Date of approval: Month of year
Date of revision: January
Rosuvastatin Calcium Capsules Instructions
Please read the instructions carefully and use under the guidance of a physician
Drug Name]
Generic Name.
Rosuvastatin Calcium Capsules
English Name: Rosuvastatin Calcium Capsules
Hanyu Pinyin: Ruishufatatinggai Jiaonang
Ingredients
The active ingredient of this product is Rosuvastatin Calcium.
Chemical name: Bis-[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-pyrimidin-5-yl](3R,5S)-3,5dihydroxyhept-6-enoic acid] calcium salt (2:1)
Chemical structure formula.
Molecular formula: (C22H27FN3O6S)2Ca
Molecular weight: 1001.13
【Properties】.
This product is a hard capsule, the contents are white or off-white granules or powder.
Indications
This product is indicated for primary hypercholesterolemia (type IIa, including heterozygous familial hypercholesterolemia) or mixed dyslipidemia (type IIb) that cannot be adequately controlled by dietary control and other non-pharmaceutical treatments (e.g. exercise therapy, weight reduction).
It is also indicated for patients with pure heterozygous familial hypercholesterolemia as an adjunct to dietary control and other lipid-lowering measures (e.g. LDL removal therapy), or when these methods are not indicated.
【Specifications】.
According to C22H28FN3O6S: (1) 5mg (2) 10mg
Dosage]
Patients should be given standard cholesterol-lowering dietary control prior to the start of treatment and maintain dietary control during treatment. The use of this product should be individualized, taking into account the individual patient’s cholesterol level, expected cardiovascular risk, and potential risk of adverse reactions.
Oral administration. The usual starting dose of this product is 5 mg once a day. The selection of the starting dose should take into account the individual patient’s cholesterol level, the expected cardiovascular risk and the potential risk of adverse events. For those patients who require a more potent reduction in low-density lipoprotein cholesterol (LDL-C), 10 mg once a day may be considered as the starting dose, and this dose will control lipid levels in most patients. If necessary, the dose may be adjusted to a higher dose level after 4 weeks of treatment. The maximum daily dose of this product is 20 mg.
This product may be administered at any time of the day and may be taken with food or on an empty stomach.
Dosing for patients with renal insufficiency
No dose adjustment is required in patients with mild and moderate renal impairment. All doses of this product are contraindicated in patients with severe renal impairment.
Dosing in patients with hepatic impairment
Systemic exposure to Rosuvastatin is not elevated in subjects with Child-Pugh scores not higher than 7. In subjects with Child-Pugh scores 8 and 9, elevated systemic exposure was observed. In these patients, assessment of renal function should be considered. There is no experience with the use of this product in patients with a Child-Pugh score greater than 9. This product is contraindicated in patients with active liver disease.
Ethnicity
Increased systemic exposure has been observed in subjects of Asian ancestry. This factor should be considered when determining dosing in patients of Asian ancestry.
Dosing in Patients with Myopathy Susceptibility Factors
The recommended starting dose for patients with a predisposition to myopathy (see [Precautions]) is 5 mg.
Adverse reactions]
The adverse reactions seen with this product are usually mild and transient. In controlled clinical trials, less than 4% of patients withdrew from the trial due to adverse events.
List of Adverse Events
Based on clinical study data and extensive post-marketing experience, the following table lists the adverse event characteristics of Rosuvastatin. The following adverse events are classified according to frequency and systemic organ class.
The frequency of adverse events is listed in the following order: common (≥1/100, <1/10); occasional (≥1/1,000, <1/100); rare (≥1/10,000, <1/1,000); very rare (<1/10,000); unknown (cannot be estimated from available data).
Systemic organ classification Common Occasional Rare Very rare Unknown Blood and lymphatic system abnormalities Thrombocytopenia Immune system abnormalities Allergic reactions (including angioedema) Endocrine disorders Diabetes mellitus1 Psychiatric abnormalities Depression Neurological abnormalities Headache
Dizziness Polyneuropathy
Memory loss Peripheral neuropathy
Sleep disorders (including insomnia and nightmares) Respiratory, thoracic, and mediastinal abnormalities Cough
Breathing difficulties Gastrointestinal abnormalities Constipation
Nausea
Abdominal pain Pancreatitis Diarrhea Liver and biliary abnormalities Elevated transaminases Jaundice
Hepatitis Skin and subcutaneous tissue abnormalities Pruritus
Rash
Urticaria Stevens-Johnson syndrome Skeletal muscle
and connective tissue abnormalities Myalgia Myopathy (including myositis)
Rhabdomyolysis arthralgia tendon damage, sometimes with rupture complications
Immune-mediated necrotizing myopathy Renal and urinary system abnormalities Hematuria Reproductive system and breast abnormalities Gynecomastia Systemic abnormalities and discomfort and weakness at the site of drug administration Edema1 Frequency depends on the presence or absence of risk factors (fasting glucose ≥ 5.6 mmol/L, BMI > 30 kg/m2, elevated triglycerides, history of hypertension).
