatin is recommended.

Dosage in patients with pre-disposing factors to myopathy: The recommended starting dose is 5 mg in patients with predisposing factors to myopathy. The 40 mg dose is contraindicated in some of these patients.

Acute Overdose

Overdosage produces dizziness, tinnitus, sweating, nausea and vomiting, confusion and hyperventilation. Gross overdosage may lead to CNS depression with coma, cardiovascular collapse and respiratory depression. If overdosage is suspected, the patient should be kept under observation for at least 24 hours, as symptoms and salicylate blood levels may not become apparent for several hours. Treatment of overdosage consists of gastric lavage and forced alkaline diuresis. Haemodialysis may be necessary in severe cases.

In the event of over dosage no adverse effects were reported and no therapy was substituted.

Symptoms: Prolonged bleeding time and subsequent bleeding complications.

Management: May restore clotting ability with platelet transfusion.

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. Haemodialysis is unlikely to be of benefit.

Storage Condition

Store in a cool and dry place, protected from light.

Store at 25° C.

Keep out of the reach of children. Store below 30° C. Keep in the original package in a cool & dry place in order to protect from light and moisture.

Innovators Monograph

You find simplified version here Rosuvas Gold


*** Taking medicines without doctor's advice can cause long-term problems.
Share