rosuvastatin

Rosuvastatin tablets are an HMG Co-A reductase inhibitor indicated for: adult patients with primary hyperlipidemia and mixed dyslipidemia as an adjunct to diet to reduce elevated total-C, LDL-C, ApoB, nonHDL-C, and TG levels and to increase HDLC pediatric patients 8 to 17 years of age with heterozygous familial hypercholesterotemia (HeFH] to reduce elevated total-C, LDL-C and ApoB after failing an adequate trial of diet therapy adult patients with hypertriglyceridemia as an adjunct to diet adult patients with primary dysbetalipoproteinemia [Type III hyperlipoproteinemia) as an adjunct to diet adult patients with homozygous familial hypercholesterolemia (HoFH) to reduce LOL-G, total-G, and ApoB slowing the progression of atherosclerosis as part of a treatment strategy lo lower total-C and LDL-C as an adjunct to diet risk reduction of MI, stroke, and arterial revascularization procedures in patients without clinically evident CHD, but with multiple risk factors Limitations of use : Rosuvastatin tablets have not been studied in Fredrickson Type I and V dyslipidemias. Pediatric use information for patients 7 to 17 years of age is approved for AstraZeneca's CRESTOR (rosuvastatin calcium) tablets. However, due to AstraZeneca's marketing exclusivity rights, this drug product is not labeled with that pediatric information. 1.3 Hypertriglyceridemia Rosuvastatin tablets are indicated as adjunctive therapy to diet for the treatment of adult patients with hypertriglyceridemia. 1.4 Primary Dysbetalipoproteinemia (Type III Hyperlipoproteinemia) Rosuvastatin tablets are indicated as an adjunct to diet for the treatment of adult patients with primary dysbetalipoproteinemia (Type III Hyperlipoproteinemia). 1.5 Adult Patients with Homozygous Familial Hypercholesterolemia Rosuvastatin tablets are 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. 1.8 Limitations of Use Rosuvastatin tablets have not been studied in Fredrickson Type I and V dyslipidemias.

Rosuvasta1in tablets can be taken with or without food, at any time of day. Dose range: 5 to 40 mg once daily. Use 40 mg dose only for patients not reaching LDL-C goal with 20 mg. Adult HoFH: Starting dose 20 mg/day. Pediatric patients with HeFH: 5 to 10 mg/day for patients 8 to less than 10 years of age, and 5 to 20 mg/day for patients 10 to 17 years of age. 2.1 General Dosing Information The dose range for rosuvastatin tablets in adults is 5 to 40 mg orally once daily. The usual starting dose is 10 to 20 mg once daily. The usual starting dose in adult patients with homozygous familial hypercholesterolemia is 20 mg once daily. The maximum rosuvastatin dose of 40 mg should be used only for those patients who have not achieved their LDL-C goal utilizing the 20 mg dose [see Warnings and Precautions ]. Rosuvastatin tablets can be administered as a single dose at any time of day, with or without food. The tablet should be swallowed whole. When initiating rosuvastatin tablets therapy or switching from another HMG-CoA reductase inhibitor therapy, the appropriate rosuvastatin tablets starting dose should first be utilized, and only then titrated according to the patient's response and individualized goal of therapy. After initiation or upon titration of rosuvastatin tablets, lipid levels should be analyzed within 2 to 4 weeks and the dosage adjusted accordingly. 2.2 Pediatric Dosing In heterozygous familial hypercholesterolemia, !he recommended dose range is 5 to 10 mg orally once daily in patients 8 to less than 10 years of age, and 510 20 mg orally once daily in patients 10 to 17 years of age. Pediatric use information for patients 7 to 17 years of age is approved for AstraZeneca's CRESTOR (rosuvastatin calcium) tablets. However, due to AstraZeneca's marketing exclusivity rights, this drug product is not labeled with that pediatric information. 2.3 Dosing in Asian Patients In Asian patients, consider initiation of rosuvastatin tablets therapy with 5 mg once daily due to increased rosuvastatin plasma concentrations. The increased systemic exposure should be taken into consideration when treating Asian patients not adequately controlled at doses up to 20 mg/day. [see Use in Specific Populations and Clinical Pharmacology ]. 2.4 Use with Concomitant Therapy Patients taking cyclosporine and darolutamide The dose of rosuvastatin tablets should not exceed 5 mg once daily [see Warnings and Precautions , Drug Interactions , Drug Interactions , and Clinical Pharmacology ]. Patients taking gemfibrozil Avoid concomitant use of rosuvastatin tablets with gemfibrozil. If concomitant use cannot be avoided, initiate rosuvastatin tablets at 5 mg once daily. The dose of rosuvastatin tablets should not exceed 10 mg once daily [see Warnings and Precautions and, Drug Interactions and Clinical Pharmacology ]. Patients taking regorafenib Concomitant use of rosuvastatin tablets and regorafenib, the dose of rosuvastatin tablets should not exceed 10 mg once daily [see Warnings and Precautions , Drug Interactions and Clinical Pharmacology ]. Patients taking atazanavir and ritonavir, lopinavir and ritonavir, simeprevir or combination of dasabuvir/ ombitasvir/paritaprevir/ritonavir, elbasvir/grazoprevir, sofosbuvir/velpatasvir and glecaprevir/pibrentasvir Initiate rosuvastatin tablets therapy with 5 mg once daily. The dose of rosuvastatin tablets should not exceed 10 mg once daily [see Warnings and Precautions , Drug Interactions and Clinical Pharmacology ]. 2.5 Dosing in Patients with Severe Renal Impairment For patients with severe renal impairment (CL <30 mL/min/1.73 m 2 ) not on hemodialysis, dosing of rosuvastatin tablets should be started at 5 mg once daily and not exceed 10 mg cr once daily [see Use in Specific Populations and Clinical Pharmacology ].