As with other HMG-CoA reductase inhibitors, the incidence of adverse reactions with this product tends to increase with increasing dose.
Effects on the kidney: Proteinuria (test paper assay) was observed in patients receiving this product, with the majority of the protein originating from the renal tubules. Less than 1% of patients had elevated proteinuria from none or trace to ++ or more at certain times during 10 mg and 20 mg therapy, and this percentage was approximately 3% in patients receiving 40 mg therapy. A mild elevation in proteinuria from none or a trace elevation to ++ was observed during treatment with the 20 mg dose. In most cases, proteinuria decreased or disappeared spontaneously with continued treatment. A causal relationship between proteinuria and acute or progressive kidney disease cannot be established based on clinical trials and post-marketing data to date.
Hematuria has been observed in patients on this product, and data from clinical trials suggest a low incidence.
Effects on skeletal muscle: Effects on skeletal muscle, such as myalgia, myopathy (including myositis), and, rarely, rhabdomyolysis, have been reported in patients treated with various doses of this product, particularly in patients using doses greater than 20 mg.
A dose-related increase in creatine kinase (CK) levels has been observed in patients taking this product; most cases are mild, asymptomatic, and transient. If creatine kinase levels are elevated (> 5 x ULN), treatment should be discontinued (see [Precautions]).
Effects on the liver: As with other HMG-CoA reductase inhibitors, dose-related transaminase elevations have been observed in a small number of patients taking this product; most cases are mild, asymptomatic, and transient.
The following adverse events have been reported with some statin therapy.
sexual dysfunction
Special cases of interstitial lung disease, especially in those receiving long-term therapy
Pediatric patient population: Pediatric and adolescent patients treated with resulvastatin were found to have creatine kinase elevations greater than 10 x ULN and concomitant muscle symptoms observed after exercise or enhanced physical activity in a 52-week clinical trial more frequently than observed in clinical trials conducted in adults. Otherwise, the safety profile of resulvastatin in pediatric and adolescent patients is similar to that of adults.
Statins.
Hyperglycemic reactions, abnormal glucose tolerance, elevated glycosylated hemoglobin levels, new-onset diabetes, and worsening glycemic control have been reported in postmarketing surveillance of statins, and hypoglycemic reactions have been reported with some statins.
Post-marketing experience: There are rare reports of cognitive impairment in the post-marketing surveillance of statin drugs abroad, manifesting as memory loss, memory loss, confusion, etc. Most of these reactions are non-serious and reversible, and can generally be recovered after discontinuation of the drug.
Contraindications
This product is contraindicated in.
People who are hypersensitive to Rosuvastatin or any of the ingredients in this product.
Patients with active liver disease, including persistent elevation of serum aminotransferases of unknown cause and any elevation of serum aminotransferases above 3 times the upper limit of normal (ULN).
Patients with severe renal impairment (creatinine clearance <30 ml/min).
Patients with myopathy.
Patients with concomitant cyclosporine use.
During pregnancy, during lactation, and in women at risk of pregnancy without adequate contraception.
[Precautions].
Effects on the kidney
Proteinuria (test paper method of detection) was observed in patients treated with high doses, especially 40 mg. Most of the protein originated from the renal tubules, and in most cases, the proteinuria was transient or intermittent. Proteinuria was not considered a precursor to acute or progressive nephropathy (see [Adverse Reactions]).
Effects on skeletal muscle
Effects on skeletal muscle, such as myalgia, myopathy, and, rarely, rhabdomyolysis, have been reported in patients treated with various doses of this product, particularly in patients using doses greater than 20 mg. Rare reports of rhabdomyolysis have been reported when ezetimibe is combined with HMG-CoA reductase inhibitors. Interaction of drug effects cannot be excluded and caution should be exercised when these drugs are combined.
Creatine kinase testing
Creatine kinase (CK) should not be tested after strenuous exercise or in the presence of plausible factors that may cause an increase in creatine kinase, as this may confuse the interpretation of the results. If the basal creatine kinase value is significantly elevated (> 5 x ULN), the test should be repeated within 5 to 7 days to confirm. If repeat testing confirms that the patient has a creatine kinase basal value of >5×ULN, treatment may not be initiated.
Before treatment
As with other HMG-CoA reductase inhibitors, caution should be exercised when using this product in patients with predisposing factors for myopathy/rhabdomyolysis. These factors include
impaired renal function
hypothyroidism
Hereditary muscle disease in self or family history
Prior history of muscle toxicity from other HMG-CoA reductase inhibitors or fibrates
Alcohol abuse
Age>70 years
Potential for elevated blood levels
Concomitant use of betablockers
In these patients, consideration should be given to the possible benefit of treatment in relation to the potential risk, and clinical monitoring is recommended. If the patient has a significantly elevated creatine kinase basal value (>5 x ULN), therapy should not be initiated.
During treatment
Patients should be asked to immediately report unexplained muscle pain, weakness, or cramps, especially if accompanied by discomfort and fever. Creatine kinase levels should be tested in these patients. If creatine kinase values are significantly elevated (> 5 x ULN) or if muscle symptoms are severe and cause discomfort throughout the day (even if creatine kinase is ≤5 x ULN), treatment should be discontinued. If symptoms resolve and creatine kinase levels return to normal, consider reintroducing the product or switching to the lowest dose of another HMG-CoA reductase inhibitor, and monitor closely.
Periodic testing of creatine kinase levels in asymptomatic patients is not required.
Immune-mediated necrotizing myopathy (IMNM) (an autoimmune myopathy) associated with statin use has been reported rarely and is characterized by proximal muscle weakness and elevated serum creatine kinase, which persists with or without discontinuation of statin therapy. Muscle biopsy showed necrotizing myopathy without significant inflammation; it improved with the application of immunosuppression.
In clinical studies, there was no evidence of increased drug effects on skeletal muscle in the few patients treated with concomitant use of this product and other treatments. However, an increased incidence of myositis and myopathy has been found in patients with other HMG-CoA reductase inhibitors in combination with febric acid derivatives (including gemfibezil), cyclosporine, nicotinic acid, pyrrole antifungals, protease inhibitors, or macrolide antibiotics. Concomitant use of gemfibezil with some HMG-CoA reductase inhibitors may increase the risk of myopathy. Therefore, the combination of this product with gemfibezil is not recommended. The benefits of combining this product with fibrates or niacin to further improve lipid levels should be carefully weighed against the potential risks of such combinations.
The combination of resulvastatin with fusidic acid is not recommended. Rhabdomyolysis (including death) has been reported in patients receiving such combinations. (See [Drug Interactions])
Do not use this product in any patient with acute severe illness suggestive of myopathy or susceptible to renal failure secondary to rhabdomyolysis (e.g., sepsis, hypotension, major surgery, trauma, severe metabolic, endocrine, and electrolyte abnormalities, or uncontrolled epilepsy).
Effects on the liver
As with other HMG-CoA reductase inhibitors, this product should be used with caution in individuals who have consumed excessive amounts of alcohol and/or have a history of liver disease. Liver function tests are recommended prior to initiation of therapy and for the 3rd month after initiation. If serum transaminases are elevated more than 3 times the upper limit of normal, this product should be discontinued or the dose reduced.
For hypercholesterolemia secondary to hypothyroidism or nephrotic syndrome, the primary disease should be treated prior to initiating treatment with this product.
Ethnicity
Pharmacokinetic studies have shown higher drug exposure in Asian subjects than in Caucasian subjects. (See [Pharmacokinetics])
Protease Inhibitors
Increased systemic exposure to resulvastatin has been observed in subjects receiving a combination of resulvastatin and a different protease inhibitor (in combination with ritonavir). The lipid-lowering benefit of this product in HIV patients receiving protease inhibitor therapy should be fully considered, as well as the possibility of increased plasma concentrations of resrivastatin when combined with protease inhibitor therapy. Combination with protease inhibitors is not recommended unless the dose of this product is adjusted.
Lactose Intolerance
Patients with rare hereditary galactose intolerance, lactase deficiency, or glucose-galactose malabsorption should not take this product.