12.1 Mechanism of Action Rosuvastatin is a selective and competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts 3-hydroxy-3-methylglutaryl coenzyme A to mevalonate, a precursor 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 LDL receptors on the cell-surface to enhance uptake and catabolism of LDL. Second, rosuvastatin inhibits hepatic synthesis of VLDL, which reduces the total number of VLDL and LDL particles.

Most frequent adverse reactions (rate ≥2%) are headache, myalgia, abdominal pain, asthenia, and nausea. To report SUSPECTED ADVERSE REACTIONS, contact Btu Pharmaceuticals, at 1-888-374-2791 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. The following serious adverse reactions are discussed in greater detail in other sections of the label: Rhabdomyolysis with myoglobinuria and acute renal failure and myopathy (including myositis) [see Warnings and Precautions ] Liver enzyme abnormalities (see Warnings and Precautions ] 6.1 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. In the rosuvastatin controlled clinical trials database (placebo or active-controlled) of 5394 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: myalgia abdominal pain nausea The most commonly reported adverse reactions (incidence >2%) in the rosuvastatin controlled clinical trial database of 5394 patients were: Headache myalgia abdominal pain Asthenia nausea 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 a treatment duration of up to 12 weeks. Table 1. Adverse Reactions Reported in ≥2% of Patients Treated with Rosuvastatin and > Placebo in Placebo-Controlled Trials (% of Patients) 1 Adverse reactions by COSTART 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 [see Warnings and Precautions ]; elevated creatine phosphokinase, transaminases, glucose, glutamyl transpeptidase, alkaline phosphatase, and bilirubin; and thyroid function abnormalities. In a 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 [see Clinical Studies ]. Adverse reactions reported in >2% of patients and at a rate greater than placebo are shown in Table 2. Table 2. Adverse Reactions Reported in >2% of Patients Treated With Rosuvastatin and > Placebo in a Trial (% of Patients) 1 Adverse reactions by MedDRA preferred term. 2 Frequency recorded as abnormal laboratory value. In a JUPITER study, 17,802 participants were treated with rosuvastatin 20 mg (n=8901) or placebo (n=8901) 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 [see Warnings and Precautions and Clinical Studies ]. Adverse reactions reported in >2% of patients and at a rate greater than placebo are shown in Table 3. Table 3. Adverse Reactions Reported in >2% of Patients Treated with Rosuvastatin and > Placebo in a Trial (% of Patients) 1 Treatment-emergent adverse reactions by MedDRA preferred term. Pediatric Patients with Heterozygous Familial Hypercholesterolemia In a 12-week controlled study in boys and postmenarcheal girts 10 to 17 years of age with heterozygous familial hypercholesterolemia with rosuvastatin 5 to 20 mg dally {see Use in Specific Populations and Clinical Studies ], elevations in serum creatine phosphokinase (CK) >10 x 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 x ULN, compared to D of 46 children on placebo. table1.jpg table2.jpg table3.jpg 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of rosuvastatin: arthralgia, fatal and non-fatal hepatic failure, hepatitis, jaundice, thrombocytopenia, depression, sleep disorders (including insomnia and nightmares), peripheral neuropathy, interstitial lung disease 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 [see Warnings and Precautions ]. There have been rare postmarketing reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, and confusion) associated with statin use. These cognitive issues have been reported for all statins. The reports are generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks).