Interstitial lung disease
Rare cases of interstitial lung disease have been reported in some statin therapy, especially in those on long-term treatment. Presenting features include dyspnea, dry cough without sputum, and decline in general health (malaise, weight loss, and fever). Patients should discontinue statin therapy when interstitial lung disease is suspected.
Diabetes mellitus
The use of 3-hydroxy-3-methyl glutaryl coenzyme A (HMG-CoA) reductase inhibitors (including this product) has been reported to be associated with elevated glycated haemoglobin A1C (HbA1c) and fasting serum glucose levels. The use of Glycated haemoglobin A1C (HbA1c) and elevated fasting serum glucose levels has been associated. Clinical and biochemical monitoring of patients at risk (fasting glucose: 5.6-6.9 mmol/L, BMI > 30 kg/m2, elevated triglycerides, hypertension) should be performed in accordance with relevant guidelines.
Pediatric patient population
Pediatric patients aged 10-17 years with Tenner’s stage at maturity of the secondary sexual characteristics were limited to one year on Rosuvastatin based on assessment of linear growth (height), weight, and BMI (body mass index). After 52 weeks of study treatment, there was no effect on growth, weight, BMI, or sexual maturation. Experience with clinical trials in pediatric and pediatric patients is limited, and the long-term (>1 year) treatment effects of resulvastatin in adolescent patients are not known.
Pediatric and adolescent patients treated with resulvastatin were found to have creatine kinase elevations greater than 10 x ULN and concomitant muscle symptoms observed after exercise or enhanced physical activity more frequently than observed in clinical trials conducted in adults over a 52-week period (see [Adverse Reactions]).
Effects on Driving Vehicles and Manipulating Machines
Studies to determine the effects of this product on driving vehicles and operating machinery have not been conducted. However, based on the pharmacodynamic properties, it is unlikely that this product will affect these abilities. When driving vehicles and operating machinery, the possibility of dizziness during treatment should be considered.
For Pregnant and Lactating Women
This product is contraindicated for use in pregnant and lactating women.
Women who are at risk of pregnancy should use appropriate contraception.
Because cholesterol and other cholesterol biosynthesis products are important for embryonic development, the risks from HMG-CoA reductase inhibition outweigh the benefits of treatment in pregnant women. Animal studies have provided limited evidence of reproductive toxicity. If a patient becomes pregnant during the use of this product, treatment should be discontinued immediately. Rosuvastatin is secreted into rat milk. There is no information on the secretion of Rosuvastatin into human milk.
Pediatric Use]
Experience with pediatric use is limited to a small number (age ≥ 6 years) of children with pure/heterozygous familial hypercholesterolemia (see [Clinical Trials]). The safety and efficacy of this product in Chinese children has not been established.
[Geriatric Use].
No dose adjustment based on age is required. Of the 10275 patients taking this product in the clinical study, 3159 (31%) were ≥65 years of age and 698 (6.8% ) were ≥75 years of age. There were no differences in overall safety and efficacy between these two populations and younger subjects. Other reports of clinical use experience also showed no differences between the older and younger populations. However, it cannot be excluded that some elderly patients are more sensitive to the drug, and advanced age is a susceptibility factor for myopathy, so caution should be exercised when applied to the elderly population.
Drug Interactions]
Combination of drugs on Rosuvastatin
Inhibitors of transport proteins: Rosuvastatin is a substrate for certain transport proteins, including the hepatic uptake transport protein OATP1B1 and the efflux transport protein BCRP. The combination of this product with pharmaceutical products that inhibit these transport proteins may result in increased plasma concentrations of Rosuvastatin and an increased risk of myopathy (including rhabdomyolysis). Consider alternative medications when possible and, if needed, temporarily discontinue treatment with this product. When the combination of these drugs with this product is unavoidable, the benefits and risks of co-administration and dose adjustment of this product should be carefully considered.
Cyclosporine: When this product is combined with cyclosporine, the AUC of resulvastatin is on average 7 times higher than that observed in healthy volunteers (compared to the same dose of this product). The combination did not affect the plasma concentration of cyclosporine. This product is contraindicated in patients receiving concomitant cyclosporine therapy.
Protease Inhibitors: Although the mechanism of drug interaction is unclear, concomitant administration of protease inhibitors may substantially increase exposure to resulvastatin. In pharmacokinetic studies, concomitant administration of 10 mg of this product with a combination formulation containing two protease inhibitors (300 mg atazanavir/100 mg ritonavir) in healthy volunteers showed an approximately 3-fold and 7-fold increase in AUC and Cmax values for resulvastatin, respectively. Based on the expected increased exposure to risuvastatin, caution should be exercised with the combined use of protease inhibitors after adjusting the dose of this product (see [Precautions]).
Gemfibezil and other lipid-lowering products: Concomitant use of this product with gemfibezil resulted in a 2-fold increase in Cmax and AUC of resulvastatin.
Based on information from dedicated interaction studies, no pharmacokinetic interactions with fenofibrate are expected, but pharmacodynamic interactions may occur.
The combination of gemfibezil, fenofibrate, other fibrates (e.g., benzofibrate), and lipid-lowering doses (≥1 g/day) of niacin with HMG-CoA reductase inhibitors increases the risk of myopathy, possibly due to their ability to cause myopathy when administered alone.
Ezetimibe: The combination of 10 mg of this product and 10 mg of ezetimibe in hypercholesterolemic subjects resulted in a 1.2-fold increase in the AUC of rasulvastatin. Adverse reactions due to pharmacodynamic interactions between this product and ezetimibe cannot be excluded.
Antacids: Simultaneous administration of this product and an antacid suspension containing aluminum magnesium hydroxide reduced the plasma concentration of resulvastatin by approximately 50%. This effect may be reduced if the antacid is given 2 hours after administration of this product. The clinical significance of this drug interaction has not been studied.
Erythromycin: The combination of this product with erythromycin resulted in a 20% decrease in AUC and a 30% decrease in Cmax of resulvastatin. This interaction may be due to increased gastrointestinal motility caused by erythromycin.
Cytochrome P450 enzymes: Data from both in vitro and in vivo studies indicate that resulvastatin is neither an inhibitor nor an enzyme inducer of cytochrome P450 isozymes. Furthermore, resrivastatin is a weak substrate for these enzymes. Therefore, drug interactions due to cytochrome P450-mediated metabolism are not estimated to exist. There are no clinically relevant interactions between resuvastatin and fluconazole (an inhibitor of CYP2C9 and CYP3A4) or ketoconazole (an inhibitor of CYP2A6 and CYP3A4).
Colchicine: Myopathy, including rhabdomyolysis, has been reported with HMG-CoA reductase inhibitors, including Rosuvastatin, in combination with colchicine; therefore, caution should be exercised when combining this product with colchicine.
Interactions Requiring Rosuvastatin Dose Adjustment.
Dose adjustments should be made when combining with drugs known to increase exposure to this product. The starting dose of this product is 5 mg once daily for an expected increase in exposure (AUC) of approximately 2-fold or greater.
The maximum daily dose of this product should be adjusted so that the expected exposure to resulvastatin does not exceed the exposure level at the maximum recommended dose.
Published clinical trials on the effect of combined dosing on exposure to resulvastatin (AUC; in descending order) Interaction drug dosing regimen Resulvastatin dosing regimen Variation in AUC of resulvastatin* Cyclosporine 75 mg BID to 200 mg BID, 6 months 10 mg OD, 10 days 7.1 times Atazanavir 300 mg/ritonavir 100 mg OD, 8 Days 10mg, single dose 3.1x Simeprevir 150mg OD, 7 days 10mg, single dose 2.8x Lopinavir 400mg/ritonavir 100mg BID, 17 days 20mg OD, 7 days 2.1x Clopidogrel 300mg loading, 24 hours post maintenance dose 75mg 20mg, single dose 2x Gemfibezil 600mg BID, 7 days 80mg, single dose 1.9x Eltrombopta 75mg OD, 5 days 10mg, single dose 1.6x Darunavir 600mg/ritonavir 100mg BID, 7 days 10mg OD, 7 days 1.5x Telanavir 500mg/ritonavir 200mg BID, 11 days 10mg, single dose 1.4x Dronedarone 400mg BID not applicable 1.4x Itraconazole 200mg OD, 5 days 10mg, single dose 1.4x** Ezetimibe 10mg OD, 14 days 10mg, OD, 14 days 1.2x** Fosamprenavir 700mg/ritonavir 100mg BID, 8 days 10mg, single dose “Aleglitazar 0.3mg, 7 days 40mg, 7 days” Silymarin 140mg TID, 5 days 10mg, single dose “Fenofibrate 67mg TID, 7 days 10mg, 7 days” Rifampin 450mg OD, 7 days 20mg, single dose “Ketoconazole 200mg BID, 80mg for 7 days, single dose” Fluconazole 200mg OD, 80mg for 11 days, single dose “Erythromycin 500mg QID, 80mg for 7 days, single dose 20% ¯ Baicalin 50mg TID, 20mg for 14 days, single dose Dose 47% ¯*The x-fold change data shown in the text represent simple ratios for combined dosing and rasuvastatin alone, and the % change shown in the text represents the % difference relative to rasuvastatin alone.