Combina1ion of sofosbuvir/velpatasvir/voxilaprevir or ledipasvir/sofosbuvir : Combination increases rosuvastatin exposure. Use with rosuvastatin is not recommended. Cyclosporine and darolutamide : Combination increases rosuvastatin exposure. Limit rosuvastatin dose to 5 mg once daily. Gemfibrozil : Combination should be avoided. If used together, limit rosuvastatin dose to 10 mg once daily. Atazanavir/ritonavir, lopinavir/ritonavir, simeprevir or combination of dasabuvir/ombitasvir/paritaprevir/ritonavir, elbasvir/grazoprevir, sofosbuvir/velpatasvir and glecaprevir/pibrentasvir : Combination increases rosuvastatin exposure. Limit rosuvastatin dose to 10 mg once daily. Regorafenib : Combination increases rosuvastatin exposure. Limit rosuvastatin dose to 10 mg once daily. Coumarin anticoagulants : Combination prolongs INR Achieve stable INR prior to starting rosuvastatin. Moni1or INR frequently until stable upon initiation or alteration of rosuvastatin therapy. Concomitant lipid-lowering therapies : Use with fibrates or lipid modifying doses (≥1 g/day) of niacin increases the risk of adverse skeletal muscle effects. Caution should be used when prescribing with rosuvastatin. 7.1 Cyclosporine Cyclosporine increased rosuvastatin exposure and may result in increased risk of myopathy. Therefore, in patients taking cyclosporine, the dose of rosuvastatin should not exceed 5 mg once daily [see Dosage and Administration , Warnings and Precautions , and Clinical Pharmacology ].

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 [see Clinical Pharmacology ]. 7.3 Anti-viral Medications Coadministration of rosuvastatin with certain anti-viral drugs has differing effects on rosuvastatin exposure and may increase risk of myopathy. The combination of sofosbuvir/velpatasvir/voxilaprevir which are anti-Hepatitis C virus (anti-HCV) drugs, increases rosuvastatin exposure. Similarly, the combination of ledipasvir/sofosbuvir may significantly increase rosuvastatin exposure. For these combinations of anti-HCV drugs, concomitant use with rosuvastatin is not recommended. Simeprevir and combinations of dasabuvir/ombitasvir/paritaprevir/ritonavir, elbasvir/grazoprevir, sofosbuvir/velpatasvir and glecaprevir/pibrentasvir which are anti-HCV drugs, increase rosuvastatin exposure. Combinations of atazanavir/ritonavir and lopinavir/ritonavir, which are anti-HIV-1 drugs, increase rosuvastatin exposure [see Table 4 – Clinical Pharmacology ]. For these anti-viral drugs, the dose of rosuvastatin should not exceed 10 mg once daily. The combinations of fosamprenavir/ritonavir or tipranavir/ritonavir, which are anti-HIV-1 drugs, produce little or no change in rosuvastatin exposure. No dose adjustment is needed for concomitant use with these combinations [see Dosage and Administration , Warnings and Precautions and Clinical Pharmacology ].

Darolutamide Darolutamide increased rosuvastatin exposure more than 5 fold.