Increases, no changes, and decreases are indicated by “”, “”, and ¯, respectively.
**Several interaction studies applying different doses of this product have been conducted and the data shown in this table are the most significant ratios.
OD = once daily; BID = twice daily; TID = three times daily; QID = four times daily
Effects of Rosuvastatin on Combination Dosing
Vitamin K antagonists: As with other HMG-CoA reductase inhibitors, initiation of this product or a gradual increase in the dose of this product may result in an increase in the international normalized ratio (INR) in patients on concomitant vitamin K antagonists (e.g., warfarin or other coumarin-based anticoagulants). Discontinuation of this product or gradual decrease in the dose of this product may result in a decrease in the INR. In such cases, appropriate testing of the INR is warranted.
Oral contraceptive/hormone replacement therapy (HRT): Concomitant use of this product and oral contraceptives increased the AUC of ethinylestradiol and norethindrone by 26% and 34%, respectively. These elevated blood levels should be considered when selecting oral contraceptive doses. No pharmacokinetic data are available for subjects using both this product and HRT; therefore, a similar interaction cannot be excluded. However, this combination has been widely used and well tolerated by patients in clinical trials.
Other drugs.
Digoxin: Based on data from dedicated drug interaction studies, it is estimated that there are no clinically relevant interactions between this product and digoxin.
Fusidic acid: No studies have been conducted on the drug-drug interaction between resulvastatin and fusidic acid. As with other statins, muscle-related events (including rhabdomyolysis) have been reported in post-marketing experience with the combination of resulvastatin and fusidic acid.
Therefore, the combination of resulvastatin with fusidic acid is not recommended. If possible, temporary discontinuation of resulvastatin therapy is recommended. If combination cannot be avoided, the patient should be monitored closely.
Other drugs that may interact with statins include telithromycin, nefazodone, and amiodarone.
Pediatric patient population: Interaction studies have only been performed in adults; information on interactions in the pediatric population is not yet available.
Overdose]
There is no specific treatment for overdose. In the event of an overdose, symptomatic treatment should be given, with supportive measures if needed. Liver function and creatine kinase levels should be monitored. Hemodialysis may not have significant efficacy.
Pharmacology and Toxicology
Pharmacological effects
Rosuvastatin is a selective, competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme in the conversion of 3-hydroxy-3-methylglutaryl coenzyme A to mevalonate, a precursor of cholesterol. The results of animal tests and cell culture tests showed that Rosuvastatin is highly and selectively taken up by the liver, which is the target organ for cholesterol-lowering effects. Results from in vivo and in vitro assays show that Rosuvastatin increases the number of hepatic LDL receptors on the cell surface, thereby enhancing the uptake and catabolism of LDL and inhibiting hepatic VLDL synthesis, thereby reducing the total number of VLDL and LDL particles.
In patients with pure and heterozygous familial hypercholesterolemia, patients with nonfamilial hypercholesterolemia, and patients with mixed dyslipidemia, Rosuvastatin reduces total cholesterol, LDL-C, ApoB, and non-HDL-C levels. Rosuvastatin also lowers TG and raises HDL-C levels. In patients with simple hypertriglyceridemia, resrivastatin lowered total cholesterol, LDL-C, VLDL-C, ApoB, non-HDL-C, and TG levels and increased HDL-C levels. The effect of Rosuvastatin on cardiovascular morbidity and mortality has not been determined.
Toxicological studies
Central Nervous System Toxicity
CNS vascular injury was found in several canine trials of similar drugs, with perivascular hemorrhage, edema, and perivascular mononuclear cell infiltration seen. A drug structurally similar to this class showed dose-dependent optic nerve degeneration (retinal-knee fiber Wallerian degeneration) in dogs at plasma drug concentrations 30 times higher than the mean concentration at the maximum recommended human dose.
One female dog given 90 mg/kg/day of rosuvastatin orally (systemic exposure equivalent to 100 times the human exposure of 40 mg/day, as extrapolated from AUC) was euthanized on day 24 due to near death, as evidenced by choroid plexus interstitial edema, hemorrhage, and partial necrosis. Canines given transoral risuvastatin 6 mg/kg/day (systemic exposure equivalent to 20 times human 40 mg/day exposure as extrapolated from AUC) for 52 weeks were seen to have corneal clouding. In dogs, 30 mg/kg/day (60 times the human exposure of 40 mg/day, as extrapolated from the AUC) of Rosuvastatin was given orally for 12 weeks, and cataracts were seen to develop. Retinal dysplasia and retinal detachment were seen in dogs administered orally with rosuvastatin 90 mg/kg/day (systemic exposure equivalent to 100 times the human 40 mg/day exposure as extrapolated by AUC) for 4 weeks. No effects on the retina were seen in dogs given at doses ≤30 mg/kg/day (systemic exposure equivalent to 60 times the human 40 mg/day exposure as extrapolated by AUC) for 1 year.
Genotoxicity
Rosuvastatin showed negative results in the Ames test, mouse lymphoma test, CHL cell chromosome aberration test, and mouse micronucleus test.
Reproductive toxicity
In the rat fertility test, no adverse effects on fertility were observed in male rats given orally from 9 weeks before to during mating and in female rats given orally from 2 weeks before mating to day 7 of gestation at 5, 15, and 50 mg/kg/day at the highest dose (systemic exposure equivalent to 10 times the human exposure of 40 mg/day, extrapolated by AUC). Spermatidic giant cells were seen in the testes of dogs given orally 30 mg/kg/day for 1 month. In monkeys, oral administration of 30 mg/kg/day for 6 months showed vacuolization of giant spermatocytes and vas deferens epithelium. These doses in dogs and monkeys were 20 and 10 times the human dose of 40 mg/day, respectively, based on body surface area. Similar phenomena were seen with similar drugs.
In female rats, oral administration of 5, 15, and 50 mg/kg/day from pre-mating to 7 days post-mating was associated with reduced fetal weight and delayed ossification in the high dose group (10 times the human exposure of 40 mg/day on an AUC basis).
In rats, oral administration of 2, 10 and 50 mg/kg/day from day 7 of gestation to day 21 of lactation (lactation), and reduced survival of pups was observed in the high dose group (12 times more than human 40 mg/day as projected by body surface area). In rabbits, oral administration of 0.3, 1, and 3 mg/kg/day (equivalent to 40 mg/day in humans based on body surface area) from day 6 of gestation to day 18 of lactation (lactation) was associated with reduced fetal survival and maternal animal mortality. Rosuvastatin doses ≤25 mg/kg/day in rats and ≤3 mg/kg/day in rabbits were not seen to be teratogenic (comparable to human 40 mg/day exposure as extrapolated by AUC and body surface area, respectively).
Carcinogenicity
In a 104-week carcinogenicity test in rats, oral doses of 2, 20, 60, and 80 mg/kg/day were administered orally. 80 mg/kg/day (20 times the human exposure of 40 mg/day, as extrapolated from the AUC) showed a significant increase in the incidence of uterine polyps in females, and no increase in the incidence was observed at the lower doses.
In a 107-week carcinogenicity test in mice, oral doses of 10, 60, and 200 mg/kg/day were administered. An increased incidence of hepatocellular adenoma/carcinoma was seen in the 200 mg/kg/day (20 times the human exposure of 40 mg/day based on AUC) dose group, but no increased incidence was seen at the lower dose.
Pharmacokinetics]
The results of pharmacokinetic studies completed abroad.
Absorption: peak blood concentration was reached after 5 hours of oral administration. Absolute bioavailability is 20%.
Distribution: Rosuvastatin is taken up in large quantities by the liver, which is the major site of cholesterol synthesis and LDL-C clearance. The volume of distribution of resrivastatin is approximately 134 L. The plasma protein binding of resrivastatin (mainly albumin) is approximately 90%.
Metabolism: Rosuvastatin undergoes limited metabolism (approximately 10%). In vitro metabolism studies using human hepatocytes have shown that resrivastatin is a weak substrate for cytochrome P450 metabolism. The major isozymes involved in metabolism are CYP2C9, 2C19, 3A4 and 2D6 involved to a lesser extent. The known metabolites are N-desmethyl and lactone metabolites. the N-desmethyl metabolite is 50% less active than risuvastatin, while the lactone metabolite is considered to be clinically inactive.
More than 90% of the inhibitory activity against circulating HMG-CoA reductase was derived from resulvastatin.