Therefore, in patients taking darolutamide, the dose of rosuvastatin should not exceed 5 mg once daily [see Dosage and Administration , Warnings and Precautions and Clinical Pharmacology ]. 7.5 Regorafenib Regorafenib increased rosuvastatin exposure and may increase the risk of myopathy. If used together, the dose of rosuvastatin should not exceed 10 mg once daily [see Dosage and Administration , Warnings and Precautions and Clinical Pharmacology ]. 7.6 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 [see Warnings and Precautions and Clinical Pharmacology ]. 7.7 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 [see Warnings and Precautions ]. 7.8 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 HMG-CoA reductase inhibitors is increased with concomitant use of fenofibrates, caution should be used when prescribing fenofibrates with rosuvastatin [see Warnings and Precautions and Clinical Pharmacology ]. 7.9 Colchicine Cases of myopathy, including rhabdomyolysis, have been reported with HMG-CoA reductase inhibitors, including rosuvastatin, coadministered with colchicine, and caution should be exercised when prescribing rosuvastatin with colchicine [see Warnings and Precautions ].

Females of reproductive potential : Advise females of reproductive to use effective contraception during treatment with rosuvastatin. Severe renal impairment (not on hemodialysis) : Starting dose is 5 mg, not to exceed 10 mg. Asian population : Consider 5 mg starting dose. 8.1 Pregnancy Risk Summary Rosuvastatin is contraindicated for use in pregnant women since safety in pregnant women has not been established and there is no apparent benefit to therapy with rosuvastatin during pregnancy. Because HMG-CoA reductase inhibitors decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, rosuvastatin may cause fetal harm when administered to pregnant women. Rosuvastatin should be discontinued as soon as pregnancy is recognized [see Contraindications ]. Limited published data on the use of rosuvastatin are insufficient to determine a drug-associated risk of major congenital malformations or miscarriage. In animal reproduction studies, there were no adverse developmental effects with oral administration of rosuvastatin during organogenesis at systemic exposures equivalent to a maximum recommended human dose (MRHD) of 40 mg/day in rats or rabbits (based on AUC and body surface area, respectively). In rats and rabbits, decreased pup/fetal survival occurred at 12 times and equivalent, respectively, to the MRHD of 40 mg/day [see Data]. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Human Data Limited published data on rosuvastatin have not shown an increased risk of major congenital malformations or miscarriage. Rare reports of congenital anomalies have been received following intrauterine exposure to other statins. In a review of approximately 100 prospectively followed pregnancies in women exposed to simvastatin or lovastatin, the incidences of congenital anomalies, spontaneous abortions, and fetal deaths/stillbirths did not exceed what would be expected in the general population. The number of cases is adequate to exclude a ≥3 to 4-fold increase in congenital anomalies over the background incidence. In 89% of the prospectively followed pregnancies, drug treatment was initiated prior to pregnancy and was discontinued at some point in the first trimester when pregnancy was identified. Animal Data Rosuvastatin crosses the placenta in rats and rabbits and is found in fetal tissue and amniotic fluid at 3% and 20%, respectively, of the maternal plasma concentration following a single 25 mg/kg oral gavage dose on gestation day 16 in rats. A higher fetal tissue distribution (25% maternal plasma concentration) was observed in rabbits after a single oral gavage dose of 1 mg/kg on gestation day 18. Rosuvastatin administration did not indicate a teratogenic effect in rats at 30 mL/min/1.73 m 2 ). Exposure to rosuvastatin is increased to a clinically significant extent in 2 patients with severe renal impairment (CLcr <30 mL/min/1.73 m 2 ) who are not receiving hemodialysis and dose adjustment is required. [see Dosage and Administration , Warnings and Precautions and Clinical Pharmacology ]. 8.7 Hepatic Impairment Rosuvastatin is contraindicated in patients with active liver disease, which may include unexplained persistent elevations of hepatic transaminase levels. Chronic alcohol liver disease is known to increase rosuvastatin exposure; rosuvastatin should be used with caution in these patients [see Contraindications , Warning and Precautions , and Clinical Pharmacology ]. 8.8 Asian Patients Pharmacokinetic studies have demonstrated an approximate 2-fold increase in median exposure to rosuvastatin in Asian subjects when compared with Caucasian controls. Rosuvastatin dosage should be adjusted in Asian patients [see Dosage and Administration and Clinical Pharmacology ].