Excretion: Approximately 90% of the dose of Rosuvastatin is excreted in its original form in the feces (both absorbed and unabsorbed active substances), with the remainder being excreted in the urine. Approximately 5% is in its original form in the urine. The plasma clearance half-life is approximately 19 hours. The clearance half-life does not increase with increasing dose. The geometric mean of plasma clearance is approximately 50 L/h (coefficient of variation 21.7%). As with other HMG-CoA reductase inhibitors, hepatic uptake of resrivastatin involves the membrane transporter OATP-C. This transporter is important in the hepatic clearance of resrivastatin.
Linearity: The systemic exposure of resrivastatin increases proportionally with dose. Pharmacokinetic parameters are unchanged after multiple dosing.
Only about 10% of the oral dose of resrivastatin is metabolized, primarily by N site demethylation.
Special Populations.
Age and gender: age or gender do not have a clinically meaningful effect on the pharmacokinetics of resrivastatin.
Renal insufficiency: In a study in patients with varying degrees of renal impairment, mild and moderate renal disease had no effect on the plasma concentrations of resulvastatin or the N-demethyl metabolite. However, compared with healthy volunteers, patients with severe renal impairment (creatinine clearance <30 ml/min) had a 3-fold increase in blood concentrations and a 9-fold increase in blood concentrations of the N-desmethyl metabolite. Steady-state blood concentrations of reseruvastatin were approximately 50% higher in hemodialysis patients than in healthy volunteers.
Hepatic insufficiency: In a study of patients with varying degrees of hepatic impairment, there was no evidence of elevated exposure in subjects with Child-Pugh scores not exceeding 7. However, 2 patients with Child-Pugh scores of 8 and 9 had at least a 2-fold increase in their exposure to Rosuvastatin compared with those with low Child-Pugh score values. There is no experience with subjects with Child-Pugh scores above 9.
Genetic Polymorphisms: The catabolism of HMG-CoA reductase inhibitors (including Rosuvastatin) involves OATP1B1 and BCRP transporter proteins. patients with genetic polymorphisms in SLCO1B1 (OATP1B1) and/or ABCG2 (BCRP) are at risk for increased exposure to Rosuvastatin. Patients with SLCO1B1 c.521TT or ABCG2 c.421CC genotypes are more likely to have elevated exposure (AUC) to Rosuvastatin compared to patients with SLCO1B1 c.521CC and ABCG2 c.421AA genetic polymorphisms. Although this particular genotyping profile has not been established in clinical practice, a lower daily dose of this product is recommended for patients with these known genetic polymorphisms.
Ethnicity: Foreign pharmacokinetic studies have shown that median values of area under the blood concentration-time curve (AUC) and peak concentration (Cmax) in Asian (including Chinese) subjects are approximately twice as high as in Western Caucasian subjects. Population pharmacokinetic analysis showed no clinically relevant differences in pharmacokinetics between Caucasian and black groups.
Results of a pharmacokinetic study in healthy Chinese volunteers conducted in China.
Pharmacokinetic parameters were determined in Chinese human healthy volunteers after single and multiple doses of 5, 10 and 20 mg of Rosuvastatin calcium tablets. The median tmax values after single dosing ranged from 2.5-5 hours, followed by an exponential decrease. The half-life (t1/2) was around 11 to 12 hours. Steady-state blood concentrations were reached on day 3 of multiple dosing. Drug accumulation after multiple dosing was minimal and dose-independent.
The pharmacokinetic properties of resulvastatin calcium in healthy Chinese volunteers were determined in conjunction with previous pharmacokinetic studies completed in Singapore and the United States. In all three studies, the pharmacokinetic parameters of Rosuvastatin Calcium were similar.
Storage】Store under light and seal.
Package】Aluminum-plastic blister package (polyvinyl chloride solid pharmaceutical hard tablets, pharmaceutical aluminum foil).
(1) 5mg: 7 capsules/box, 10 capsules/box, 14 capsules/box, 20 capsules/box, 21 capsules/box, 28 capsules/box.
(2) 10mg: 7 capsules/box, 10 capsules/box, 14 capsules/box, 20 capsules/box.
Expiration date】24 months
【Execution standard
Approval No.】5mg National Drug Certificate H20140135
10mg National Drug Certificate H20140136
Manufacturer
Company Name: Hainan General Sanyo Pharmaceutical Co.
Address: No. 8, Haili Road, Xiuying District, Haikou City
Postal Code: 570312
Telephone number: 0898-68710202
Fax number: 0898-68713640